Smooth Muscle (smooth + muscle)

Distribution by Scientific Domains
Distribution within Medical Sciences

Kinds of Smooth Muscle

  • airway smooth muscle
  • arterial smooth muscle
  • bladder smooth muscle
  • bronchial smooth muscle
  • cavernosal smooth muscle
  • cavernosum smooth muscle
  • circular smooth muscle
  • corpus cavernosum smooth muscle
  • detrusor smooth muscle
  • guinea-pig tracheal smooth muscle
  • intestinal smooth muscle
  • longitudinal smooth muscle
  • tracheal smooth muscle
  • vascular smooth muscle

  • Terms modified by Smooth Muscle

  • smooth muscle actin
  • smooth muscle actin expression
  • smooth muscle bundle
  • smooth muscle cell
  • smooth muscle cell function
  • smooth muscle cell proliferation
  • smooth muscle content
  • smooth muscle contractility
  • smooth muscle contraction
  • smooth muscle fibre
  • smooth muscle layer
  • smooth muscle marker
  • smooth muscle relaxation
  • smooth muscle strip
  • smooth muscle tissue
  • smooth muscle tone
  • smooth muscle tumor

  • Selected Abstracts


    Catalina Romero-Mndez
    SUMMARY 1In the present study, we investigated the series of events involved in the contraction of tracheal smooth muscle induced by the re-addition of Ca2+ in an in vitro experimental model in which Ca2+ stores had been depleted and their refilling had been blocked by thapsigargin. 2Mean (SEM) contraction was diminished by: (i) inhibitors of store-operated calcium channels (SOCC), namely 100 mol/L SKF-96365 and 100 mol/L 1-(2-trifluoromethylphenyl) imidazole (to 66.3 4.4 and 41.3 5.2% of control, respectively); (ii) inhibitors of voltage-gated Ca2+ channels CaV1.2 channels, namely 1 mol/L nifedipine and 10 mol/L verapamil (to 86.2 3.4 and 76.9 5.9% of control, respectively); and (iii) 20 mol/L niflumic acid, a non-selective inhibitor of Ca2+ -dependent Cl, channels (to 41.1 9.8% of control). In contrast, contraction was increased 2.3-fold by 100 nmol/L iberiotoxin, a blocker of the large-conductance Ca2+ -activated K+ (BK) channels. 3Furthermore, contraction was significantly inhibited when Na+ in the bathing solution was replaced by N -methyl,d -glucamine (NMDG+) to 39.9 7.2% of control, but not when it was replaced by Li+ (114.5 24.4% of control). In addition, when Na+ had been replaced by NMDG+, contractions were further inhibited by both nifedipine and niflumic acid (to 3.0 1.8 and 24.4 8.1% of control, respectively). Nifedipine also reduced contractions when Na+ had been replaced by Li+ (to 10.7 3.4% to control), the niflumic acid had no effect (116.0 4.5% of control). 4In conclusion, the data of the present study demonstrate the roles of SOCC, BK channels and CaV1.2 channels in the contractions induced by the re-addition of Ca2+ to the solution bathing guinea-pig tracheal rings under conditions of Ca2+ -depleted sacroplasmic reticulum and inhibition of sarcoplasmic/endoplasmic reticulum calcium ATPase. The contractions were highly dependent on extracellular Na+, suggesting a role for SOCC in mediating the Na+ influx. [source]


    Shigeru Hishinuma
    SUMMARY 1In guinea-pig taenia caeci smooth muscle we have found that 10,4 mol/L carbachol-induced desensitization to muscarinic agonists develops within 15,30 s, followed by transient resensitization at 1 min, whereas the desensitization to depolarizing high K+ develops with maximal desensitization at 1 min followed by sustained resensitization up to 30 min. In both cases, Ca2+ -dependent processes play a crucial role in determining the development of desensitization. 2To elucidate whether these peculiar processes of desensitization/resensitization may be induced by a lower concentration of carbachol, we examined the development of desensitization induced by 10,6 mol/L carbachol, because at this concentration carbachol is known to induce biphasic changes in intracellular Ca2+ concentrations, with a smaller transient increase followed by a larger sustained increase than seen with 10,4 mol/L carbachol. 3Contractile responses to muscarinic agonists (carbachol or AHR-602) and high K+ were desensitized by pretreatment with 10,6 mol/L carbachol for 30 min in a manner dependent on the presence of extracellular Ca2+. 4The development of 10,6 mol/L carbachol-induced desensitization to these muscarinic agonists in the presence of extracellular Ca2+ showed three successive phases: fast desensitization within 30 s, followed by transient resensitization at 1 min and the subsequent development of desensitization up to 30 min. In contrast, desensitization to high K+ did not develop up to 10 min and significant desensitization occurred at 30 min, with no apparent resensitization phase. 5These results suggest that the characteristics of the Ca2+ -dependent development of desensitization to muscarinic agonists, but not to high K+, are well maintained in desensitization induced by a lower concentration of carbachol. [source]


    Darren J Fernandes
    SUMMARY 1.,Airway smooth muscle (ASM) has recently been termed the ,frustrated' cell of the lung given that contraction of ASM has no proven useful physiological function in adults and yet is indelibly associated with pathological conditions by virtue of its unwanted airflow-limiting actions in asthma. In contrast, pulmonary vascular smooth muscle contraction plays an essential role in the control of blood flow through the lung. 2.,Little is known of the differences in phenotype between human ASM and pulmonary vascular smooth muscle (VSM) tissues, but differences in contractile protein and transcription factor expression and regulation of contractile protein promoter activity have been documented. Similarly, the embryological signals in mice required for differentiation of ASM versus pulmonary VSM are distinct. 3.,Bronchoconstriction in asthma is currently treated with ,2 -adrenoceptor agonists, which relax contracted ASM cells. An additional approach may be to use gene therapy to render ASM unable to contract (via disruption of their contractile apparatus organization). 4.,Application of ASM-specific gene therapies would rely on minimal actions on other lung smooth muscle tissues, including pulmonary and bronchial vascular smooth muscle. The combination of mRNA analysis of laser-captured microdissected tissue with in situ immunohistochemical staining for protein should be very useful in terms of being able to characterize definitively the differences in mRNA and protein expression between the smooth muscle species of the lung. Any discovery of an ASM-selective target could provide a novel lead for ASM-directed anti-asthma therapy. [source]

    A Theoretical Model for the Myogenic Response Based on the Length,Tension Characteristics of Vascular Smooth Muscle

    MICROCIRCULATION, Issue 4 2005
    ABSTRACT Objective: A theoretical model is developed to describe the myogenic response of resistance vessels to changes in intravascular pressure, based on a consideration of the active and passive length,tension characteristics of vascular smooth muscle (VSM). The dependence of model parameters on vessel diameter is examined. Methods: The vessel wall is represented mechanically as a nonlinear passive component in parallel with an active contractile component. The level of VSM tone is assumed to have a sigmoidal dependence on circumferential wall tension or stress. Model parameters are optimized for each of 18 independent experimental data sets previously obtained using pressure or wire myograph systems. Results: Close fits between model predictions and experimental data are found in each case. An alternative formulation in which VSM tone depends on circumferential wall stress is found also to be consistent with available data. Significant trends in model parameters as a function of diameter are found. Conclusions: The results support the hypothesis that circumferential tension or stress in the wall provides the signal for myogenic responses. The model provides a basis for simulating steady-state myogenic responses in vascular networks containing a range of vessel diameters. [source]

    In Vitro and In Vivo Relaxation of Corpus Cavernosum Smooth Muscle by the Selective Myosin II Inhibitor, Blebbistatin

    Xin-hua Zhang MD
    ABSTRACT Introduction., Blebbistatin (BLEB) is a small cell permeable molecule originally reported as a selective inhibitor of myosin II isoforms expressed by striated muscle and non-muscle cells (IC50 = 0.5,5 M) with poor inhibition of turkey gizzard smooth muscle (SM) myosin II (IC50,80 M). However, recently it was found that BLEB can potently inhibit mammalian arterial SM (IC50,5 M). Aim., To investigate the effect of BLEB on corpus cavernosum SM (CCSM) tone and erectile function (EF). Methods., CC tissue obtained from penile implant patients along with CC, aorta and bladder from adult male rats were used for BLEB organ bath studies. Intracavernosal BLEB was administered to rats and EF was assessed via intracavernous pressure (ICP). Main Outcome Measures., Effects of BLEB on agonist-induced CCSM, aorta and bladder contraction in vitro and ICP in vivo. Results., BLEB completely relaxed human CCSM pre-contracted with phenylephrine (PE) in a dose-dependent manner decreasing tension by 76.5% at 10 M. BLEB pre-incubation attenuated PE-induced contraction of human CC by ,85%. Human CC strips pre-contracted with endothelin-1 or KCl were almost completely relaxed by BLEB. Rat CCSM pre-contracted with PE showed BLEB relaxation comparable to human CCSM. BLEB inhibition was similar for rat aorta but slower for bladder. Both maximal ICP and ICP/mean arterial pressure were dose-dependently increased by BLEB intracavernous injections with full erection at 1 micromole. Conclusion., Our novel data reveals that BLEB nearly completely relaxes rat and human CCSM pre-contracted with a variety of potent agonists and exhibits tissue selectivity. Coupled with our in vivo data in which nanomole doses of BLEB significantly increase ICP, our data substantiates an important role for the SM contractile apparatus in the molecular mechanism for EF and suggests the possibility of BLEB binding at myosin II as a therapeutic treatment for ED by targeting SM contractile pathways. Zhang X, Aydin M, Kuppam D, Melman A, and DiSanto ME. In vitro and in vivo relaxation of corpus cavernosum smooth muscle by the selective myosin II inhibitor, blebbistatin. J Sex Med 2009;6:2661,2671. [source]

    Insulin-Like Growth Factor-1 Restores Erectile Function in Aged Rats: Modulation the Integrity of Smooth Muscle and Nitric Oxide-Cyclic Guanosine Monophosphate Signaling Activity

    Xiao-Yong Pu MD
    ABSTRACT Introduction., Insulin-like growth factor-1 (IGF-1) is one of the growth factors that have a wide range of biologic effects. We have confirmed that gene transfer of IGF-1 to the penis could improve erectile capacity. However, there are some limitations in gene therapies, such as toxicity or a risk of insertional mutagenesis. Protein treatment may be another choice for decreasing these risks. Aim., To investigate whether intracavernosal injection of IGF-1 protein can restore erectile function in the aging rat. Main Outcome Measures., Erectile responses, morphological changes, and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling pathways-related marker were determined. Methods., Ten young (4 months) and 30 old (24 months) Sprague-Dawley male rats were enrolled in this study. The old rats were divided into three groups: vehicle-only (N = 10), IGF-1 1 g/kg (N = 10) and IGF-1 10 g/kg treatment group (N = 10). After 4 and 8 weeks of single IGF-1 injection treatment, intracavernous pressure (ICP) responses with electrical stimulation to the cavernous nerve were evaluated. The percent of smooth muscle in corpus cavernosum tissue, the expression of mRNA and protein of endothelial nitric oxide synthase (eNOS) were also evaluated. The activity of nitric oxide synthase (NOS) and concentration of guanosine 3,,5,-cyclic-monophosphate (cGMP) that act upon the major NO-cGMP signaling pathways in penile tissue were also analyzed. Results., After IGF-1 treatment, the ICP responses was significantly increased as the young control group in both the IGF-1 1 g/kg and the IGF-1 10 g/kg group compared with the vehicle-only group at 4 and 8 weeks (P < 0.05). Masson's trichrom staining showed the percentage of cavernosal smooth muscle was increased in IGF-1 treatment group. IGF-1 increased e-NOS expression. NOS activities and cGMP concentrations were also significantly increased in IGF-1 treatment rats. Conclusions., IGF-1 improved erectile function in aged rats via restoration the integrity of smooth muscle of corpus cavernosum and modulation of NO-cGMP pathways. Pu, X-Y, Wang X-H, Gao W-C, Yang Z-H, and Li S-L. Insulin-like growth factor-1 restores erectile function in aged rats: Modulation the integrity of smooth muscle and nitric oxide-cyclic guanosine monophosphate signaling activity. J Sex Med 2008;5:1345,1354. [source]

    Contractile Changes of the Clitoral Cavernous Smooth Muscle in Female Rabbits with Experimentally Induced Overactive Bladder

    Soon-Chul Myung MD
    ABSTRACT Introduction., Recently, growing clinical evidence has suggested that sexual dysfunction is more prevalent in women with overactive bladder (OAB). Aims., However, there has been no basic research to clarify the relationship between OAB and female sexual dysfunction. Therefore, we investigated this issue using a rabbit model of OAB. Methods., Twenty-seven New Zealand white female rabbits were randomly divided into the OAB and control groups. Main Outcome Measures., The contractile responses of clitoral cavernous strips to K+, phenylephrine (PE), Bay K 8644, and endothelin (ET)-1, and the relaxation responses of acetylcholine (ACh), sodium nitroprusside (SNP), and Y-27632 to PE-induced contraction by measuring isometric tension. Results., The contractile responses to K+, PE, Bay K 8644, and ET-1 were significantly more increased in the OAB group in a dose-dependant manner than in the control group (P < 0.05), and the responses to ET-1 were more prominent than those to the remaining substances (P < 0.01). The increased contractile responses to ET-1 were blocked by BQ123 (ETA receptor antagonist) but not by BQ788 (ETB receptor antagonist). Clitoral cavernosal strips from the OAB group were more difficult to relax than those from the control group in terms of ACh- and SNP-induced relaxation (P < 0.05). The Y-27632-induced relaxant responses to PE- and ET-1-induced contraction were less prominent in the OAB group than in the control group. Conclusions., The results of this study provide evidence that female OAB may deteriorate clitoral engorgement, which is associated with a greater force generation by increased calcium sensitization and subsequently decreased of relaxation. The activation of ET and Rho-kinase system may be crucial to negatively effect the clitoral smooth muscle relaxation in experimentally induced OAB animal model. But whether these vasomotor effects are revived in human clitoris is still debatable. Myung S-C, Lee M-Y, Lee S-Y, Yum S-H, Park S-H, and Kim S-C. Contractile changes of the clitoral cavernous smooth muscle in female rabbits with experimentally induced overactive bladder. J Sex Med 2008;5:1088,1096. [source]

    Emodin Inhibits Voltage-Dependent Potassium Current in Guinea Pig Gallbladder Smooth Muscle

    Zhi-Xuan Wu
    We studied the effects of emodin on the contraction of gallbladder smooth muscle and voltage-dependent K+ current in gallbladder smooth muscle cells. Gallbladder muscle strips were obtained from adult guinea pigs and the resting tension was recorded. Gallbladder smooth muscle cells were isolated by enzymatic digestion, and K+ current was recorded by the whole-cell patch clamp method. Emodin increased the resting tension of gallbladder smooth muscle strips and inhibited voltage-dependent K+ current in a dose-dependent manner. When 10 M emodin was applied to gallbladder smooth muscle cells for 3,6 min., the amplitude of voltage-dependent K+ current was decreased by 31.5 0.5% at +40 mV, and this inhibitory effect mostly recovered after washout. The steady-state inactivation curves were shifted in a hyperpolarizing direction by emodin. In the presence of the protein kinase C inhibitors staurosporine and chelerythrine, the effect of emodin on voltage-dependent K+ current was significantly attenuated. In conclusion, emodin promotes gallbladder contraction, mainly by inhibiting voltage-dependent K+ current via the protein kinase C pathway. These findings provide theoretical foundation for the application of emodin in gallbladder motility disorders. [source]

    Functional Roles Of KATP Channels In Vascular Smooth Muscle

    Joseph E Brayden
    SUMMARY 1. ATP-sensitive potassium channels (KATP) are present in vascular smooth muscle cells and play important roles in the vascular responses to a variety of pharmacological and endogenous vasodilators. 2. The KATP channels are composed of four inwardly rectifying K+ channel subunits and four regulatory sulphonylurea receptors. The KATP channels are inhibited by intracellular ATP and by sulphonylurea agents. 3. Pharmacological vasodilators such as cromakalim, pinacidil and diazoxide directly activate KATP channels. The associated membrane hyperpolarization closes voltage-dependent Ca2+ channels, which leads to a reduction in intracellular Ca2+ and vasodilation. 4. Endogenous vasodilators such as calcitonin gene-related peptide, vasoactive intestinal polypeptide, prostacylin and adenosine activate KATP by stimulating the formation of cAMP and increasing the activity of protein kinase A. Part of the mechanism of contraction of endogenous vasoconstrictors is due to inhibition of KATP channels. 5. The KATP channels appear to be tonically active in some vascular beds and contribute to the physiological regulation of vascular tone and blood flow. These channels also are activated under pathophysiological conditions, such as hypoxia, ischaemia, acidosis and septic shock, and, in these disease states, may play an important role in the regulation of tissue perfusion. [source]

    Agonist-evoked Ca2+ wave progression requires Ca2+ and IP3

    John G. McCarron
    Smooth muscle responds to IP3 -generating agonists by producing Ca2+ waves. Here, the mechanism of wave progression has been investigated in voltage-clamped single smooth muscle cells using localized photolysis of caged IP3 and the caged Ca2+ buffer diazo-2. Waves, evoked by the IP3 -generating agonist carbachol (CCh), initiated as a uniform rise in cytoplasmic Ca2+ concentration ([Ca2+]c) over a single though substantial length (,30,m) of the cell. During regenerative propagation, the wave-front was about 1/3 the length (,9,m) of the initiation site. The wave-front progressed at a relatively constant velocity although amplitude varied through the cell; differences in sensitivity to IP3 may explain the amplitude changes. Ca2+ was required for IP3 -mediated wave progression to occur. Increasing the Ca2+ buffer capacity in a small (2,m) region immediately in front of a CCh-evoked Ca2+ wave halted progression at the site. However, the wave front does not progress by Ca2+ -dependent positive feedback alone. In support, colliding [Ca2+]c increases from locally released IP3 did not annihilate but approximately doubled in amplitude. This result suggests that local IP3 -evoked [Ca2+]c increases diffused passively. Failure of local increases in IP3 to evoke waves appears to arise from the restricted nature of the IP3 increase. When IP3 was elevated throughout the cell, a localized increase in Ca2+ now propagated as a wave. Together, these results suggest that waves initiate over a surprisingly large length of the cell and that both IP3 and Ca2+ are required for active propagation of the wave front to occur. J. Cell. Physiol. 224: 334,344, 2010. 2010 Wiley-Liss, Inc. [source]

    Regulation of urogenital smooth muscle patterning by testosterone and estrogen during prostatic induction

    THE PROSTATE, Issue 7 2006
    Holly Chrisman
    Abstract Background Smooth muscle (SM) has been proposed to play an important role in controlling prostate organogenesis by regulating signaling between inductive mesenchyme and developing epithelial prostatic buds. Methods We have examined the effects of testosterone and estrogen upon SM patterning in the embryonic rat urogenital tract (UGT) using in vitro organ cultures, immunohistochemistry, and Western blotting. Results We observed that testosterone elicited a sexually dimorphic difference in SM structure of embryonic UGTs, in cultures grown with testosterone. The addition of estrogen led to an increase in the rate of SM closure, in both males and females. To quantify the effects of steroids upon SM we used Western blotting of SM actin, which showed that estrogen stimulated SM content, while testosterone reduced SM content. Finally, we examined the expression of ER,, ER,, PR, and SM actin under different hormonal treatments of UGTs grown in vitro. The expression patterns of ER, and ER, were largely unchanged by hormonal treatment, while PR showed a much broader expression pattern in response to estradiol. Conclusions Our results indicate that testosterone can directly regulate SM patterning and content in the UGT, and that SM is sensitive to both androgens and estrogens. 2006 Wiley-Liss, Inc. [source]

    78 Use of a rabbit model to investigate the feasibility of using an innervated neosphincter transplant for the treatment of stress urinary incontinence.

    Aim:, To examine the feasibility of using an innervated smooth muscle wrap as a neosphincter in a rabbit model of urinary incontinence. Methods:, Rabbits were rendered incontinent surgically by lesion of the proximal urethral wall to the level of the submucosa (n = 20). In twelve animals a strip of dartos smooth muscle was wrapped around the lesioned urethra to create a new urethral sphincter and stimulating electrodes were inserted into the muscle. After a recovery period of at least one-week cystometrograms were established for control (urethra intact), lesioned and lesion plus neosphincter animals. Results:, Infusion of saline into the bladder of control animals caused a slow rise in bladder pressure until, at approximately 20,30 ml, there was an increase in pressure that rose steeply and was associated with bladder emptying. The threshold for this reflex emptying was 2,3 cm H2O, and the maximum pressure during the reflex was 6,15 cm H2O. After the bladder emptied, the pressure dropped to 0,2 cm H2O. In rabbits with lesioned sphincters, it was not possible to obtain a normal cystometrogram because there was leakage of fluid from the urethral opening before a volume and pressure sufficient to elicit a reflex was achieved. The loss of the majority of fluid often occurred without a significant pressure increase, that is, there was no true emptying reflex. Similar results were observed in animals in which the urethra had been lesioned and implanted with the smooth muscle neosphincter. Prior to electrical stimulation of the neosphincter, with constant current pulses at 2 Hz, substantial leak occurred at 11.4 2.5 ml, whereas during stimulation voiding occurred at 17.8 1.4 ml. At void or emptying, the peak pressure was 6.1 0.1 cm H20 in control, 0.7 0.2 in operated but not stimulated and 3.5 0.6 in the same animals during stimulation. A satisfactory improvement of continence was observed for a period of up to 6 months postsurgery. At the end of the study, histological examination confirmed the neosphincter to be both healthy and viable. Conclusion:, Smooth muscles of the dartos display contractile properties which make them suitable for use as transplantable sphincters. A smooth muscle neosphincter, controlled by electrical stimulation, can restore continence after urethral damage. [source]

    Effects of long-term vardenafil treatment on the development of fibrotic plaques in a rat model of Peyronie's disease

    BJU INTERNATIONAL, Issue 3 2006
    OBJECTIVES To determine whether the phosphodiesterase-5 (PDE5) inhibitor, vardenafil, given orally and in different regimens, has a similar effect to that of the PDE5 inhibitor sildenafil, which prevented the development of a Peyronie's disease (PD)-like plaque formation induced by injecting transforming growth factor ,1 (TGF-,1) into the tunica albuginea of the rat. MATERIALS AND METHODS Vardenafil was given to male rats (eight per group) either in the drinking water or as an oral instillation once daily, at ,,1 and ,,3 mg/kg/day for 45 days after one injection with TGF-,1 into the tunica albuginea, as an ,early preventive' treatment for TGF-,1-induced formation of a PD-like plaque. Other groups received the two doses of vardenafil only in the drinking water, starting with a well-formed plaque, for 42 days (,late, therapeutic' administration). Sections of penile tissue were stained histochemically or immunohistochemically, followed by quantitative image analysis for collagen/smooth muscle and collagen III/I ratios, myofibroblast content (,-smooth muscle actin), TGF-,1 expression, and apoptotic index. RESULTS Preventative treatment with vardenafil at the higher dose (both continuous and once-daily treatments) reduced the collagen/smooth muscle and collagen III/I ratios, and the numbers of myofibroblasts and TGF-,1-positive cells, and selectively increased the apoptotic index in the PD-like plaque. The lower dose was less effective, When vardenafil was given continuously in the drinking water for 41 days after the PD-like plaque was formed, there was only a partial reduction of the plaque. CONCLUSIONS Long-term oral treatment with vardenafil slows and reverses the early stages of an experimental PD-like plaque in the rat, and might ameliorate a more advanced plaque. [source]

    Uridine adenosine tetraphosphate affects contractility of mouse aorta and decreases blood pressure in conscious rats and mice

    ACTA PHYSIOLOGICA, Issue 2 2010
    P. B. Hansen
    Abstract Aim:, In the anaesthetized rat, uridine adenosine tetraphosphate (Up4A) is a circulating, endothelium-derived vasoconstrictor presumably operating as such in un-anaesthetized animals. The present study investigated the in vivo effects of Up4A in conscious mice and rats, and its direct vascular effects in the mouse aorta in vitro. Methods:,In vivo, Up4A was given as step-up infusion at rates of 8,512 nmol min,1 kg,1 for 30 min periods in chronically catheterized rodents. In vitro, the effect of Up4A on rings of mouse aortae mounted in a myograph was tested. Results:, High doses of Up4A (mice: 512 nmol min,1 kg,1; rats: 128 nmol min,1 kg,1) caused hypotension (99 4 to 64 7 mmHg and 114 3 to 108 3 mmHg, respectively, both P < 0.01). In rats, Up4A significantly decreased sodium excretion by >75% and potassium excretion by ,60% without significant changes in urine flow. Exposure of phenylephrine-contracted rings to increasing concentrations of Up4A elicited contraction at 10,7 and 10,6 mol L,1 (18 2% and 76 16% respectively); unexpectedly, 10,5 mol L,1 caused a biphasic response with a contraction (19 6%) followed by a relaxation (,46 6%). No relaxation was observed when the concentration was increased further. Bolus exposure to 10,5 mol L,1 of Up4A caused contraction (+80 2%). Added successively to untreated vessels, increasing concentrations of Up4A (10,7,10,5 mol L,1) induced a biphasic response of contraction followed by relaxation. Conclusion:, Up4A has direct biphasic effects on vascular smooth muscle of the mouse aorta but vasoconstriction dominates at low concentrations. In conscious rodents, step-up infusions of Up4A elicit hypotension and electrolyte retention. [source]

    Potential Role of Type 5 Phosphodiesterase Inhibition in the Treatment of Congestive Heart Failure

    Stuart D. Katz MD
    Endothelial dysfunction is associated with impairment of aerobic capacity in patients with heart failure and may play a role in the progression of disease. Impaired endothelium-dependent vasodilation in patients with heart failure can be attributed to decreased bioavailability of nitric oxide and attenuated responses to nitric oxide in vascular smooth muscle. Impaired vasodilation in response to nitric oxide derived from vascular endothelium or organic nitrates in vascular smooth muscle may be related in part to increased degradation of the second messenger cyclic guanosine monophosphate by type 5 phosphodiesterase. Sildenafil, a specific type 5 phosphodiesterase inhibitor currently approved for the treatment of erectile dysfunction, has been shown to acutely enhance endothelium-dependent vasodilation in patients with heart failure. Further studies are warranted to characterize the safety and efficacy of type 5 phosphodiesterase inhibition in the treatment of chronic heart failure. [source]

    Estimation of endogenous adenosine activity at adenosine receptors in guinea-pig ileum using a new pharmacological method

    ACTA PHYSIOLOGICA, Issue 2 2010
    K. F. Nilsson
    Abstract Aim:, Adenosine modulates neurotransmission and in the intestine adenosine is continuously released both from nerves and from smooth muscle. The main effect is modulation of contractile activity by inhibition of neurotransmitter release and by direct smooth muscle relaxation. Estimation of adenosine concentration at the receptors is difficult due to metabolic inactivation. We hypothesized that endogenous adenosine concentrations can be calculated by using adenosine receptor antagonist and agonist and dose ratio (DR) equations. Methods:, Plexus-containing guinea-pig ileum longitudinal smooth muscle preparations were made to contract intermittently by electrical field stimulation in organ baths. Schild plot regressions were constructed with 2-chloroadenosine (agonist) and 8-(p -sulfophenyl)theophylline (8-PST; antagonist). In separate experiments the reversing or enhancing effect of 8-PST and the inhibiting effect of 2-chloroadenosine (CADO) were analysed in the absence or presence of an adenosine uptake inhibitor (dilazep), and nucleoside overflow was measured by HPLC. Results:, Using the obtained DR, baseline adenosine concentration was calculated to 28 nm expressed as CADO activity, which increased dose dependently after addition of 10,6 m dilazep to 150 nm (P < 0.05). HPLC measurements yielded a lower fractional increment (80%) in adenosine during dilazep, than found in the pharmacological determination (440%). Conclusion:, Endogenous adenosine is an important modulator of intestinal neuro-effector activity, operating in the linear part of the dose,response curve. Other adenosine-like agonists might contribute to neuromodulation and the derived formulas can be used to calculate endogenous agonist activity, which is markedly affected by nucleoside uptake inhibition. The method described should be suitable for other endogenous signalling molecules in many biological systems. [source]

    Angiotensin II enhances the afferent arteriolar response to adenosine through increases in cytosolic calcium

    ACTA PHYSIOLOGICA, Issue 4 2009
    E. Y. Lai
    Abstract Aims:, Angiotensin II (Ang II) is a strong renal vasoconstrictor and modulates the tubuloglomerular feedback (TGF). We hypothesized that Ang II at low concentrations enhances the vasoconstrictor effect of adenosine (Ado), the mediator of TGF. Methods:, Afferent arterioles of mice were isolated and perfused, and both isotonic contractions and cytosolic calcium transients were measured. Results:, Bolus application of Ang II (10,12 and 10,10 m) induced negligible vasoconstrictions, while Ang II at 10,8 m reduced diameters by 35%. Ang II at 10,12, 10,10 and 10,8 m clearly enhanced the arteriolar response to cumulative applications of Ado (10,11 to 10,4 m). Ado application increased the cytosolic calcium concentrations in the vascular smooth muscle, which were higher at 10,5 m than at 10,8 m. Ang II (10,11 to 10,6 m) also induced concentration-dependent calcium transients, which were attenuated by AT1 receptor inhibition. Simultaneously applied Ang II (10,10 m) additively enhanced the calcium transients induced by 10,8 and 10,5 m Ado. The transients were partly inhibited by AT1 or A1 receptor antagonists, but not significantly by A2 receptor antagonists. Conclusion:, A low dose of Ang II enhances Ado-induced constrictions, partly via AT1 receptor-mediated calcium increase. Ado increases intracellular calcium by acting on A1 but not A2 receptors. The potentiating effect of Ang II on Ado-induced arteriolar vasoconstrictions may involve calcium sensitization of the contractile machinery, as Ang II only additively increased cytosolic calcium concentrations, while its effect on the arteriolar constriction was more than additive. The potentiating effect of Ang II might contribute to the resetting of TGF. [source]

    Incidence and cytological features of pulmonary hamartomas indeterminate on CT scan

    CYTOPATHOLOGY, Issue 3 2008
    A. Saqi
    Objective:, Pulmonary hamartomas have a characteristic heterogeneous radiological appearance. However, when composed predominantly of undifferentiated mesenchymal fibromyxoid component, their homogeneous appearance on computed tomography is indeterminate for malignancy. Rendering an accurate preoperative diagnosis in these cases can alter management. The aim of this study was to determine the incidence and accuracy of cytodiagnosis for hamartomas ,indeterminate' by imaging. Methods:, We retrospectively reviewed records for hamartomas diagnosed by transthoracic fine needle aspiration (FNA) including immediate impressions and final diagnoses. Cytological features evaluated included the presence of fibromyxoid stroma, bronchioloalveolar cell hyperplasia, fibroadipose tissue, cartilage and smooth muscle. Results:, Eighteen (1.3%) hamartomas were identified from 1355 transthoracic FNAs. The immediate impression was hamartoma in 13 (72%), carcinoid in one (6%), mucinous bronchioloalveolar carcinoma in two (11%) and non-diagnostic in two (11%). The final diagnosis of hamartoma in cases diagnosed as carcinoid, mucinous bronchioloalaveolar carcinoma and non-diagnostic on immediate impression was rendered following assessment of all cytological material. Conclusion:, Overall, FNAs are highly reliable for diagnosing hamartomas even when composed principally of undifferentiated mesenchymal fibromyxoid stroma, especially with the aid of all available preparations including Diff-Quik smears, Papanicolaou smears, ThinPreps and cell block material. [source]

    Platelet-derived growth factor receptors expressed in response to injury of differentiated vascular smooth muscle in vitro: effects on Ca2+ and growth signals

    ACTA PHYSIOLOGICA, Issue 2 2001
    A. Lindqvist
    Vascular smooth muscle cells (VSMCs) in the intact vascular wall are differentiated for contraction, whereas the response to vascular injury involves transition towards a synthetic phenotype, with increased tendency for proliferation. Platelet-derived growth factor (PDGF) is thought to be important for this process. We investigated expression and functional coupling of PDGF receptors (PDGFRs) , and , in rat tail arterial rings kept in organ culture, in order to capture early events in the phenotypic transition. In freshly dissected rings no PDGFR immunoreactivity was found in medial VSMCs, whereas PDGFR , was detected in nerve fibres. After organ culture for 1,4 days PDGFR , and , as well as phospholipase C,2 (PLC,2), known to couple to PDGFR, were expressed in VSMCs within 100 ,m of the cut ends. Calponin, a marker for the contractile phenotype, was decreased near the injured area, suggesting that cells were in transition towards synthetic phenotype. In these cells, which showed functional Ca2+ -release from the sarcoplasmic reticulum, PDGF-AB (100 ng mL,1) had no effect on [Ca2+]i, whereas cultured VSMCs obtained from explants of rat tail arterial rings responded to PDGF-AB with an increase in [Ca2+]i. However, PDGFR within the cultured rings coupled to growth signalling pathways, as PDGF-AB caused a tyrphostin AG1295-sensitive activation of extracellular signal-regulated kinases 1 and 2 and of [3H]-thymidine incorporation. Thus, early expression of PDGFR in VSMC adjacent to sites of vascular injury coincides with signs of dedifferentiation. These receptors couple to growth signalling, but do not activate intracellular Ca2+ release. [source]

    Chicken gizzard filamin, retina filamin and cgABP260 are respectively, smooth muscle-, non-muscle- and pan-muscle-type isoforms: Distribution and localization in muscles

    CYTOSKELETON, Issue 4 2005
    Kazuyo Ohashi
    Abstract We determined the full cDNA sequences of chicken gizzard filamin and cgABP260 (chicken gizzard actin-binding protein 260). The primary and secondary structures predicted by these sequences were similar to those of chicken retina filamin and human filamins. Like mammals, chickens have 3 filamin isoforms. Comparison of their amino acid sequences indicated that gizzard filamin, retina filamin, and cgABP260 were the counterparts of human FLNa (filamin a), b, and c, respectively. Antibodies against the actin-binding domain (ABD) of these 3 filamin isoforms were raised in rabbits. Using immunoabsorption and affinity chromatography, we prepared the monospecific antibody against the ABD of each filamin. In immunoblotting, the antibody against the gizzard filamin ABD detected a single band in gizzard, but not in striated muscles or brain. In brain, only the antibody against the retina filamin ABD produced a strong single band. The antibody against the cgABP260 ABD detected a single peptide band in smooth, skeletal, and cardiac muscle. In immunofluorescence microscopy of muscular tissues using these antibodies, the antibody against the gizzard filamin ABD only stained smooth muscle cells, and the antibody against the retina filamin ABD strongly stained endothelial cells of blood vessels and weakly stained cells in connective tissue. The antibody against the cgABP260 ABD stained the Z-lines and myotendinous junctions of breast muscle, the Z-lines and intercalated disks of cardiac muscle, and dense plaques of smooth muscle. These findings indicate that chicken gizzard filamin, retina filamin, and cgABP260 are, respectively, smooth muscle-type, non-muscle-type, and pan-muscle-type filamin isoforms. Cell Motil. Cytoskeleton 61:214,225, 2005. 2005 Wiley-Liss, Inc. [source]

    Induction of initial heart ,-actin, smooth muscle ,-actin, in chick pregastrula epiblast: The role of hypoblast and fibroblast growth factor-8

    Hiroko Matsui
    During heart development at the gastrula stage, inhibition of bone morphogenetic protein (BMP) activity affects the heart specification but does not impair the expression of smooth muscle , -actin (SMA), which is first expressed in the heart mesoderm and recruited into initial heart myofibrils. Interaction of tissues between posterior epiblast and hypoblast at the early blastula stage is necessary to induce the expression of SMA, in which Nodal and Chordin are thought to be involved. Here we investigated the role of fibroblast growth factor-8 (FGF8) in the expression of SMA. In situ hybridization and reverse transcription,polymerase chain reaction showed that Fgf8b is expressed predominantly in the nascent hypoblast. Anti-FGF8b antibody inhibited the expression of SMA, cTNT, and Tbx5, which are BMP-independent heart mesoderm/early cardiomyocyte genes, but not Brachyury in cultured posterior blastoderm, and combined FGF8b and Nodal, but neither factor alone induced the expression of SMA in association with heart specific markers in cultured epiblast. Although FGF8b did not induce the upregulation of phospho-Smad2, anti-FGF8b properties suppressed phospho-Smad2 in cultured blastoderm. FGF8b was able to reverse the BMP-induced inhibition of cardiomyogenesis. The results suggest that FGF8b acts on the epiblast synergistically with Nodal at the pregastrula stage and may play a role in the expression of SMA during early cardiogenesis. [source]

    In vivo and in vitro analysis of the vasculogenic potential of avian proepicardial and epicardial cells,

    Juan A. Guadix
    Abstract Coronary vessel formation is a special case in the context of embryonic vascular development. A major part of the coronary cellular precursors (endothelial, smooth muscle, and fibroblastic cells) derive from the proepicardium and the epicardium in what can be regarded as a late event of angioblastic and smooth muscle cell differentiation. Thus, coronary morphogenesis is dependent on the epithelial,mesenchymal transformation of the proepicardium and the epicardium. In this study, we present several novel observations about the process of coronary vasculogenesis in avian embryos, namely: (1) The proepicardium displays a high vasculogenic potential, both in vivo (as shown by heterotopic transplants) and in vitro, which is modulated by vascular endothelial growth factor (VEGF) and basic fibroblast growth factor signals; (2) Proepicardial and epicardial cells co-express receptors for platelet-derived growth factor-BB and VEGF; (3) Coronary angioblasts (found all through the epicardial, subepicardial, and compact myocardial layers) express the Wilms' tumor associated transcription factor and the retinoic acid-synthesizing enzyme retinaldehyde-dehydrogenase-2, two markers of the coelomic epithelium involved in coronary endothelium development. All these results contribute to the development of our knowledge on the vascular potential of proepicardial/epicardial cells, the existent interrelationships between the differentiating coronary cell lineages, and the molecular mechanisms involved in the regulation of coronary morphogenesis. Developmental Dynamics 235:1014,1026, 2006. 2006 Wiley-Liss, Inc. [source]

    Potential roles for BMP and Pax genes in the development of iris smooth muscle

    Abbie M. Jensen
    Abstract The embryonic optic cup generates four types of tissue: neural retina, pigmented epithelium, ciliary epithelium, and iris smooth muscle. Remarkably little attention has focused on the development of the iris smooth muscle since Lewis ([1903] J. Am. Anat. 2:405,416) described its origins from the anterior rim of the optic cup neuroepithelium. As an initial step toward understanding iris smooth muscle development, I first determined the spatial and temporal pattern of the development of the iris smooth muscle in the chick by using the HNK1 antibody, which labels developing iris smooth muscle. HNK1 labeling shows that iris smooth muscle development is correlated in time and space with the development of the ciliary epithelial folds. Second, because neural crest is the only other neural tissue that has been shown to generate smooth muscle (Le Lievre and Le Douarin [1975] J. Embryo. Exp. Morphol. 34:125,154), I sought to determine whether iris smooth muscle development shares similarities with neural crest development. Two members of the BMP superfamily, BMP4 and BMP7, which may regulate neural crest development, are highly expressed by cells at the site of iris smooth muscle generation. Third, because humans and mice that are heterozygous for Pax6 mutations have no irides (Hill et al. [1991] Nature 354:522,525; Hanson et al. [1994] Nat. Genet. 6:168,173), I determined the expression of Pax6. I also examined the expression of Pax3 in the developing anterior optic cup. The developing iris smooth muscle coexpresses Pax6 and Pax3. I suggest that some of the eye defects caused by mutations in Pax6, BMP4, and BMP7 may be due to abnormal iris smooth muscle. Developmental Dynamics 232:385,392, 2005. 2004 Wiley-Liss, Inc. [source]

    The pharmacology of cilostazol

    Karsten Schrr
    Cilostazol (6-[4-(1-cyclohexyl- 1H -tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone; OPC-13013) is a 2-oxo-quinoline derivative with antithrombotic, vasodilator, antimitogenic and cardiotonic properties. The compound is a potent inhibitor of phosphodiesterase (PDE) 3A, the isoform of PDE 3 in the cardiovascular system (IC50: 0.2 m). In addition, there is inhibition of adenosine uptake, eventually resulting in changes in cAMP levels, dependent on the type of adenosine receptors (A1 or A2). Cilostazol inhibits platelet aggregation and has considerable antithrombotic effects in vivo. The compound relaxes vascular smooth muscle and inhibits mitogenesis and migration of vascular smooth muscle cells. In the heart, cilostazol causes positive inotropic and chronotropic effects. Most, if not all, of these actions are cAMP-mediated, including the modification of cAMP-controlled gene expression. Cilostazol decreases levels of serum triglycerides and causes some increase in HDL-cholesterol levels. The compound has a number of additional effects which might contribute to its overall clinical efficacy. Cilostazol undergoes intensive and finally complete hepatic metabolism via the cytochrome P450 systems. This might result in some drug interaction, i.e. with erythromycin and omeprazole. The half-life is approximately 10 h, resulting in about 2-fold accumulation of the drug during repeated administration. [source]

    A tethered ascorbate-norepinephrine compound, 4-UT, displays long-acting adrenergic activity on rabbit aortic smooth muscle

    Robert Root-Bernstein
    Abstract We previously demonstrated that adrenergic and histaminergic receptors have an ascorbic acid (vitamin C) binding site on the first extracellular loop, immediately adjacent to the aminergic binding site. Binding of ascorbate to this site strongly potentiates any sub-maximal dose of an adrenergic or histaminergic compound, significantly increasing its duration of activity. We report here the successful synthesis of a tethered compound that mimics the combined effects of a mixture of ascorbate with norepinephrine. The tethered compound uses a four-unit polyethylene linker to tether ascorbate to norepinephrine. The tethered compound is about tenfold less effective than norepinephrine in stimulating rabbit aortic smooth muscle, but has a very significantly enhanced duration of activity compared with norepinephrine alone and comparable to a mixture of norepinephrine and ascorbate. Additional ascorbate does not enhance the tethered compound's effects and we demonstrate that the compound binds to a synthetic peptide spanning the ascorbate binding site of the receptor. These experiments strongly suggest that the compound binds to both the adrenergic binding site and the ascorbate binding site simultaneously. Tethered compounds with linkers of other lengths did not have these properties. We believe that the synthesis of enhanced adrenergic and histaminergic drugs by tethering them to potentiators such as ascorbate will permit a new class of potential drugs to be created with high specificity and long duration of activity. Drug Dev Res 69:242,250, 2008. 2008 Wiley-Liss, Inc. [source]

    Xanthine-analog, KMUP-2, enhances cyclic GMP and K+ channel activities in rabbit aorta and corpus cavernosum with associated penile erection

    Rong-Jyh Lin
    Abstract The pharmacological properties of KMUP-2 were examined in isolated rabbit aorta and corpus cavernosum smooth muscle (CCSM). KMUP-2 caused relaxations that were attenuated by removed endothelium, high K+, and pretreatment with the soluble guanylate cyclase (sGC) inhibitors methylene blue (10 ,M) and ODQ (1 ,M), a NOS inhibitor, L-NAME (100 ,M), a K+ channel blocker TEA (10 mM), a KATP channel blocker glibenclamide (1 ,M), a voltage-dependent K+ channel blocker 4-AP (100 ,M), and the Ca2+ -dependent K+ channel blockers apamin (1 ,M) and charybdotoxin (ChTX, 0.1 ,M). The relaxant responses of KMUP-2 (0.01, 0.05, 0.1 ,M) together with a PDE inhibitor, IBMX (0.5 ,M), had additive effects on rabbit aorta and CCSM. Additionally, KMUP-2 (100 ,M) also affected cGMP metabolism, due to its inhibiting activity on PDE in human platelets. KMUP-2 (0.1,100 ,M) further induced an increase of intracellular cGMP levels in the primary cultured rabbit aortic and CCSM cells. These increases in cGMP content were abolished in the presence of methylene blue (100 ,M) and ODQ (10 ,M). Obviously, the relaxant effects of KMUP-2 on rabbit isolated tissues are more sensitive in CCSM than in aorta. Moreover, KMUP-2 also stimulated NO/sGC/cGMP pathway and subsequent elevation of cGMP by blockade of PDE and enhanced opening of K+ channels in rabbit aorta and CCSM. KMUP-2 (0.2, 0.4, 0.6 mg/kg), similar to KMUP-1 and sildenafil, caused increases of intracavernous pressure (ICP) and duration of tumescene (DT) in a dose-dependent manner. It is concluded that both the increases of cGMP and the opening activity of K+ channels play prominent roles in KMUP-2-induced aortic smooth muscle and CCSM relaxation and increases of ICP in rabbits. Drug Dev. Res. 55:162,172, 2002. 2002 Wiley-Liss, Inc. [source]

    Synthesis and calcium channel modulating effects of modified Hantzsch nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(pyridinyl or 2-trifluoromethylphenyl)-5-pyridinecarboxylates

    Ramin Miri
    Abstract A group of racemic nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(pyridinyl or 2-trifluoromethylphenyl)-5-pyridinecarboxylates 8a,o were synthesized using modified Hantzsch reactions. In vitro calcium channel antagonist activities, determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay, showed that compounds 8a,o exhibited weaker calcium antagonist activity (10,5 to 10,7 M range) than the reference drug nifedipine (IC50 = 1.43 10,8 M). Compounds 8 possessing a C-4 R1 = 2-pyridyl substituent were always more potent than the approximately equiactive analogs having an R1 = 3-pyridyl, 4-pyridyl or 2-CF3 -C6H4 -substituent, within each subgroup of nitrooxyalkyl compounds [R2 = , (CH2)nONO2 (n = 2, 3, 4) or ,CH(CH2ONO2)2]. Although the length of the R2 = ,(CH2)nONO2 substituent (n = 2,4) was not a determinant of smooth muscle calcium antagonist activity when the C-4 R1 -substituent was 2-pyridyl, when R1 was a 3-pyridyl, 4-pyridyl, or 2-CF3 -C6H4 -substituent, the relative potency order with respect to the R2 = ,(CH2)nONO2 substituent was n = 3 and 4 > n = 2. Replacement of the isopropyl substituent of the ester moiety of the calcium antagonist ()-2-pyridyl 3a by a ,(CH2)nONO2 (n = 2,4) moiety increased calcium antagonist activity on GPILSM by 8-fold. In contrast, replacement of the isopropyl substituent of the ester moiety of the calcium agonists ()-3-pyridyl 3b, ()-4-pyridyl 3c or the methyl substituent of the ester moiety of Bay K8644 by a R2 nitrooxyalkyl substituent resulted in abolition of their calcium agonist effects on GPILSM that is replaced by a smooth muscle calcium antagonist effect. These calcium antagonist data support the concept that incorporation of a nitrooxyalkyl ester substituent constitutes a valuable drug design strategy to enhance Hantzsch 1,4-dihydropyridine calcium antagonist and/or abolish calcium agonist effects on smooth muscle. Replacement of the isopropyl (8b,c), or the methyl (8d) group by a ,CH2CH2ONO2 moiety resulted in retention of the cardiac positive inotropic effect where the relative potency order with respect to the C-4 substituent was 2-CF3 -C6H6 - (8d) > 3-pyridyl (8b) , 4-pyridyl (8c). Model hybrid (calcium channel modulation, NO release) compounds, that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4-dihydropyridine CC modulator that offers a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure,function relationship of calcium channels. Drug Dev. Res. 51:225,232, 2000. 2001 Wiley-Liss, Inc. [source]

    Hantzsch 1,4-dihydropyridines containing a nitrooxyalkyl ester moiety to study calcium channel antagonist structure,activity relationships and nitric oxide release

    Jeffrey-Tri Nguyen
    Abstract A group of 3-nitrooxyalkyl 5-alkyl 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates were prepared using a modified Hantzsch reaction that involved the condensation of a nitrooxyalkyl acetoacetate with an alkyl 3-aminocrotonate and a pyridinecarboxaldehyde. 1H NMR nuclear Overhauser enhancement (nOe) studies for 3-(3-nitrooxypropyl) 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(2-pyridyl)-3,5-pyridinedicarboxylate (17) indicates a predominant rotamer exists in solution where the pyridyl nitrogen atom is orientated above the 1,4-DHP ring system, and the pyridyl nitrogen atom is antiperiplanar to the 1,4-DHP ring H-4 proton. Variable temperature 1H NMR studies (,30 to +60C) showed the 1,4-DHP NH proton in 17 is H-bonded in CHCl3 solution. This interaction is believed to be due to intermolecular H-bonding between the pyridyl nitrogen free electron pair and the 1,4-DHP NH proton. In vitro calcium channel antagonist (CCA) activities were determined using a muscarinic-receptor-mediated Ca+2 -dependent contraction of guinea pig ileal longitudinal smooth muscle assay. This class of compounds exhibited lower CCA activity (IC50 = 5.3 10,6 to 3.5 10,8 M range) than the reference drug nifedipine (IC50 = 1.4 10,8 M). For compounds having C-3 ,CH2CH2ONO2 and C-4 pyridyl substituents, the C-5 alkyl was a determinant of CCA (i -Pr > the approximately equipotent i -Bu, t -Bu, and Et analogs). The point of attachment of the isomeric C-4 pyridyl substituent was a determinant of CCA when C-3 ,CH2CH2ONO2 and C-5 i -Pr substituents were present providing the potency profile 2-pyridyl , 3-pyridyl > 4-pyridyl. CCA with respect to the C-3 nitrooxyalkyl substituent was inversely dependent on the length of the alkyl spacer. The percent nitric oxide (NO) released in vitro by this group of compounds (range of 0.03,0.43%/ONO2 group), quantified as nitrite by reaction with the Griess reagent, was lower than that for the reference drug glycerol trinitrate (3.81%/ONO2 group). Nitric oxide release studies showed that the %NO released was dependent on the number of ONO2 groups/molecule. A QSAR study for this group of compounds showed a correlation between the specific polarizability descriptor (SpPol) and %NO release. Drug Dev. Res. 51:233,243, 2000. 2001 Wiley-Liss, Inc. [source]

    In vitro effects of lidocaine on the contractility of equine jejunal smooth muscle challenged by ischaemia-reperfusion injury

    Summary Reasons for performing study: Post operative ileus (POI) in horses is a severe complication after colic surgery. A commonly used prokinetic drug is lidocaine, which has been shown to have stimulatory effects on intestinal motility. The cellular mechanisms through which lidocaine affects smooth muscle activity are not yet known. Objectives: To examine the effects of lidocaine on smooth muscle in vitro and identify mechanisms by which it may affect the contractility of intestinal smooth muscle. Hypothesis: Ischaemia and reperfusion associated with intestinal strangulation can cause smooth muscle injury. Consequently, muscle cell functionality and contractile performance is decreased. Lidocaine can improve basic cell functions and thereby muscle cell contractility especially in ischaemia-reperfusion-challenged smooth muscle. Methods: To examine the effects of lidocaine on smooth muscle function directly, isometric force performance was measured in vitro in noninjured and in vivo ischaemia-reperfusion injured smooth muscle tissues. Dose-dependent response of lidocaine was measured in both samples. To assess membrane permeability as a marker of basic cell function, release of creatine kinase (CK) was measured by in vitro incubations. Results: Lidocaine-stimulated contractility of ischaemia-reperfusion injured smooth muscle was more pronounced than that of noninjured smooth muscle. A 3-phasic dose-dependency was observed with an initial recovery of contractility especially in ischaemia-reperfusion injured smooth muscle followed by a plateau phase where contractility was maintained over a broad concentration range. CK release was decreased by lidocaine. Conclusion: Lidocaine may improve smooth muscle contractility and basic cell function by cellular repair mechanisms which are still unknown. Improving contractility of smooth muscle after ischaemia-reperfusion injury is essential in recovery of propulsive intestinal motility. Potential relevance: Characterisation of the cellular mechanisms of effects of lidocaine, especially on ischaemia-reperfusion injured smooth muscle, may lead to improved treatment strategies for horses with POI. [source]

    Spasmogenic action of endothelin-1 on isolated equine pulmonary artery and bronchus

    A. E. M. BENAMOU
    Summary Reasons for performing study: There is currently little published information about the effects of endothelin-1 (ET-1), a potent endogenous spasmogen of vascular and airway smooth muscle, on pulmonary vasculature and airways or which ET receptor subtypes mediate ET-1-induced vasoconstrictive and bronchoconstrictive action in the horse. Objectives: To investigate the effect of endothelin-1 (ET-1) on smooth muscle from isolated equine pulmonary artery and bronchus. In addition, the roles of ETA and ETB receptors in ET-1 mediated contraction in these tissues were assessed. Methods: The force generation of ring segments from pulmonary arteries or third-generation airways (obtained from horses subjected to euthanasia fororthopaedic reasons) were studied in an organ bath at 37C in response to exogenous endothelin and selective endothelin A (BQ123) or B receptor (BQ788) antagonists. Results: ET-1 produced concentration-dependent contractions of the equine pulmonary artery and bronchus. The threshold for contraction was 10,10 and 10,9 mol/l ET-1 for pulmonary artery and bronchus, respectively. The maximal contraction induced by the highest ET-1 concentration (10,7 mol/l) was 173 and 194% of the contraction obtained with 100 mmol/l KCl in pulmonary artery and bronchus, respectively. ET-1 potency was 25 times greater in equine pulmonary artery than in equine bronchus (concentration of ET-1 producing 50% of maximal contraction [EC50] = 5.6 10,9 mol/l and 2.2 10,8 mol/l, respectively). In pulmonary artery, ET-1 induced contractions were significantly inhibited by the ETA receptor antagonist BQ123 (1 ,mol/l; dose-response curve to ET-1 was shifted to the right by 5.4-fold), but not by the ETB antagonist BQ788. In bronchus, dose-responses curves to ET-1 were shifted to the right by BQ123 (1 ,mol/l; 2.5-fold), but not by BQ788 (1 ,mol/l). In the presence of both antagonists, the dose-response curve to ET-1 was shifted to the right by 4.5-fold. Conclusions: These functional studies demonstrate that ET-1 is a potent spasmogen of equine third generation pulmonary artery and bronchus, and that contractions are mediated via ETA receptors in the former and both ETA and ETB receptors in the latter. Potential clinical relevance: Endothelin receptor antagonists may have potential for treating equine pulmonary hypertension or bronchoconstriction. [source]