Vascular Smooth Muscle (vascular + smooth_muscle)

Distribution by Scientific Domains
Distribution within Medical Sciences

Terms modified by Vascular Smooth Muscle

  • vascular smooth muscle cell
  • vascular smooth muscle cell proliferation

  • Selected Abstracts


    CAN WE DIFFERENTIATE BETWEEN AIRWAY AND VASCULAR SMOOTH MUSCLE?

    CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2004
    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
    BRIAN E. CARLSON
    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]


    Functional Roles Of KATP Channels In Vascular Smooth Muscle

    CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2002
    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]


    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

    CONGESTIVE HEART FAILURE, Issue 1 2003
    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]


    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]


    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]


    The pharmacology of cilostazol

    DIABETES OBESITY & METABOLISM, Issue 2002
    Karsten Schrör
    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 µm). 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]


    Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities

    FEBS JOURNAL, Issue 9 2000
    Jackie D. Corbin
    In addition to its cGMP-selective catalytic site, cGMP-binding cGMP-specific phosphodiesterase (PDE5) contains two allosteric cGMP-binding sites and at least one phosphorylation site (Ser92) on each subunit [Thomas, M.K., Francis, S.H. & Corbin, J.D. (1990) J. Biol. Chem.265, 14971,14978]. In the present study, prior incubation of recombinant bovine PDE5 with a phosphorylation reaction mixture [cGMP-dependent protein kinase (PKG) or catalytic subunit of cAMP-dependent protein kinase (PKA), MgATP, cGMP, 3-isobutyl-1-methylxanthine], shown earlier to produce Ser92 phosphorylation, caused a 50,70% increase in enzyme activity and also increased the affinity of cGMP binding to the allosteric cGMP-binding sites. Both effects were associated with increases in its phosphate content up to 0.6 mol per PDE5 subunit. Omission of any one of the preincubation components caused loss of stimulation of catalytic activity. Addition of the phosphorylation reaction mixture to a crude bovine lung extract, which contains PDE5, also produced a significant increase in cGMP PDE catalytic activity. The increase in recombinant PDE5 catalytic activity brought about by phosphorylation was time-dependent and was obtained with 0.2,0.5 ,m PKG subunit, which is approximately the cellular level of this enzyme in vascular smooth muscle. Significantly greater stimulation was observed using cGMP substrate concentrations below the Km value for PDE5, although stimulation was also seen at high cGMP concentrations. Considerably higher concentration of the catalytic subunit of PKA than of PKG was required for activation. There was no detectable difference between phosphorylated and unphosphorylated PDE5 in median inhibitory concentration for the PDE5 inhibitors, sildenafil, or zaprinast 3-isobutyl-1-methylxanthine. Phosphorylation reduced the cGMP concentration required for half-maximum binding to the allosteric cGMP-binding sites from 0.13 to 0.03 ,m. The mechanism by which phosphorylation of PDE5 by PKG could be involved in physiological negative-feedback regulation of cGMP levels is discussed. [source]


    Expression of ,1 integrins in human dental pulp in vivo: a comparative immunohistochemical study on healthy and chronic marginal periodontitis samples

    INTERNATIONAL ENDODONTIC JOURNAL, Issue 1 2001
    F. Ta
    Abstract Aim The objective of this study was to determine the tissue distribution of ,1 integrin chains in sound human dental pulps and to compare the findings with connective tissue compartments of other organs and to pulp tissue in teeth extracted due to periodontal disease. Methodology Freshly frozen pulp tissue samples from teeth extracted for orthodontic reasons were examined and compared to samples from teeth extracted due to chronic (marginal) periodontitis. ,1 integrin chains were determined using an indirect-immunoperoxidase technique. Seven monoclonal antibodies recognizing ,1, ,2, ,3, ,4, ,5, ,6 and ,1 chains of Very Late Activation Antigen (VLA) integrins were used for this purpose. Results VLA-1, VLA-2, VLA-3 and VLA-5 were expressed by vascular endothelium and vascular smooth muscle in varying intensities in both groups. VLA-6 reactivity was observed in the basal surfaces of arterial, venous and capillary endothelia. Our results indicate that there was no significant difference in the expression of VLA integrins in sound pulp tissue when compared to the samples from chronic (marginal) periodontitis and the connective tissue compartments of other viscera. Conclusion The present findings suggest that human dental pulp tissue is not different from other connective tissue compartments in the body with respect to VLA integrin expression, and chronic marginal periodontitis does not affect pulp tissue to a histopathologically detectable extent. [source]


    Angioleiomyoma: a clinical, pathological and radiological review

    INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 6 2004
    P. Ramesh
    Summary Angioleiomyoma is a benign tumour arising from the vascular smooth muscle (tunica media) and presents commonly between third and fifth decades of life. Although there are sporadic reports about this tumour in the literature, none describes all the information in detail. This review is an attempt to collate all the facts in one concise article. Angioleiomyoma presents as a painful mass in approximately 60% of the cases. One of the distinct clinical feature noted is the increase in size of the swelling with physical activity of the involved part, especially in the hand. It should be considered in the differential diagnosis of painful nodular lesions of the extremity. Pre-operative diagnosis is difficult, but with a high index of suspicion and awareness, it is possible. The use of ultrasound and magnetic resonance imaging should be considered. It causes minimal morbidity and excision is usually curative. Histological examination using smooth muscle Actin stain portraits the smooth muscle bundles clearly. [source]


    Lead-dependent effects on arachidonic acid accumulation and the proliferation of vascular smooth muscle

    JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 5 2002
    Robert V. Dorman
    Abstract Lead (Pb2+) has been implicated in the development of hypertension and atherosclerosis. The proliferation of vascular smooth muscle cells (VSMC) is a central feature of both conditions and there is evidence that Pb2+ potentiates serum-dependent cell growth. The aim of this work was to examine the role of phospholipase A2 in mitogen-dependent VSMC proliferation and determine if Pb2+ interacts with this system in order to potentiate mitotic events. It was observed that cell proliferation induced by angiotensin II, or fetal bovine serum, required the activation of a Ca2+ -dependent cytosolic phospholipase A2 and the subsequent release of unesterified arachidonic acid. This path was affected by Pb2+ as the metal increased the amount of arachidonic acid accumulation induced by either mitogen. In addition, Pb2+ potentiated mitogen-induced DNA synthesis when present at lower doses (0.02 or 0.2 mg%), but had no effect on DNA synthesis, or cell numbers, in unstimulated cells. However, a high dose (2 mg%) of Pb2+ attenuated the DNA synthesis stimulated by angiotensin II, or serum, but induced the accumulation of unesterified arachidonic acid in unstimulated cells. A biphasic effect of Pb2+ on cell numbers and viability was also observed as 0.02 or 0.2 mg% Pb2+ did not affect cell numbers or trypan blue exclusion in unstimulated cells, while 2 mg% Pb2+ reduced cell numbers and viability. It appeared, therefore, that the lower concentrations of Pb2+ increased arachidonic acid release and DNA synthesis only in stimulated VSMC, perhaps due to further activation of a Ca2+ -dependent processes. In contrast, the high dose of Pb2+ reduced DNA synthesis in stimulated cells and reduced cell numbers and viability in unstimulated cells, which may relate to the noted increase in unesterified arachidonic acid. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:245,253, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10045 [source]


    FRNK, the autonomously expressed C-terminal region of focal adhesion kinase, is uniquely regulated in vascular smooth muscle: Analysis of expression in transgenic mice

    JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2005
    Haruko Hayasaka
    Abstract FRNK, the autonomously expressed carboxyl-terminal region of focal adhesion kinase (FAK), is expressed in tissues that are rich in vascular smooth muscle cells (VSMCs). Here we report the generation of transgenic mice harboring the putative FRNK promoter fused to LacZ and examine the promoter activity in situ via expression of ,-galactosidase. The transgenic mice exhibited expression of ,-galactosidase predominantly in arterial VSMCs in large and small blood vessels of major organs. Upregulation of ,-galactosidase activity was observed in tunica media following carotid injury, indicating that the FRNK promoter is activated in VSMCs in response to injury. Robust expression of ,-galactosidase in blood vessels was also detected in the developing embryo. However, expression was also observed in the midline, the nose and skin epidermis, indicating distinct transcriptional regulation of the FRNK promoter in embryogenesis. To analyze FRNK expression in vitro, we identified a 116 bp sequence in the FRNK promoter that was sufficient to function as an enhancer when fused to the minimal actin promoter and expressed in cultured smooth muscle cells. Mutation of AP-1 and NF-E2 binding consensus sequences within this element abrogated enhancer activity, supporting the involvement of this promoter element in VSMC expression of FRNK. © 2005 Wiley-Liss, Inc. [source]


    Nifedipine enhances cGMP production through the activation of soluble guanylyl cyclase in rat ventricular papillary muscle

    JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2005
    Kazuhiko Seya
    It is known that nifedipine, an L-type calcium channel blocker, increases cGMP production, which partially contributes to the relaxation of vascular smooth muscle. The aim of our investigation was to clarify whether or not nifedipine regulates cGMP production, which has a physiological role in cardiac muscle. To measure contractile responses and tissue cGMP levels, left ventricular papillary muscles prepared from male Wistar rats (350,400 g) were mounted in the isolated organ chamber under isometric conditions and electrically paced by means of platinum punctate electrodes (1 Hz, 1 ms duration). In papillary muscle preparation, the negative inotropic effect induced by nifedipine (30 to 300 nm) was significantly inhibited in the presence of ODQ (1H-[1,2,4]oxidazolo[4,3-a]quinoxaline-1-one; 10 ,m), a soluble guanylyl cyclase inhibitor. Furthermore, nifedipine (100 nm) strongly increased the tissue cGMP level, which was significantly decreased in the presence of ODQ. On the other hand, NG -monomethyl-l-arginine (100 ,m), a nitric oxide synthase inhibitor, did not inhibit either the negative inotropic effect or cGMP production induced by nifedipine. These results indicate that in rat left ventricular papillary muscle, nifedipine augments its negative inotropic effect at least partly through direct activation of cardiac soluble guanylyl cyclase but not nitric oxide synthase. [source]


    A Mechanism of Vasodilatory Action of Polyamines and Acetylpolyamines: Possible Involvement of their Ca2+ Antagonistic Properties

    JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2000
    CHANG-SEON MYUNG
    Polyamines, a class of low-molecular weight organic polycations, have been shown to produce relaxing effects in vascular smooth muscles, although the mechanism has not been carefully examined. In this study, the mechanism of vascular action of polyamines and their metabolites, acetylpolyamines, was pharmacologically examined in the rabbit isolated thoracic aorta focusing on an endothelium-dependent component of vasodilatation and Ca2+ influx through plasma membrane channels. Both polyamines and acetylpolyamines (except N1 -acetylputrescine, which produced no response or very slight contraction) caused concentration-dependent relaxation in pre-constricted aortic rings containing an intact endothelium. Aortic rings denuded of endothelium were also responsive to both polyamines and acetylpolyamines. Inhibitors of nitric oxide (reduced haemoglobin and N, -nitro- l -arginine methyl ester), vasodilator prostaglandins (indomethacin) and guanylyl cyclase (methylene blue) did not affect the relaxation induced by both polyamines and acetylpolyamines in either endothelium-intact or -denuded aortic rings. Both polyamines and acetylpolyamines inhibited the concentration-dependent contraction for phenylephrine and K+. The Ca2+ agonist Bay K 8644 induced concentration-dependent contraction in segments of rabbit aorta partially depolarized with 15 mm KCl, and both polyamines and acetylpolyamines relaxed the Bay K 8644-induced contraction in a concentration-dependent manner. Interestingly, both polyamines and acetylpolyamines also decreased contractions evoked by the Ca2+ ionophore A23187. The concentration-response curve to exogenous Ca2+ in K+ -depolarization medium (K+ = 120 mm) was shifted to the right by both polyamines and acetylpolyamines. The response elicited by Ca2+ was increased by Bay K 8644 (10,6m), and this potentiation was also inhibited by both polyamines and acetylpolyamines. The results indicate that both polyamines and acetylpolyamines can induce vasorelaxation of rabbit thoracic aorta by an endothelium-independent mechanism in-vitro and relax vascular smooth muscle by acting at the plasma membrane level, decreasing the influx of Ca2+. Therefore, polyamines and acetylpolyamines may have Ca2+ antagonistic properties which may, in part, be involved in the mechanism of rabbit aortic vascular smooth muscle relaxation. [source]


    Possible therapeutic benefits of adenosine-potentiating drugs in reducing age-related degenerative disease in dogs and cats

    JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2003
    R. J. Scaramuzzi
    Adenosine is a ubiquitous, biologically important molecule that is a precursor of other biologically active molecules. It also is a component of some co-factors and has distinct physiological actions in its own right. Levels are maintained by synthesis from dietary precursors and re-cycling. The daily turnover of adenosine is very high. Adenosine can act either as a hormone by binding to adenosine receptors, four adenosine receptor subtypes have been identified, and as an intracellular modulator, after transport into the cell by membrane transporter proteins. One of the principal intracellular actions of adenosine is inhibition of the enzyme phosphodiesterase. Extracellular adenosine also has specific neuromodulatory actions on dopamine and glutamate. Selective and nonselective agonists and antagonists of adenosine are available. The tasks of developing, evaluating and exploiting the therapeutic potential of these compounds is still in its infancy. Adenosine has actions in the central nervous system (CNS), heart and vascular system, skeletal muscle and the immune system and the presence of receptors suggests potential actions in the gonads and other organs. Adenosine agonists improve tissue perfusion through actions on vascular smooth muscle and erythrocyte fluidity and they can be used to improve the quality of life in aged dogs. This article reviews the therapeutic potential of adenosine-potentiating drugs in the treatment of age-related conditions in companion animals, some of which may be exacerbated by castration or spaying at an early age. [source]


    Medicinal chemistry and therapeutic potential of muscarinic M3 antagonists

    MEDICINAL RESEARCH REVIEWS, Issue 6 2009
    Ilaria Peretto
    Abstract Muscarinic acetylcholine receptors belong to the G-protein-coupled receptors family. Currently five different receptor subtypes have been identified and cloned. M3 receptor subtypes are coupled to Gq family proteins and increase phosphatidyl inositol hydrolysis and calcium release from internal stores. They are widely distributed both in the central nervous system and in the periphery. At the central level, M3 receptor subtypes are involved in modulation of neurotransmitter release, temperature homeostasis, and food intake, while in the periphery they induce smooth muscle contraction, gland secretion, indirect relaxation of vascular smooth muscle, and miosis. The main therapeutic applications of M3 antagonists include overactive bladder (OAB), chronic obstructive pulmonary disease (COPD), and pain-predominant irritable bowel syndrome (IBS). The introduction of selective M3 antagonists has not improved clinical efficacy compared with the old non-selective antimuscarinics but has reduced the rate of adverse events mediated by the blockade of cardiac M2 receptors (tachycardia) and central M1 receptors (cognitive impairment). Improved tolerability has been obtained also with controlled release or with inhaled formulations. However, there is still a need for safer M3 antagonists for the treatment of COPD and better-tolerated and more effective compounds for the therapy of OAB. New selective muscarinic M3 antagonists currently in early discovery and under development have been designed to address these issues. However, as M3 receptors are widely located in various tissues including salivary glands, gut smooth muscles, iris, and ciliary muscles, further clinical improvements may derive from the discovery and the development of new compounds with tissue rather than muscarinic receptor subtype selectivity. © 2009 Wiley Periodicals, Inc. Med Res Rev, 29, No. 6, 867,902, 2009 [source]


    Role of Vascular Heme Oxygenase in Reduced Myogenic Reactivity Following Chronic Hypoxia

    MICROCIRCULATION, Issue 2 2006
    JAY S. NAIK
    ABSTRACT Objective: Exposure to chronic hypoxia (CH) results in a persistent endothelium-dependent vascular smooth muscle hyperpolarization that diminishes vasoconstrictor reactivity. Experiments were performed to test the hypothesis that products of both cytochrome P450 epoxygenase (CYP) and heme oxygenase (HO) are required for the persistent diminished myogenic reactivity following CH. Methods: The authors examined myogenic responses of mesenteric arteries isolated from control and CH (48 h; PB = 380 mmHg) rats in the presence of a HO inhibitor (zinc protoporphyrin IX; ZnPPIX) or combined HO and CYP epoxygenase inhibition (sulfaphenazole). Arteries were isolated and cannulated and the vascular smooth muscle was loaded with the Ca2 + indicator Fura-2. Results: Control vessels maintained their internal diameter in response to step increases in intraluminal pressure, whereas arteries from CH animals passively distended. ZnPPIX augmented myogenic reactivity and [Ca2 +] in arteries from CH animals. Combined administration of sulfaphenazole and ZnPPIX did not have an additional effect compared to ZnPPIX alone. Myogenic reactivity in control vessels was not altered by ZnPPIX or ZnPPIX + sulfaphenazole. Conclusions: HO appears to play a role in regulating myogenic reactivity following CH. Furthermore, these data suggest that products of HO and CYP are both required for the observed attenuation in vasoreactivity following CH. [source]


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

    MICROCIRCULATION, Issue 4 2005
    BRIAN E. CARLSON
    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]


    Proteomic profiling and identification of cofilin responding to oxidative stress in vascular smooth muscle

    PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 24 2006
    Chang-Kwon Lee
    Abstract We used 2-DE and MALDI-TOF/TOF to identify proteins of vascular smooth muscle cells whose expression was or was not altered by exposure to 500,,M H2O2 for 30,min. We detected more than 800 proteins on silver-stained gels of whole protein extracts from rat aortic smooth muscle strips. Of these proteins, 135 clearly unaffected and 19 having levels altered by exposure to H2O2 were identified. Protein characterization revealed that the most prominent vascular smooth muscle proteins were those with antioxidant, cytoskeletal structure, or muscle contraction. In addition, cofilin, an isoform of the actin depolymerizing factor family, shifted to its basic site on the 2-DE gel as a result of H2O2 treatment. In Western blot analysis of proteins from A7r5 aortic smooth muscle cells, the phosphorylation, but not the expression, of cofilin was decreased by H2O2 in a dose-dependent manner. The H2O2 -induced dephosphorylation of cofilin and apoptosis was inhibited by Na3VO4, an inhibitor of protein tyrosine phosphatase (PTP). These results suggest that cofilin is one of the proteins regulated by H2O2 treatment in vascular smooth muscle, and has an important role in the induction of vascular apoptosis through PTP-dependent mechanisms. [source]


    Rate-sensitive contractile responses of lymphatic vessels to circumferential stretch

    THE JOURNAL OF PHYSIOLOGY, Issue 1 2009
    Michael J. Davis
    Phasic contractile activity in rat portal vein is more sensitive to the rate of change in length than to absolute length and this response is widely assumed to be a general characteristic of myogenic behaviour for vascular smooth muscle. Previously, we found that rat lymphatic vessels exhibit phasic contractile behaviour similar to that of portal vein. In the present study, we hypothesized that lymphatic muscle would exhibit rate-sensitive contractile responses to stretch. The hypothesis was tested on rat mesenteric lymphatics (90,220 ,m, i.d.) using servo-controlled wire- and pressure-myograph systems to enable ramp increases in force or pressure at different rates. Under isometric conditions in wire-myograph preparations, both the amplitude and the frequency of phasic activity were enhanced at more optimal preloads, but superimposed upon this effect were bursts of contractions that occurred only during fast preload ramps. In such cases, the ratio of contraction frequency during the ramp to that at the subsequent plateau (at optimal preload) was > 1. Further, the frequency ratio increased as a function of the preload ramp speed, consistent with a rate-sensitive mechanism. In contrast, the amplitude ratio was < 1 and declined further with higher ramp speeds. Downward preload ramps produced corresponding rate-sensitive inhibition of contraction frequency but not amplitude. Similar findings were obtained in pressurized lymphatics in response to pressure ramps and steps. Our results suggest that lymphatics are sensitive to the rate of change in preload/pressure in a way that is different from portal vein, possibly because the pacemaker for generating electrical activity is rate sensitive but lymphatic muscle is not. The behaviour may be widely present in collecting lymphatic vessels and is probably an important mechanism for rapid adaptation of the lymphatic pump to local vascular occlusion. [source]


    Tail arteries from chronically spinalized rats have potentiated responses to nerve stimulation in vitro

    THE JOURNAL OF PHYSIOLOGY, Issue 2 2004
    Melanie Yeoh
    Patients with severe spinal cord lesions that damage descending autonomic pathways generally have low resting arterial pressure but bladder or colon distension or unheeded injuries may elicit a life-threatening hypertensive episode. Such episodes (known as autonomic dysreflexia) are thought to result from the loss of descending baroreflex inhibition and/or plasticity within the spinal cord. However, it is not clear whether changes in the periphery contribute to the exaggerated reflex vasoconstriction. The effects of spinal transection at T7,8 on nerve- and agonist-evoked contractions of the rat tail artery were investigated in vitro. Isometric contractions of arterial segments were recorded and responses of arteries from spinalized animals (,spinalized arteries') and age-matched and sham-operated controls were compared. Two and eight weeks after transection, nerve stimulation at 0.1,10 Hz produced contractions of greater force and duration in spinalized arteries. At both stages, the ,-adrenoceptor antagonists prazosin (10 nm) and idazoxan (0.1 ,m) produced less blockade of nerve-evoked contraction in spinalized arteries. Two weeks after transection, spinalized arteries were supersensitive to the ,1 -adrenoceptor agonist phenylephrine, and the ,2 -adrenoceptor agonist, clonidine, but 8 weeks after transection, spinalized arteries were supersensitive only to clonidine. Contractions of spinalized arteries elicited by 60 mm K+ were larger and decayed more slowly at both stages. These findings demonstrate that spinal transection markedly increases nerve-evoked contractions and this can, in part, be accounted for by increased reactivity of the vascular smooth muscle to vasoconstrictor agents. This hyper-reactivity may contribute to the genesis of autonomic dysreflexia in patients. [source]


    Mechanisms influencing the vasoactive effects of lidocaine in human skin,

    ANAESTHESIA, Issue 2 2007
    D. J. Newton
    Summary The vasodilator properties of lidocaine are believed to be due mainly to the inhibition of action potentials via sodium channel blocking in vasoconstrictor sympathetic nerves. However, mechanisms involving the vascular endothelium may also play a role, and in this study we investigated the potential influences of nitric oxide release, the cyclo-oxygenase pathway and the ,-adrenoceptors of vascular smooth muscle. Laser Doppler imaging was used to measure microvascular blood flow responses to intradermal injection of lidocaine 2%, with or without the addition of preservatives, in eight healthy, male volunteers. Co-injection of the nitric-oxide,synthase inhibitor N,-nitro- l -arginine methyl ester caused a 60% reduction in the response after about 20 min, and this reduction was enhanced with the lidocaine solution containing the preservatives methylhydroxybenzoate and propylhydroxybenzoate. No reduction in response was seen after blocking the cyclo-oxygenase or ,-adrenoceptor pathways. Nitric oxide release contributes to the vasoactivity of lidocaine in human skin. [source]


    Homocysteine is positively associated with cytokine IL-18 plasma levels in coronary artery bypass surgery patients

    BIOFACTORS, Issue 2 2005
    Craig Steven Mclachlan
    Abstract Homocysteine, cytokines (IL-18, IL-6, IL-8) are involved in vascular inflammation and coronary artery disease. Homocysteine influences endothelial IL-6 and IL-8 cytokine expression and release, however, an association between homocysteine and IL-18 has not been previously investigated in endothelial/smooth muscle cells and or in coronary artery disease. We report in 9 coronary artery bypass surgery (CABG) patients a positive correlation r=0.86 between homocysteine and IL-18 plasma levels (p<0.05). Plasma IL-18 levels are significantly higher in those patients with elevated homocysteine compared to those with normal levels (p<0.02; 153 ± 19 pg/ml versus 116 ± 14 pg/ml respectively). Our in vitro cell culture studies suggest that the source of IL-18 in CABG patients with elevated homocysteine is not from vascular smooth muscle or endothelial cells. [source]


    Regulation by FK506 and rapamycin of Ca2+ release from the sarcoplasmic reticulum in vascular smooth muscle: the role of FK506 binding proteins and mTOR

    BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2009
    D MacMillan
    Background and purpose:, The sarcoplasmic reticulum (SR), regulates the cytoplasmic Ca2+ concentration ([Ca2+]cyto) in vascular smooth muscle. Release from the SR is controlled by two intracellular receptor/channel complexes, the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (IP3R). These receptors may be regulated by the accessory FK506-binding protein (FKBP) either directly, by binding to the channel, or indirectly via FKBP modulation of two targets, the phosphatase, calcineurin or the kinase, mammalian target of rapamycin (mTOR). Experimental approach:, Single portal vein myocytes were voltage-clamped in whole cell configuration and [Ca2+]cyto measured using fluo-3. IP3Rs were activated by photolysis of caged IP3 and RyRs activated by hydrostatic application of caffeine. Key results:, FK506 which displaces FKBP from each receptor (to inhibit calcineurin) increased the [Ca2+]cyto rise evoked by activation of either RyR or IP3R. Rapamycin which displaces FKBP (to inhibit mTOR) also increased the amplitude of the caffeine-evoked, but reduced the IP3 -evoked [Ca2+]cyto rise. None of the phosphatase inhibitors, cypermethrin, okadaic acid or calcineurin inhibitory peptide, altered either caffeine- or IP3 -evoked [Ca2+]cyto release; calcineurin did not contribute to FK506-mediated potentiation of RyR- or IP3R-mediated Ca2+ release. The mTOR inhibitor LY294002, like rapamycin, decreased IP3 -evoked Ca2+ release. Conclusions and implications:, Ca2+ release in portal vein myocytes, via RyR, was modulated directly by FKBP binding to the channel; neither calcineurin nor mTOR contributed to this regulation. However, IP3R-mediated Ca2+ release, while also modulated directly by FKBP may be additionally regulated by mTOR. Rapamycin inhibition of IP3 -mediated Ca2+ release may be explained by mTOR inhibition. [source]


    Tamoxifen dilates porcine coronary arteries: roles for nitric oxide and ouabain-sensitive mechanisms

    BRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2006
    H S Leung
    Background and purpose: Experiments were designed to determine the mechanism of the relaxation induced by tamoxifen in porcine coronary arteries at the tissue, cellular and molecular levels. Experimental approach: Porcine left circumflex coronary arteries were isolated and isometric tension was measured. [Ca2+]i in native endothelial cells of intact arteries was determined by a calcium fluorescence imaging technique and eNOS ser1177 phosphorylation was assayed by Western blotting. Key results: Tamoxifen induced an endothelium-dependent relaxation that was antagonized by ICI 182,780 and abolished by NG -nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadizolo[4,3-a]quinoxalin-1-one (ODQ). L-Arginine reversed the effect of L-NAME while indomethacin was without effect. Tamoxifen-induced relaxation was attenuated by charybdotoxin (CTX) plus apamin, ouabain or by incubation in a K+ -free solution. Moreover, tamoxifen triggered extracellular Ca2+ -dependent increases in endothelial [Ca2+]i and this effect was abolished by ICI 182,780. Endothelium-independent relaxation to sodium nitroprusside was also inhibited by ouabain or in a K+ -free solution. Furthermore, tamoxifen increased endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177 and ICI 182,780 prevented this effect. Conclusions and Implications: The present results suggest that tamoxifen mainly induces endothelium-dependent relaxation and that endothelial nitric oxide (NO) is the primary mediator of this effect. NO-dependent responses may result from elevated [Ca2+]i in endothelial cells; an effect abolished by ICI 182,780. NO activates Na+/K+ -ATPase in vascular smooth muscle, leading to relaxation. These results suggest that tamoxifen is able to modulate eNOS phosphorylation directly. British Journal of Pharmacology (2006) 149, 703,711. doi:10.1038/sj.bjp.0706921 [source]


    The actions of azelnidipine, a dihydropyridine-derivative Ca antagonist, on voltage-dependent Ba2+ currents in guinea-pig vascular smooth muscle

    BRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2006
    H-L Zhu
    Background and purpose: Although azelnidipine is used clinically to treat hypertension its effects on its target cells, Ca2+ channels, in smooth muscle have not been elucidated. Therefore, its effects on spontaneous contractions and voltage-dependent L-type Ca2+ channels were investigated in guinea-pig portal vein. Experimental approach: The inhibitory potency of azelnidipine on spontaneous contractions in guinea-pig portal vein was compared with those of other dihydropyridine (DHP)-derived Ca antagonists (amlodipine and nifedipine) by recording tension. Also its effects on voltage-dependent nifedipine-sensitive inward Ba2+ currents (IBa) in smooth muscle cells dispersed from guinea-pig portal vein were investigated by use of a conventional whole-cell patch-clamp technique. Key results: Spontaneous contractions in guinea-pig portal vein were reduced by all of the Ca antagonists (azelnidipine, Ki=153 nM; amlodipine, Ki=16 nM; nifedipine, Ki=7 nM). In the whole-cell experiments, azelnidipine inhibited the peak amplitude of IBa in a concentration- and voltage-dependent manner (-60 mV, Ki=282 nM; ,90 mV, Ki=2 ,M) and shifted the steady-state inactivation curve of IBa to the left at ,90 mV by 16 mV. The inhibitory effects of azelnidipine on IBa persisted after 7 min washout at ,60 mV. In contrast, IBa gradually recovered after being inhibited by amlodipine, but did not return to control levels. Both azelnidipine and amlodipine caused a resting block of IBa at -90 mV. Only nifedipine appeared to interact competitively with S(-)-Bay K 8644. Conclusions and implications: These results suggest that azelnidipine induces long-lasting vascular relaxation by inhibiting voltage-dependent L-type Ca2+ channels in vascular smooth muscle. British Journal of Pharmacology (2006) 149, 786,796. doi:10.1038/sj.bjp.0706919 [source]


    Ginsenoside Rg3 inhibits phenylephrine-induced vascular contraction through induction of nitric oxide synthase

    BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003
    Nak Doo Kim
    Ginsenoside Rg3 (Rg3) isolated from Panax ginseng relaxes vessels and exerts a cytoprotective effect. In view of the fact that nitric oxide (NO) is involved in vascular hyporeactivity and immunostimulation, the effects of total ginsenosides (GS) and Rg3 on the vascular responses and the expression of inducible nitric oxide synthase (iNOS) were investigated. Vasocontraction of endothelium-denuded aortic ring was induced by phenylephrine with or without GS or Rg3. The expression of iNOS was assessed by Western blot and RT,PCR analyses. NF- ,B activation was monitored by gel shift, immunoblot and immunocytochemical analyses. Incubation of the endothelium-denuded aortic ring with GS or Rg3 inhibited phenylephrine-induced vasocontraction, which was abrogated by NOS inhibition. GS or Rg3 increased NO production in aortic rings, but Rb1, Rc, Re and Rg1 had no effect. Aortic rings obtained from rats treated with GS or Rg3 responded to phenylnephrine to a lesser extent, while producing NO to a larger extent, than those from control animals. GS or Rg3 induced iNOS in vascular smooth muscle. Rg3 induced iNOS with increase in NO production in Raw264.7 cells. Rg3 increased NF- ,B DNA binding, whose band was supershifted with anti-p65 and anti-p50 antibodies, and elicited p65 nuclear translocation, which was accompanied by phosphorylation and degradation of I- ,B,. PKC regulated iNOS induction by Rg3. In conclusion, Rg3 relaxes vessels as a consequence of NO production, to which iNOS induction contributes, and iNOS induction by Rg3 accompanied NF- ,B activation, which involves phosphorylation and degradation of I- ,B, and nuclear translocation of p65. British Journal of Pharmacology (2003) 140, 661,670. doi:10.1038/sj.bjp.0705490 [source]


    Prevention of a hypoxic Ca2+i response by SERCA inhibitors in cerebral arterioles

    BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2002
    C Guibert
    The aim of the study was to investigate the mechanism of a novel effect of hypoxia on intracellular Ca2+ signalling in rabbit cerebral arteriolar smooth muscle cells, an effect that was resistant to the L-type Ca2+ channel antagonist methoxyverapamil (D600). [Ca2+]i of smooth muscle cells in intact arteriolar fragments was measured using the Ca2+ -indicator dye fura-PE3. Hypoxia (PO2 10 , 20 mmHg) lowered basal [Ca2+]i but did not inhibit Ca2+ entry pathways measured by Mn2+ -quenching of fura-PE3. The effect of hypoxia was completely prevented by thapsigargin or cyclopiazonic acid, selective inhibitors of sarcoplasmic reticulum Ca2+ ATPase (SERCA). Since these inhibitors do not block Ca2+ extrusion or uptake via the plasma membrane, the data indicate that the effect of hypoxia depends on a functional sarcoplasmic reticulum. Because actions of nitric oxide (NO) on vascular smooth muscle are also prevented by SERCA inhibitors it was explored whether the effect of hypoxia occurred via modulation of endogenous NO release. Residual NOS-I and NOS-III were detected by immunostaining, and there were NO-dependent effects of NOS inhibitors on Ca2+i -signalling. Nevertheless, inhibition of endogenous NO production did not prevent the effect of hypoxia on [Ca2+]i. The experiments reveal a novel nitric oxide-independent effect of hypoxia that is prevented by SERCA inhibitors. British Journal of Pharmacology (2002) 135, 927,934; doi:10.1038/sj.bjp.0704547 [source]


    Citrulline does not relax isolated rat and rabbit vessels

    BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2000
    Stephen Marx
    The study was prompted by the report of Ruiz E. & Tejerina T., 1998 describing endothelium-independent relaxation by L-citrulline via activation of particulate guanylate cyclase. We compared the effects of L-citrulline and L -arginine in isolated aortic rings of rats and in isolated aortic, carotid and femoral artery rings of rabbits. No significant relaxation to either L-citrulline or L -arginine was found in the concentration range of 10,12 to 10,3 M, while 3-morpholinosydnonimine hydrochloride (SIN-1, 10,6 M) relaxed vascular tissues. This study does not support the conclusion that L-citrulline has direct vasorelaxing action on vascular smooth muscle. British Journal of Pharmacology (2000) 130, 713,716; doi:10.1038/sj.bjp.0703372 [source]