Phosphodiesterase Inhibitor (phosphodiesterase + inhibitor)

Distribution by Scientific Domains
Distribution within Medical Sciences


Selected Abstracts


Prevention of Ventricular Fibrillation by Cilostazol, an Oral Phosphodiesterase Inhibitor, in a Patient with Brugada Syndrome

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 7 2002
TAKESHI TSUCHIYA M.D.
Cilostazol and Brugada Syndrome. We report the case of 67-year-old man with Brugada syndrome, in whom daily episodes of ventricular fibrillation (VF) occurred every early morning for 4 days. The episodes of VF were completely prevented by an oral administration of cilostazol, a phosphodiesterase inhibitor. This effect was confirmed by the on-and-off challenge test, in which discontinuation of the drug resulted in recurrence of VF and resumption of the drug again prevented VF. This effect may be related to the suppression of Ito secondary to the increase in heart rate and/or to an increase in Ca2+ current (ICa) due to an elevation of intracellular cyclic AMP concentration via inhibition of phosphodiesterase activity. This drug might have an anti-VF potential in patients with Brugada syndrome. [source]


Genitourinary dysfunction in Parkinson's disease,

MOVEMENT DISORDERS, Issue 1 2010
Ryuji Sakakibara MD
Abstract Bladder dysfunction (urinary urgency/frequency) and sexual dysfunction (erectile dysfunction) are common nonmotor disorders in Parkinson's disease (PD). In contrast to motor disorders, genitourinary autonomic dysfunctions are often nonresponsive to levodopa treatment. The brain pathology causing the bladder dysfunction (appearance of overactivity) involves an altered dopamine-basal ganglia circuit, which normally suppresses the micturition reflex. By contrast, hypothalamic dysfunction is mostly responsible for the sexual dysfunction (decrease in libido and erection) in PD, via altered dopamine-oxytocin pathways, which normally promote libido and erection. The pathophysiology of the genitourinary dysfunction in PD differs from that in multiple system atrophy; therefore, it might aid in differential diagnosis. Anticholinergic agents are used to treat bladder dysfunction in PD, although these drugs should be used with caution particularly in elderly patients who have cognitive decline. Phosphodiesterase inhibitors are used to treat sexual dysfunction in PD. These treatments might be beneficial in maximizing the patients' quality of life. 2010 Movement Disorder Society [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]


Activation of receptors negatively coupled to adenylate cyclase is required for induction of long-term synaptic depression at Schaffer collateral-CA1 synapses

DEVELOPMENTAL NEUROBIOLOGY, Issue 3 2006
Linda A. Santschi
Abstract Chemical LTD (CLTD) of synaptic transmission is triggered by simultaneously increasing presynaptic [cGMP] while inhibiting PKA. Here, we supply evidence that class II, but not III, metabotropic glutamate receptors (mGluRs), and A1 adenosine receptors, both negatively coupled to adenylate cyclase, play physiologic roles in providing PKA inhibition necessary to promote the induction of LTD at Schaffer collateral-CA1 synapses in hippocampal slices. Simultaneous activation of group II mGluRs with the selective agonist (2S,2,R,3,R)-2-(2,,3,-dicarboxy-cyclopropyl) glycine (DCGIV; 5 ,M), while raising [cGMP] with the type V phosphodiesterase inhibitor, zaprinast (20 ,M), resulted in a long-lasting depression of synaptic strength. When zaprinast (20 ,M) was combined with a cell-permeant PKA inhibitor H-89 (10 ,M), the need for mGluR IIs was bypassed. DCGIV, when combined with a "submaximal" low frequency stimulation (1 Hz/400 s), produced a saturating LTD. The mGluR II selective antagonist, (2S)-alpha-ethylglutamic acid (EGLU; 5 ,M), blocked induction of LTD by prolonged low frequency stimulation (1 Hz/900 s). In contrast, the mGluR III selective receptor blocker, (RS)-a-Cyclopropyl-[3- 3H]-4-phosphonophenylglycine (CPPG; 10 ,M), did not impair LTD. The selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 100 nM), also blocked induction of LTD, while the adenosine A1 receptor agonist N6 -cyclohexyl adenosine (CHA; 50 nM) significantly enhanced the magnitude of LTD induced by submaximal LFS and, when paired with zaprinast (20 ,M), was sufficient to elicit CLTD. Inhibition of PKA with H-89 rescued the expression of LTD in the presence of either EGLU or DPCPX, confirming the hypothesis that both group II mGluRs and A1 adenosine receptors enhance the induction of LTD by inhibiting adenylate cyclase and reducing PKA activity. 2005 Wiley Periodicals, Inc. J Neurobiol, 2006 [source]


Intra-Arterial Milrinone for Reversible Cerebral Vasoconstriction Syndrome

HEADACHE, Issue 1 2009
Manon Bouchard MD
Reversible cerebral vasoconstriction syndrome (RCVS) usually presents with recurrent thunderclap headaches and is characterized by multifocal and reversible vasoconstriction of cerebral arteries that can sometimes evolve to severe cerebral ischemia and stroke. We describe the case of a patient who presented with a clinically typical RCVS and developed focal neurological symptoms and signs despite oral treatment with calcium channel blockers. Within hours of neurological deterioration, she was treated with intra-arterial milrinone, a phosphodiesterase inhibitor, which resulted in a rapid and sustained neurological improvement. [source]


Prevention of Ventricular Fibrillation by Cilostazol, an Oral Phosphodiesterase Inhibitor, in a Patient with Brugada Syndrome

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 7 2002
TAKESHI TSUCHIYA M.D.
Cilostazol and Brugada Syndrome. We report the case of 67-year-old man with Brugada syndrome, in whom daily episodes of ventricular fibrillation (VF) occurred every early morning for 4 days. The episodes of VF were completely prevented by an oral administration of cilostazol, a phosphodiesterase inhibitor. This effect was confirmed by the on-and-off challenge test, in which discontinuation of the drug resulted in recurrence of VF and resumption of the drug again prevented VF. This effect may be related to the suppression of Ito secondary to the increase in heart rate and/or to an increase in Ca2+ current (ICa) due to an elevation of intracellular cyclic AMP concentration via inhibition of phosphodiesterase activity. This drug might have an anti-VF potential in patients with Brugada syndrome. [source]


Effect of aging on corticosterone secretion in diestrous rats

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2006
Ming-Jae Lo
Abstract The roles of age and prolactin (PRL) in regulating glucocorticoid secretion in diestrous rats were investigated. Adrenal zona fasciculata-reticularis (ZFR) cells from young, adult, middle (mid)-aged, and old female rats were isolated. Estrous cycle stage was determined by light microscopy after vaginal smears. Blood samples were collected from right jugular vein at 0, 30, 60, and 120 min after challenge with adrenocorticotropin (ACTH). During the diestrous phase, plasma levels of estradiol and progesterone were lower in mid-aged and old rats than in either young or adult rats. Age-dependent increases of the basal levels of plasma PRL and corticosterone were observed. No difference of ACTH-increased plasma concentrations of corticosterone was observed among young, adult, mid-aged, and old rats. Aging increased the basal, ACTH-, PRL-, forskolin (an adenylate cyclase activator)-, and 3-isobutyl-l-methylxanthine (IBMX, a non-selective phosphodiesterase inhibitor)-stimulated release of corticosterone and production of adenosine 3,, 5,-cyclic monophosphate (cAMP) in ZFR cells. However, the 8-Br-cAMP (a membrane-permeable cAMP)-stimulated release of corticosterone was not affected by age. Taken together, these data indicated that aging increased corticosterone secretion in female rats during diestrous phase, which is in part due to an increase in cAMP accumulation. In conclusion, aging and PRL play a stimulatory role in the co-regulation of corticosterone secretion. J. Cell. Biochem. 2005 Wiley-Liss, Inc. [source]


Nitric Oxide-Sensitive Guanylyl Cyclase Activity Inhibition Through Cyclic GMP-Dependent Dephosphorylation

JOURNAL OF NEUROCHEMISTRY, Issue 5 2000
Rut Ferrero
Abstract: The soluble form of guanylyl cyclase (sGC) plays a pivotal role in the transduction of inter- and intracellular signals conveyed by nitric oxide. Here, a feedback inhibitory mechanism triggered by cyclic guanosine-3,,5,-monophosphate (cGMP)-dependent protein kinase (PKG) activation is described. Preincubation of chromaffin cells with C-type natriuretic peptide, which increased cGMP levels and activated PKG, or with cGMP-permeant analogue (which also activates PKG), in the presence of a broad-spectrum phosphodiesterase inhibitor, resulted in a decrease in subsequent sodium nitroprusside (SNP)-dependent cGMP elevations. This inhibitory effect was mimicked by activating a protein phosphatase and counteracted by the selective PKG inhibitor KT-5823 and by different protein phosphatase inhibitors. Immunoprecipitation of sGC from cells submitted to different treatments followed by immunodetection with antiphosphoserine antibodies (clone 4A9) showed changes in phosphorylation levels of the , subunit of sGC, and these changes correlated well with differences in SNP-elicited cGMP accumulations. Pretreatment of cells with several PKG inhibitors or protein phosphatase inhibitors produced an enhancement of SNP-stimulated cGMP rises without changing the SNP concentration required to produce half-maximal or maximal responses. Taken together, these results indicate that the catalytic activity of sGC is closely coupled to the phosphorylation state of its , subunit and that the tonic activity of PKG or its stimulation regulates sGC activity through dephosphorylation of the , subunit. [source]


Retrospective Evaluation of Sildenafil Citrate as a Therapy for Pulmonary Hypertension in Dogs

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 5 2006
Jonathan F. Bach DACVIM (SA-IM)
Pulmonary arterial hypertension (PH) is a pathologic condition in dogs characterized by abnormally high pressures in the pulmonary circulation and has been associated with a poor outcome. Sildenafil is a type V phosphodiesterase inhibitor that produces nitric oxide-mediated vasodilatation. Sildenafil treatment decreases pulmonary arterial pressure and pulmonary vascular resistance in people with PH. The purpose of this study was to describe the clinical characteristics and outcome of dogs with PH treated with sildenafil. The cardiology database was searched for dogs with PH treated with sildenafil. PH was defined as systolic pulmonary arterial pressure (PAPS) 25 mmHg at rest. Medical records were reviewed for the following information: signalment, duration and type of clinical signs before treatment, underlying disease, estimated or measured PAPS, dosage and dosing interval of sildenafil, and the effect of treatment on clinical signs and pulmonary arterial pressure and survival time. Thirteen affected dogs were identified. Clinical signs included collapse, syncope, respiratory distress, and cough. Duration of clinical signs before presentation ranged from 3 days to 5 months. An underlying cause was identified in 8 dogs. The median sildenafil dosage was 1.9 mg/kg. Ten dogs received concurrent medications. Median PAPS was 90 mmHg; 8 dogs were reevaluated after therapy, and the median decrease in PAPS was 16.5 mmHg. The median survival time of all dogs was 91 days. Sildenafil appeared to be well tolerated in dogs with PH and was associated with decreased PAPS and amelioration of clinical signs in most. Sildenafil represents a reasonable treatment option for dogs with pulmonary hypertension. [source]


Characterization of bovine neutrophil ,2 -adrenergic receptor function

JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2010
T. P. LaBRANCHE
LaBranche, T. P., Ehrich, M. F., Eyre, P. Characterization of bovine neutrophil ,2 -adrenergic receptor function. J. vet. Pharmacol. Therap. doi: 10.1111/j.1365-2885.2009.01143.x. This study compares bovine leukocyte ,-adrenergic receptor densities to that of the rat, demonstrates for the first time a functional ,2 -adrenergic receptor signaling pathway in steer neutrophils, and investigates the effect of an inflammatory stimulus on that signaling pathway. The ,1 -/,2 -adrenergic antagonist [3H]CGP-12177 demonstrated that rat lymphocyte specific binding-site density was highest, followed by steer and dairy cow lymphocytes, and lastly steer and dairy cow neutrophils. The ,2 -adrenergic agonist terbutaline stimulated steer neutrophil adenosine 3,5-cyclic monophosphate (cAMP) production, an effect increased by inclusion of ,1 10,8 m phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C. Both terbutaline and the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) independently decreased steer neutrophil superoxide anion production in a concentration-dependent manner, with 1 10,4 m IBMX enhancing both the potency and efficacy of the terbutaline effect (up to 74% reduction in superoxide anion production). Superoxide anion production was also reduced by the synthetic cAMP analog 8-bromo-cAMP, which increased the potency of the IBMX effect on superoxide anion production. Taken together, these data demonstrate the presence of a ,2 -adrenergic receptor signaling pathway in bovine neutrophils much like that described in other animal species, as well as the potential for an inflammatory stimulus to alter its function. [source]


Caffeine treatment of ovine cytoplasts regulates gene expression and foetal development of embryos produced by somatic cell nuclear transfer

MOLECULAR REPRODUCTION & DEVELOPMENT, Issue 10 2010
Inchul Choi
Abstract Treatment of ovine oocytes during the latter stages of maturation in vitro with caffeine, a phosphodiesterase inhibitor, can increase the activities of maturation promoting factor and mitogen-activated protein kinases at metaphase II. When used as cytoplast recipients for somatic cell nuclear transfer (NT), caffeine-treated oocytes produced blastocysts with increased cell numbers. The objectives of these studies were to determine the effects of caffeine treatment on the expression profile of genes involved in early embryonic development and whether induction or maintenance of pregnancy was subsequently altered. No differences in overall expression patterns were observed between fertilised, caffeine-treated fertilised and parthenogenetic embryos. In control NT embryos, altered levels of gene expression were found for OCT4, five genes regulated by OCT4 (H2AF.Z, NANOG, SOX2, FGF4 and INFT) and the heat-shock response genes (HSP27 and HSP70.1). Levels of OCT4, H2AF.Z, NANOG, HSP 27 and FGF4 decreased, while those of INFT, HSP70.1 and SOX2 increased. In contrast, expression levels of these genes in caffeine-treated NT embryos were similar to those in fertilised controls. Following transfer to surrogate recipients no differences were observed in the frequency of pregnancy; however, ewes receiving caffeine-treated embryos maintained pregnancies for longer periods and delivered a live lamb. Taken together, these results suggest that treatment of ovine oocytes with caffeine can affect gene expression and improve developmental competence. Further studies on the mechanisms behind this alteration of gene expression are required and will aid in understanding the molecular mechanisms involved in nuclear reprogramming. Mol. Reprod. Dev. 77:876,887, 2010. 2010 Wiley-Liss, Inc. [source]


Type 4 phosphodiesterase inhibitor suppresses experimental bladder inflammation

BJU INTERNATIONAL, Issue 10 2008
Takeya Kitta
OBJECTIVE To evaluate the effects of orally administered YM976, a specific inhibitor of type 4 phosphodiesterase (PDE4), on bladder activity in a rat model with hydrochloric acid (HCl)-induced cystitis (IC), hypothesizing that a PDE4 inhibitor might suppress bladder overactivity and bladder pain responses in bladder-hypersensitive disorders such as IC. MATERIALS AND METHODS Wistar rats with HCl-induced IC were treated with YM976 or vehicle and their voiding observed and assessed by cystometry. The severity of bladder inflammation (BI) was quantified using the BI index (BII), which comprises three factors (oedema, leukocyte infiltration and haemorrhage). Nociceptive neural activity was also examined using an immunohistochemical study of spinal c-fos expression. RESULTS YM976 significantly reduced the number of voids, and the volume per void was significantly higher than in control (vehicle) group. Cystometry showed a significant increase in bladder capacity, voided volume and voiding efficiency, and a decrease in the amplitude of voiding pressure in rats treated with YM976. All BII scores were significantly lower in the YM976 than in the control group. c-fos expression in the spine was less in the YM976 than in the control group. CONCLUSIONS Oral administration of YM976 significantly improved the voiding behaviour and histological damage in rats with IC induced by HCl. These results indicate that PDE4 inhibitor might be effective in relieving bladder symptoms with IC. [source]


Enhancement of the anti-inflammatory and anti-arthritic effects of theophylline by a low dose of a nitric oxide donor or non-specific nitric oxide synthase inhibitor

BRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2009
Adel Gomaa
Background and purpose:, Although there are many new specific phosphodiesterase inhibitors with anti-inflammatory activity, none have yet reached the market because of their low therapeutic efficacy. Our study was aimed to evaluate the anti-inflammatory and anti-arthritic effect of an established phosphodiesterase inhibitor, theophylline, and to investigate the effect of the nitric oxide (NO) donor, sodium nitroprusside (SNP) or NO synthase inhibitor, L-NG -monomethyl arginine (L-NMMA) on its actions. Experimental approach:, The effects of theophylline alone and combined with SNP or L-NMMA on the pathogenesis of adjuvant-induced arthritis in rats were evaluated. Key results:, Prophylactic or therapeutic doses of theophylline significantly ameliorated the pathogenesis of adjuvant arthritis in rats as evidenced by a significant decrease in the arthritis index, hind paws volume, ankle joint diameter, fever, body weight loss and hyperalgesia in a dose-dependent manner. Inflammatory cellular infiltrate in synovium of ankle joint and pannus formation were also markedly inhibited. Interleukin-10 (IL-10) levels were significantly increased in arthritic rats given theophylline alone or in combination with either SNP or L-NMMA. Co-administration of a low dose of SNP or L-NMMA enhanced significantly the anti-inflammatory and anti-arthritic effect of theophylline. In contrast, a high dose of SNP counteracted the anti-inflammatory and anti-arthritic effects of theophylline. Conclusions and Implication:, These findings confirm the anti-inflammatory and anti-arthritic activities of theophylline and suggest a new approach to enhance the anti-inflammatory and anti-arthritic effects of theophylline would be to administer it in combination with a low dose of a NO donor or a non-specific NO synthase inhibitor. [source]


Theophylline attenuates Ca2+ sensitivity and modulates BK channels in porcine tracheal smooth muscle

BRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2003
Shinji Ise
Theophylline, a nonselective phosphodiesterase inhibitor, has long been regarded as a major bronchodilator in the treatment of human asthma. Using front-surface fluorometry with fura-2 and , -toxin permeabilization, the effects of theophylline on intracellular Ca2+ concentration ([Ca2+]i), tension development and Ca2+ sensitivity of the contractile apparatus were investigated in porcine tracheal smooth muscle strips. Application of theophylline induced a relaxation without a significant decrease in [Ca2+]i when strips were precontracted by 40 mM K+ depolarization, while theophylline significantly decreased both [Ca2+]i and tension induced by carbachol. The effects of theophylline on the increases in [Ca2+]i and tension induced by carbachol were significantly inhibited by iberiotoxin, an inhibitor of large-conductance Ca2+ -activated K+ channels. In the absence of extracellular Ca2+, theophylline significantly attenuated carbachol-induced transient increases in tension development, while it did not affect carbachol-induced transient increase in [Ca2+]i. The [Ca2+]i,force relationship, which was determined by cumulative applications of extracellular Ca2+ (0,5 mM) during 40 mM K+ depolarization, was significantly shifted to the right by theophylline. In , -toxin permeabilized strips, theophylline significantly increased the EC50 value of [Ca2+]i for contraction and enhanced the effect of cAMP, but not of cGMP. These results indicate that theophylline induces relaxation of the porcine tracheal smooth muscle through an activation of BK channels, and a resultant decrease in [Ca2+]i and an attenuation of Ca2+ sensitivity, presumably through the action of cAMP. British Journal of Pharmacology (2003) 140, 939,947. doi:10.1038/sj.bjp.0705508 [source]


Experimental study of a type 3 phosphodiesterase inhibitor on liver graft function

BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 1 2001
T. Ikegami
Background: The number of liver transplant recipients is increasing but donor organ shortages have become more severe. The effect of milrinone, a type 3 phosphodiesterase inhibitor (PDEI), on non-heart-beating donor grafts was evaluated using an orthotopic liver transplantation model in rats. Methods: Type 3 PDEI or normal saline (control group) was given intravenously to the donor animals for 60 min continuously (50 g kg,1 min,1 ) before 60 min of warm ischaemia followed by cold preservation and subsequent transplantation. Survival, serum chemistry, bile output, histopathological findings and tissue cyclic 3,,5,-adenosine monophosphate (cAMP) concentrations were then compared. Results: Five of seven animals in the PDEI group were alive at 7 days, compared with only one of seven rats in the control group (P < 001). Serum levels of alanine aminotransferase 2 and 6 h after reperfusion, and hyaluronic acid levels 6 h after reperfusion, were significantly lower in the PDEI group than in the control group. Bile output from the transplanted graft was significantly greater in the PDEI group than in controls 2 h after reperfusion (P < 001). The mean necrotic area 6 h after reperfusion was also reduced in the PDEI-treated grafts (P < 001). cAMP levels in liver tissue at the end of both warm and cold ischaemia, and 2 and 6 h after reperfusion, were significantly higher in the PDEI group compared with those in the control group. Conclusion: Type 3 PDEI attenuated the graft injury caused by warm and cold ischaemia and subsequent reperfusion injury via an increase in intracellular cAMP levels. This treatment may be a novel pharmacological intervention for safe and efficient usage of liver grafts from non-heart-beating donors. 2001 British Journal of Surgery Society Ltd [source]


Mechanisms of renal hyporesponsiveness to ANP in heart failure

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 9 2003
A. Charloux
Abstract The atrial natriuretic peptide (ANP) plays an important role in chronic heart failure (CHF), delaying the progression of the disease. However, despite high ANP levels, natriuresis falls when CHF progresses from a compensated to a decompensated state, suggesting emergence of renal resistance to ANP. Several mechanisms have been proposed to explain renal hyporesponsiveness, including decreased renal ANP availability, down-regulation of natriuretic peptide receptors and altered ANP intracellular transduction signal. It has been demonstrated that the activity of neutral endopeptidase (NEP) is increased in CHF, and that its inhibition enhances renal cGMP production and renal sodium excretion. In vitro as well as in vivo studies have provided strong evidence of an increased degradation of intracellular cGMP by phosphodiesterase in CHF. In experimental models, ANP-dependent natriuresis is improved by phosphodiesterase inhibitors, which may arise as new therapeutic agents in CHF. Sodium-retaining systems likely contribute to renal hyporesponsiveness to ANP through different mechanisms. Among these systems, the renin-angiotensin-aldosterone system has received particular attention, as angiotensin II and ANP have renal actions at the same sites and inhibition of angiotensin-converting enzyme and angiotensin-receptor blockade improve ANP hyporesponsiveness. Less is known about the interactions between the sympathetic nervous system, endothelin or vasopressin and ANP, which may also blunt ANP-induced natriuresis. To summarize, renal hyporesponsiveness to ANP is probably multifactorial. New treatments designed to restore renal ANP efficiency should limit sodium retention in CHF patients and thus delay the progression to overt heart failure. [source]


The Secretory Response of the Rat Colon to the Flavonol Quercetin is Dependent on Ca2+ -Calmodulin

EXPERIMENTAL PHYSIOLOGY, Issue 3 2000
R. Cermak
The dietary flavonol quercetin induces chloride secretion in rat intestine. To clarify the underlying mechanisms, experiments were performed in Ussing chambers with tissue from rat proximal and distal colon. Quercetin induced an increase in short-circuit current (Isc), which was largely independent of submucosal neurons, as it was not affected by the neurotoxin tetrodotoxin. The effect of quercetin was blocked by the calmodulin antagonists trifluoperazine and ophiobolin A and was diminished by a blocker of Ca2+ release from intracellular stores (TMB-8), whereas the muscarinic receptor antagonist atropine was ineffective. The quercetin-induced Isc was abolished in Ca2+ -free solution. The flavonol was able to further increase Isc after maximal stimulation of the cAMP pathway by forskolin. The Isc increase by the flavonol was differently affected by two analogous phosphodiesterase inhibitors. Whereas 3-isobutyl-1-methylxanthine (IBMX) antagonized the effect of quercetin, 8-methoxymethyl-IBMX had no effect. Both phosphodiesterase inhibitors similarly influenced the Isc increase induced by forskolin. These results indicate that the chloride secretion induced by quercetin in rat colon depends on Ca2+ and calmodulin. The cAMP pathway and inhibition of phosphodiesterase appear not to be responsible for the secretory activity of the flavonol. [source]


Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: Advances in the development of specific phosphodiesterase inhibitors

MEDICINAL RESEARCH REVIEWS, Issue 2 2005
Ana Castro
Abstract The activity of phosphodiesterases (PDEs) is associated with a wide variety of diseases and an intense effort toward the development of specific PDEs inhibitors has been generated for the last years. They are the enzymes responsible for the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate, and their complexity, as well as their different functional role, makes these enzymes a very attractive therapeutic target. This review is focused on the role of PDEs played on immunomodulatory processes and the advance on the development of specific inhibitors, covering PDEs mainly related to the regulation of autoimmune processes, PDE4 and PDE7. The review also highlights the novel structural classes of PDE4 and PDE7 inhibitors, and the therapeutic potential that combined PDE4/PDE7 inhibitors offer as immunomodulatory agents. 2004 Wiley Periodicals, Inc. Med Res Rev [source]


Enhancement of the anti-inflammatory and anti-arthritic effects of theophylline by a low dose of a nitric oxide donor or non-specific nitric oxide synthase inhibitor

BRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2009
Adel Gomaa
Background and purpose:, Although there are many new specific phosphodiesterase inhibitors with anti-inflammatory activity, none have yet reached the market because of their low therapeutic efficacy. Our study was aimed to evaluate the anti-inflammatory and anti-arthritic effect of an established phosphodiesterase inhibitor, theophylline, and to investigate the effect of the nitric oxide (NO) donor, sodium nitroprusside (SNP) or NO synthase inhibitor, L-NG -monomethyl arginine (L-NMMA) on its actions. Experimental approach:, The effects of theophylline alone and combined with SNP or L-NMMA on the pathogenesis of adjuvant-induced arthritis in rats were evaluated. Key results:, Prophylactic or therapeutic doses of theophylline significantly ameliorated the pathogenesis of adjuvant arthritis in rats as evidenced by a significant decrease in the arthritis index, hind paws volume, ankle joint diameter, fever, body weight loss and hyperalgesia in a dose-dependent manner. Inflammatory cellular infiltrate in synovium of ankle joint and pannus formation were also markedly inhibited. Interleukin-10 (IL-10) levels were significantly increased in arthritic rats given theophylline alone or in combination with either SNP or L-NMMA. Co-administration of a low dose of SNP or L-NMMA enhanced significantly the anti-inflammatory and anti-arthritic effect of theophylline. In contrast, a high dose of SNP counteracted the anti-inflammatory and anti-arthritic effects of theophylline. Conclusions and Implication:, These findings confirm the anti-inflammatory and anti-arthritic activities of theophylline and suggest a new approach to enhance the anti-inflammatory and anti-arthritic effects of theophylline would be to administer it in combination with a low dose of a NO donor or a non-specific NO synthase inhibitor. [source]


Modulation of tear film protein secretion with phosphodiesterase inhibitors

CLINICAL & EXPERIMENTAL OPHTHALMOLOGY, Issue 3 2000
Victoria Evans BOptom
ABSTRACT A double-blind randomized clinical study was conducted to determine whether nicardipine hydrochloride was a useful treatment for dry eye. We examined its effect on the tear film, ocular surface and ocular comfort. Nicardipine hydrochloride, 3-isobutyl-1-methylxanthine and pilocarpine hydrochloride were dissolved in an artificial tear vehicle and applied topically to one eye of 12 subjects on separate days. Ocular physiology, ocular comfort and tear volume were assessed. The trial was repeated with nicardipine in an aqueous gel vehicle. Tears were collected and assessed for protein concentration and protein profile, using electrophoresis and mass spectrometry. Nicardipine induced conjunctival redness and symptoms of dryness and irritation. There was no change in total tear protein concentration or volume. An increase in a 68 kDa protein was observed, this was probably due to conjunctival vessel dilation and leakage of albumin. The adverse symptomatology and increased conjunctival redness experienced with nicardipine make it an undesirable treatment for dry eye. [source]


Inotropes in the beta-blocker era

CLINICAL CARDIOLOGY, Issue S3 2000
B. D. Lowes M.D.
Abstract Beta-adrenergic blocking agents are now standard treatment for mild to moderate chronic heart failure (CHF). However, although many subjects improve on beta blockade, others do not, and some may even deteriorate. Even when subjects improve on beta blockade, they may subsequently decompensate and need acute treatment with a positive inotropic agent. In the presence of full beta blockade, a beta agonist such as dobutamine may have to be administered at very high (> 10 ,g/kg/min) doses to increase cardiac output, and these doses may increase afterload. In contrast, phosphodiesterase inhibitors (PDEIs) such as milrinone or enoximone retain their full hemodynamic effects in the face of beta blockade. This is because the site of PDEI action is beyond the beta-adrenergic receptor, and because beta blockade reverses receptor pathway desensitization changes, which are detrimental to PDEI response. Moreover, when the combination of a PDEI and a beta-blocking agent is administered long term in CHF, their respective efficacies are additive and their adverse effects subtractive. The PDEI is administered first to increase the tolerability of beta-blocker initiation by counteracting the myocardial depressant effect of adrenergic withdrawal. With this combination, the signature effects of beta blockade (a substantial decrease in heart rate and an increase in left ventricular ejection fraction) are observed, the hemodynamic support conferred by the PDEI appears to be sustained, and clinical results are promising. However, large-scale placebo-controlled studies with PDEIs and beta blockers are needed to confirm these results. [source]