Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) donors are believed to exert their vasodilatory action through the activation of soluble guanylate cyclase (sGC), the heme site of which can be specifically inhibited by 1H-[1,2, 4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). We examined the vascular relaxation of the rat aorta mediated by eight different NO donors in the presence of ODQ (0.1, 1, or 10 microM), and demonstrated that these NO donors displayed different sensitivities toward ODQ inhibition (ANOVA, P <.05). Among the NO donors studied, S-nitrosothiols such as S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione exhibited partial resistance toward ODQ inhibition at 0.1 microM ODQ, whereas nitroglycerin (NTG) showed nearly complete inhibition at this concentration of ODQ. Three NO donors representing increasing sensitivity toward ODQ inhibition, SNAP < sodium nitroprusside (SNP) < NTG, were chosen for additional mechanistic studies. ODQ (1 microM) inhibition of vascular relaxation by SNAP and SNP, but not that by NTG, was partially reversed by a sulfhydryl donor, N-acetylpenicillamine (100 microM), and by a phosphodiesterase inhibitor, zaprinast (10 microM), specific for cGMP. Our results strongly indicate that the vascular relaxation mechanism(s) of NO donors is not identical for each. In the rat aorta, NTG appeared to exhibit its vasodilatory effect exclusively through activation of the heme site of sGC. On the other hand, in the intact vascular tissue, SNAP and SNP could bring about vasodilation through a secondary pathway. These results are consistent with the view that SNAP and SNP, but not NTG, can induce vascular relaxation additionally through the activation of the sulfhydryl site of sGC.
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PMID:Differential sensitivity among nitric oxide donors toward ODQ-mediated inhibition of vascular relaxation. 1064 Mar 13

Nitric oxide (NO) donors including organic nitrates dilate capacitance vessels. As inhibition of phosphodiesterase type 5 results in the accumulation of guanosine 3'5'-cyclic monophosphate (cGMP), specific phosphodiesterase type 5 inhibitors are expected to have a vasodilator property similar to that of NO donors. To test this hypothesis, we examined the effect of methyl2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032), a novel specific phosphodiesterase type 5 inhibitor, on mean arterial pressure and mean circulatory filling pressure (an index of venodilation) compared with that of nitroglycerin and diltiazem in mecamylamine- and noradrenaline-treated anesthetized rats. Intravenous infusion of T-1032 (0.1, 1, 10 microg/kg/min) dose-dependently decreased mean arterial pressure (-3.8+/-0.3%, -9.1+/-0.8%, -16.8+/-1.5% at doses of 0.1, 1 and 10 microg/kg/min, respectively) and mean circulatory filling pressure (-6.1+/-0.9%, -12.5+/-0.7%, -18.6+/-3.0% at doses of 0.1, 1 and 10 microg/kg/min, respectively). The mean circulatory filling pressure-mean arterial pressure relationship revealed that T-1032 had a selective action on the mean circulatory filling pressure compared with diltiazem (10, 100 microg/kg/min) and a similar or more selective effect than nitroglycerin (0.3, 3 and 30 microg/kg/min). In the next study, we calculated venous compliance and unstressed volume from the mean circulatory filling pressure-volume relationship. Intravenous infusion of T-1032 (3 microg/kg/min) increased venous compliance (3.35+/-0.40 in T-1032 vs. 2.31+/-0.15 ml/kg/mm Hg in vehicle, P<0.05) without changing the unstressed volume (37.2+/-2.80 in T-1032 vs. 42.6+/-2.37 ml/kg in vehicle, P>0.05). It was concluded that T-1032 increased venous capacitance by increasing venous compliance, and that this selective phosphodiesterase type 5 inhibitor appeared to have a different vasodilator action from that of an NO donor and a Ca(2+) channel antagonist in that it had a selective action on the mean circulatory filling pressure.
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PMID:T-1032, a novel specific phosphodiesterase type 5 inhibitor, increases venous compliance in anesthetized rats. 1143 Sep 21

The effects of KF31327 (3-ethyl-8-[2-(4-hydroxymethylpiperidino)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thione dihydrochloride) on phosphodiesterase 5 (cyclic GMP-specific phosphodiesterase) activity and platelet aggregation were investigated and compared with those of sildenafil, a well-known phosphodiesterase 5 inhibitor. KF31327 inhibited phosphodiesterase 5 from canine trachea (K(i)=0.16 nM) more potently than sildenafil (K(i)=7.2 nM). The kinetic analysis revealed that KF31327 was a non-competitive inhibitor. In the presence of nitroglycerin (nitric oxide generator), both compounds inhibited the collagen-induced aggregation of rabbit platelets at less than 0.1 microM, augmenting intracellular cyclic GMP level without affecting cyclic AMP. In contrast, in the absence of nitroglycerin, a higher concentration (10 microM) of KF31327 was required to inhibit platelet aggregation and increased both cyclic nucleotide levels. However, 10 microM sildenafil did not affect aggregation despite elevation of cyclic GMP comparable to that in the presence of nitroglycerin. These results indicate that in the presence of nitroglycerin, the inhibition of platelet aggregation by KF31327 is due to the elevation of cyclic GMP, whereas the mechanism underlying the inhibition without nitroglycerin might be related to a rise in intracellular cyclic AMP.
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PMID:KF31327, a new potent and selective inhibitor of cyclic nucleotide phosphodiesterase 5. 1171 38

We examined the contribution of K+ channels to the relaxation responses induced by different redox forms of nitric oxide (NO., NO- and NO+) in comparison with those evoked by electrical field stimulation (EFS) of nitrergic nerves in the sheep urethra. K+ channel blockers with different selectivity profile were used. Sodium nitroprusside (SNP) and different S-nitrosothiols were used as NO+ donors, Angeli's salt as an NO- donor and nitroglycerin (GTN) was chosen as a representative compound known to require metabolic activation in the target tissue. Pure NO gas was used to prepare NO. solutions. Relaxation evoked by EFS of nitrergic nerves or by exogenous NO was not inhibited by any of the K+ channel blockers, but was enhanced by 4-aminopyridine [inhibitor of voltage-dependent K+ (KV) channels]. This suggests that, whereas K+ channel activation and hyperpolarization of the postsynaptic membrane do not contribute to relaxation, prejunctional modulation of the nitrergic neurotransmission by Kv channels may be relevant. Relaxation induced by NO+ or NO- donors was not affected by K+ channel blockade with the following exceptions: glybenclamide, a blocker of ATP-sensitive K+ channels (KATP), enhanced responses to SNP and Angeli's salt, 4-aminopyridine inhibited relaxation evoked by Angeli's salt and GTN, and charybdotoxin, a blocker of large-conductance, Ca2+-activated K+ channels (BKCa) inhibited those induced by the S-nitrosothiol S-nitrosoglutathione. These results do not suggest the existence of a general mechanism of action on K+ channels for compounds releasing either NO+ or NO- in the sheep urethra. None of the K+ channel blockers affected relaxation induced by the membrane-permeable analogue of cGMP, 8-bromo-cGMP. However, the fact that the addition of the phosphodiesterase inhibitor zaprinast (0.1 mM) enhanced the relaxation to Angeli's salt, while preventing the inhibition induced by 4-aminopyridine, suggests that involvement of guanylate cyclase activation in the action of NO donors on K+ channels can not be excluded. Accordingly, the guanylate cyclase inhibitors 1H-[1,2,4]-oxadiazole-[4,3-a]-quinoxalin-1-one (ODQ, 10 microM) and 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one (NS 2028, 10 microM) almost abolished relaxations to EFS and Angeli's salt. In contrast, ODQ only moderately inhibited relaxations to NO.. In addition, the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl imidazoline-1-oxyl 3-oxide (carboxy-PTIO) effectively inhibited responses to NO. whilst not affecting those to EFS or NO-, suggesting a close similarity between the nitrergic transmitter and nitroxyl ion. We conclude that nitrergic relaxation induced either by the endogenous transmitter or by exogenous NO donors in the ovine urethra is not mediated by postsynaptic alterations in the K+ conductance; only a prejunctional modulation through Kv channels seems to be significant. In addition, the production and/or release of alternative redox forms of NO, such as NO-, may be involved in neurotransmission processes in the urethra.
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PMID:Nitrergic relaxation in urethral smooth muscle: involvement of potassium channels and alternative redox forms of NO. 1177 6

The effects of nitroglycerin (NG) on the L-type Ca2+ current (ICa,L) were investigated in guinea-pig ventricular myocytes. NG did not affect the basal ICa,L significantly. The ICa,L was increased by NG when the ICa,L was augmented by the pre-treatment with isoproterenol (Iso), and this increase was abolished by the pretreatment with methylene blue (MB), a guanylate cyclase inhibitor. NG also increased ICa,L in the myocytes undergoing the pretreatment with isobutylmethylxanthine (IBMX). The NG-induced increase in ICa,L was also observed in the myocytes intracellularly dialyzed with cyclic adenosine monophosphate (cAMP). The order of the Iso-induced increase in ICa,L was Iso, IBMX and cAMP. Relatively a lower concentration of the extracellularly applied 8bromo-cyclic guanosine monophosphate (8Br-cGMP) increased ICa,L in the myocytes dialyzed with cAMP, whereas the higher concentration of 8Br-cGMP decreased ICa,L. NG produced a marked increase in cGMP levels, and a slight increase in cAMP levels in the ventricular tissues. These results suggest that the stimulatory effect of NG on the ICa,L is due to an inhibition of cGMP-inhibitable cAMP-phosphodiesterase (PDE) and a possible activation of cGMP-dependent protein kinase via the NG-induced increase in cGMP levels in guinea-pig ventricular myocytes.
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PMID:Cyclic AMP-mediated increase in L-type calcium current (ICa,L) by nitroglycerin in guinea-pig ventricular myocytes. 1199 Apr 53

Sildenafil inhibits cGMP breakdown by phosphodiesterase 5. In vitro, increased cGMP levels inhibit cAMP breakdown by phosphodiesterase 3. It is uncertain, however, whether sildenafil increases biological effects of interventions increasing cAMP levels in vivo. The objective of the present study in 40 healthy male volunteers was to determine the existence and extent of interactions with sildenafil and vasodilators acting via cGMP or cAMP or independently from these mediators on the arterial tone of the human forearm. Forearm blood flow (FBF) responses (plethysmography) to brachial artery infusions of 3 doses each of nitroglycerin, which increases cGMP levels; of isoprenaline and milrinone, which increase cAMP levels; and of verapamil as a control were assessed at baseline and 80 minutes after 50 mg oral sildenafil in 10 volunteers each. Sildenafil increased FBF (2.5+/-0.1 to 3.5+/-0.2 mL/min per 100 mL, P<0.001; n=40). At equipotent vasodilator dosages, sildenafil increased FBF from 7.5+/-1.0 to 9.8+/-1.2 mL/min per 100 mL for nitroglycerin, from 8.3+/-1.0 to 10.4+/-1.4 mL/min per 100 mL for isoprenaline, and from 8.1+/-1.0 to 10.3+/-1.2 mL/min per 100 mL for milrinone and slightly decreased FBF from 7.7+/-1.3 to 7.1+/-1.2 mL/min per 100 mL for verapamil. ANOVA for repeated measures revealed a significant interaction between sildenafil and the type of vasodilator on FBF (P<0.01). The responses of FBF to nitroglycerin, milrinone, and isoprenaline after sildenafil were similarly increased compared with the response to verapamil (P<0.01). Sildenafil markedly enhanced the arterial vasodilator response to nitroglycerin, milrinone, and isoprenaline. The response to milrinone and isoprenaline is compatible with an interaction between cGMP and phosphodiesterase 3 or an enhancement of the NO component of cAMP-mediated vasodilation, and raises the possibility of enhanced biological effects of interventions leading to increases of cAMP in the presence of sildenafil.
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PMID:Interaction of sildenafil with cAMP-mediated vasodilation in vivo. 1262 68

We examined the hemodynamic property of T-1032 (methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridylmethoxy)-4-(3,4,5-trimethoxy-phenyl)-3-isoquinoline carboxylate sulfate), a novel selective phosphodiesterase type 5 (PDE5) inhibitor, and evaluated the chronic effect of T-1032 on cardiac remodeling and its related death in monocrotaline (MCT)-induced pulmonary hypertensive rats. T-1032 (1, 10, 100 micro g/kg, i.v.) significantly reduced mean arterial pressure (MAP) and right ventricular systolic pressure (RVSP) without a change in heart rate. The change in RVSP was more potent than that in MAP with 1 micro g/kg T-1032 treatment (RVSP: -8.2+/-1.2%, mean arterial pressure: -5.7+/-1.2%), and reductions in RVSP and MAP reached a peak at doses of 1 and 10 micro g/kg, respectively. In contrast, nitroglycerin (0.1, 1, 10 micro g/kg, i.v.) and beraprost (0.1, 1 micro g/kg, i.v.) did not cause a selective reduction in RVSP at any dose. When T-1032 (300 ppm in diet) was chronically administered, it delayed the death, and significantly suppressed right ventricular remodeling (T-1032-treated: 0.318+/-0.021 g, control: 0.401+/-0.013 g, p<0.05). Our present results suggest that T-1032 selectively reduces RVSP, and resulting in the suppression of right ventricular remodeling with a delay of the death in MCT-induced pulmonary hypertensive rats.
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PMID:Acute and chronic effects of T-1032, a novel selective phosphodiesterase type 5 inhibitor, on monocrotaline-induced pulmonary hypertension in rats. 1241 52

To examine the hypothesis that maturation modulates nitric oxide (NO)-induced relaxation in cerebral arteries, we quantified concentration-relaxation relations and the corresponding dynamic responses of guanosine 3':5'-cyclic monophosphate (cGMP) and adenosine 3':5'-cyclic monophosphate (cAMP) levels following administration of nitroglycerin and S-nitroso-N-acetyl-penicilamine (SNAP), an NO donor, in posterior communicating and middle cerebral arteries from newborn (3-7 days) and adult sheep. The results offer 5 main observations: (1) the efficacy and potency of NO donors were generally greater in newborn than in adult cerebral arteries; (2) rates of relaxation, and presumably rates of NO release, were faster for equimolar concentrations of SNAP than for nitroglycerin in both newborn and adult arteries; (3) basal concentrations were greater for cAMP than for cGMP, and both were greater in newborn than adult cerebral arteries; (4) in adult cerebral arteries, NO-induced increases in cGMP occurred faster but relaxation developed more slowly than in newborn cerebral arteries, and (5) responses to NO donors involved significant cross-reactivity between cGMP and cAMP, the characteristics of which were age, artery, and agent specific. From these results, we conclude that postnatal changes in reactivity to NO reflect corresponding changes in soluble guanylate cyclase activity and possible decreases in NO half-life. We also conclude that maturation slows the mechanisms mediating NO-induced relaxation, and that this effect is more pronounced in distal than in proximal cerebral arteries. The data also suggest that the rate-limiting step governing rates of response to NO is probably downstream from cGMP synthesis. From the basal cyclic nucleotide levels, we conclude that basal ratios of synthesis to hydrolysis were greater in fetal than adult arteries. Because NO increased both cGMP and cAMP, we speculate that Type III phosphodiesterase has a possible influence upon cerebrovascular responses to NO, and that this influence varies with postnatal age and artery type. Together, these findings emphasize that the cerebrovascular effects of NO are highly age dependent and artery specific, and should be carefully considered when administering NO therapeutically in the neonate.
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PMID:Maturation alters cyclic nucleotide and relaxation responses to nitric oxide donors in ovine cerebral arteries. 1257 57

Human BNP serves to compensate for deteriorating cardiac function causing preload and afterload reductions, natriuresis, diuresis, suppression of the renin-angiotensin-aldosterone system (RAAS) and endothelin-1, and lowering of norepinephrine. Based on its unique pharmacologic profile, nesiritide results in clinically significant balanced vasodilation of arteries and veins, and may be well suited for patients presenting with various scenarios of decompensated CHF usually due to volume overload (NYHA classes II-IV). More than 1000 subjects have participated in clinical trials with nesiritide and more than 55,000 patients have been treated with nesiritide since it was approved for use in August 2001. Unlike nitroglycerin, tachyphylaxis did not appear to occur with Natrecor. The complete efficacy profile of nesiritide included preload reduction (PCWP and RAP), reductions in pulmonary artery pressures, afterload reduction (systemic vascular resistance), and increases in cardiac index and stroke volume index (which are dose-dependent and not the result of a direct inotropic effect), without increasing heart rate. Unlike inotropes, the beneficial hemodynamic effects produced by nesiritide do not cause an increase in myocardial oxygen consumption (MVO(2)), an important consideration for patients with acutely decompensated heart failure. Because Nesiritide is not an inotrope, it does not affect myocardial contractility, as does a beta-adrenergic receptor agonist, or a phosphodiesterase III inhibitor. As a result, nesiritide is not arrhythmogenic. Nesiritide should be considered for patients presenting with acutely typical or useful decompensated heart failure, especially those with dyspnea at rest or with minimal activity.
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PMID:Nesiritide: a new therapy for the treatment of heart failure. 1266 89

The standard treatment for acute heart failure (synonymous with pulmonary edema) is an upright posture, oxygen, morphine (often accompanied by an antiemetic), and intravenous diuretics. This treatment has remained unchanged for many years, and the precise mechanism by which each of these methods alleviates symptoms in patients is unclear. Nitrates, oral or intravenous, are also used with benefit, and have some hemodynamic advantages over intravenous diuretics. Recently, three new forms of treatment have been investigated. The use of milrinone, a phosphodiesterase inhibitor, for exacerbation of heart failure in patients with a background of chronic heart failure was not advantageous. The trials of levosimendan, a calcium sensitizer, in patients with pulmonary edema hinted at benefit. Nesiritide, a formulation of brain natriuretic peptide, does bring about hemodynamic improvement in acute heart failure, and is at least as effective as nitroglycerin, easier to prescribe, but prone to cause hypotension. These are small but important advances that increase our knowledge of the pathophysiology of acute heart failure, and also provide an indication of which drugs are preferable for the treatment of this distressing condition.
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PMID:New therapies for the management of acute heart failure. 1269 42


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