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)

To define the vasorelaxation mechanism of FK409, we examined the effect of the compound on vascular tension and cyclic nucleotide levels in isolated rat thoracic aorta contracted with norepinephrine, and on activities of guanylate cyclase and cyclic GMP phosphodiesterase prepared from rat or rabbit thoracic aorta. FK409 (1 x 10(-9) to 1 x 10(-6) M), like nitroglycerin (1 x 10(-9) to 1 x 10(-6) M), produced a potent vasorelaxant effect associated with an increase in cyclic GMP content of the tissue. There was no change in cyclic AMP levels. The vasorelaxant effect of FK409 was independent of the integrity of the endothelium, and was unaffected by L-NG-monomethylarginine (0.1 mM) or oxyhemoglobin (1 microM). On the other hand, FK409 (3.2 x 10(-7) M) activated soluble guanylate cyclase, and the activating effect was completely inhibited by oxyhemoglobin (10 nM). Cyclic GMP phosphodiesterase was unaffected by FK409 (1 x 10(-7) to 1 x 10(-5) M). Furthermore, in rat aortic soluble fraction FK409 (3 mM) was found to liberate nitric oxide (NO) which was evaluated spectrophotometrically after diazotization of sulfanilic acid and coupling with N-(1-naphthyl)-ethylenediamine. The liberation occurred even in the absence of L-cysteine (5 mM), in contrast to the case with nitroglycerin (3 mM). These results suggest that the vasorelaxant effect of FK409 is associated with an increase in intracellular cyclic GMP, and that the cyclic GMP accumulation is due to activation of soluble guanylate cyclase. The enzyme activation is probably due to NO released from the compound molecule in the vascular smooth muscle cells.
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PMID:Vasorelaxant mechanism of the new vasodilator, FK409. 790 Oct 40

The purpose of this study was to examine and compare pulmonary vascular smooth muscle relaxation by clinically used agents as related to cGMP mediation (sodium nitroprusside, nitroglycerin) and cAMP mediation (isoproterenol, prostaglandin E1 (PGE1), and amrinone) in isolated rat pulmonary arterial rings. Isolated rat pulmonary arterial rings were suspended on a fine wire tensiometer in individual organ chambers. After confirming the endothelial integrity of the rings (response to acetylcholine), the rings were preconstricted with phenylephrine 10(-6) M. Dose-response curves for sodium nitroprusside, nitroglycerin, isoproterenol, amrinone, and PGE1 were then generated. Each of these agents was tested on six rings. Each ring was tested with each agent in a random order. The doses of sodium nitroprusside, isoproterenol, and nitroglycerin required to produce relaxation of isolated pulmonary arterial rings were not statistically different, but were significantly less than those required by amrinone and PGE1 (P < 0.05). These data suggest that relaxation of pulmonary vascular smooth muscle is more readily achieved via cGMP by guanylate cyclase activation (sodium nitroprusside, nitroglycerin) and via beta-adrenergic cAMP mediation (isoproterenol) than via cAMP-mediated pathways requiring either prostaglandin receptor activation (PGE1) or phosphodiesterase inhibition (amrinone).
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PMID:Pulmonary vascular smooth muscle relaxation by cGMP- versus cAMP-mediated mechanisms. 791 47

The objectives of this study were to determine the potency and selectivity of the structurally novel cyclic nucleotide phosphodiesterase (PDE) inhibitor, WIN 58237 (1-cyclopentyl-3-methyl-6-(4- pyridyl)pyrazolo[3,4-d]pyrimidin-4-(5H)-one), and to determine if this compound possesses cyclic GMP (cGMP) PDE inhibitory activity in vitro and in vivo. WIN 58237 is a competitive inhibitor of cGMP PDE V from canine aorta, with a Ki value of 170 nM. It is a relatively less potent inhibitor of calmodulin-sensitive PDE I and cGMP-inhibitable cyclic AMP PDE III; but does inhibit cyclic AMP PDE IV with an IC50 value of approximately 300 nM. In vitro, WIN 58237 is a functional cGMP PDE inhibitor at submicromolar concentrations as evident by potentiation of both sodium nitroprusside- and atrial natriuretic factor-mediated vasorelaxation of contracted, endothelial-denuded rat aortic rings. Moreover, WIN 58237 possesses vasorelaxant activity in the presence of an intact endothelium or nitric oxide. Similar results are evident in vivo, as WIN 58237 (0.3-3.0 mg/kg i.v.) decreases mean arterial pressure in conscious spontaneously hypertensive rats with an associated increase in vascular (aortic) cGMP content in vivo. Both the decrease in mean arterial blood pressure and increase in aortic cGMP content are attenuated by the nitric oxide synthase inhibitor, N omega-nitro-l-arginine. However, WIN 58237 may possess an additional depressor mechanism of action. WIN 58237 restores vasorelaxation responsiveness to nitroglycerin in vitro and in vivo in models of vascular tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic GMP potentiation by WIN 58237, a novel cyclic nucleotide phosphodiesterase inhibitor. 799 19

1. The relaxant responses of S-nitroso-L-cysteine (CysNO), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), S-nitroso-N-acetyl-L-cysteine (SNAC) and S-nitrosoglutathione (GSNO) in the rat gastric fundus (forestomach) were studied and compared to the relaxant responses obtained in response to nitric oxide (NO) and electrical field stimulation (EFS, 10 s strains) of non-adrenergic non-cholinergic (NANC) nerves. 2. CysNO (10(-7)-3 x 10(-4) M) caused transient relaxation of the precontracted rat gastric fundus, comparable to the response to NO (10(-6)-10(-4) M) and EFS. SNAP, SNAC and GSNO elicited more sustained relaxations. 3. The cyclic GMP-specific phosphodiesterase inhibitor, zaprinast (3 x 10(-5) M) increased the relaxant effect of CysNO, SNAP and GSNO while the NO-synthase inhibitor, NG-nitro-L-arginine (L-NOARG, 3 x 10(-4) M) had no influence. 4. In the presence of LY 83583 (10(-5) M), which releases superoxide anions, the relaxant response to NO and CysNO was decreased, whereas that to all other stimuli was unaltered. The inhibitory effect of LY 83583 on CsNO-induced relaxations was prevented by superoxide dismutase (SOD, 1000 u ml-1). 5. Tissues incubated for 1 h with 5.5 x 10(-4) M nitroglycerin (GTN) became tolerant to GTN. In this condition, the relaxant response to 10(-5) M NO was maintained, while the relaxations by EFS (8 Hz) and 3 x 10(-5) M SNAP were significantly decreased. The reduction of the response to the other S-nitrosothiols was not significant. 6. The combination of nitrate tolerance and 10-5 M LY 83583 caused a significantly larger inhibition of the relaxant response to EFS (8 Hz) than nitrate tolerance alone. The combination of LY 83583 and GTN tolerance reduced the relaxant effect of 10-5 M NO to a similar extent to LY 83583 alone, while the relaxant response to 10-4 M GTN was reduced to the same extent as after 1 h exposure to 5.5 x 10-4 M GTN alone.7. It is concluded that S-nitrosothiols potently relax the rat gastric fundus, possibly by a cyclic GMP-dependent mechanism and S-nitrosothiols such as SNAC and GSNO may be involved in NANC neurotransmission.
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PMID:Influence of S-nitrosothiols and nitrate tolerance in the rat gastric fundus. 803 15

The role of blood platelets in the pathogenesis of atherosclerosis, thrombosis, thromboembolism and stroke (hemorrhagic/thrombotic) is well established. In view of this recognized role played by platelets in the complications associated with coronary artery disease and cerebrovascular disease, there is considerable interest in the pharmacology of platelet activation inhibitory drugs. These drugs exert their effect by blocking several different activation signalling mechanisms. Some of the known compounds that modulate platelet function include: inhibitors of arachidonic acid metabolism (nonsteroidal anti-inflammatory drugs and thromboxane synthetase inhibitors), drugs that alter membrane phospholipid composition (omega 3 fatty acids), stimulators of adenylyl cyclase and guanylyl cyclase (PGE1, PGI2, PGD2/ERRF [nitric oxide], nitroglycerin, nitroprusside), phosphodiesterase inhibitors (dipyridamole and methylxanthines) and calcium antagonists (verapamil, nifedipine, diltiazem). Current research on the pharmacology of platelet activation inhibitory drugs is focused on the development of specific receptor antagonists (antibodies, peptides, receptor antagonists). Since platelets have multiple mechanisms for achieving activation, and the process of thrombosis involves multicellular modulation of platelet activity, it will be rather difficult to develop a compound that is capable of causing complete inhibition of activation mechanisms. Therefore, future research will be devoted to development of designer drugs that will be used for preventing discrete platelet responses. This approach may be useful as total inhibition of platelet activation, although it may prevent thrombotic events, may possibly precipitate hemorrhagic conditions. A better understanding of cell signalling pathways and the mechanisms involved in the pathogenesis of cardiovascular cerebrovascular disease will facilitate the development of efficient antiplatelet drugs.
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PMID:Pharmacology of platelet activation-inhibitory drugs. 806 66

In rat aorta, KT2-734 inhibited contractile responses to 5-hydroxytryptamine (5-HT) and KCl. KT2-734 inhibited the relaxing effect of verapamil, but not nifedipine. Similarly, verapamil, but not nifedipine, inhibited the vasorelaxing effect of KT2-734. KT2-734 relaxation was inhibited by endothelium removal but not by atropine and propranolol. Methylene blue, a guanylyl cyclase inhibitor, and NG-monomethyl arginine also inhibited the relaxation both in the presence and absence of endothelium. In the absence of endothelium, KT2-734 potentiated the relaxation induced by L-arginine, nitroglycerin and isoproterenol. In addition, M & B 22,948, a cGMP phosphodiesterase inhibitor, and theophylline inhibited and potentiated, respectively, KT2-734-induced relaxation. However, methylene blue inhibited the potentiation of isoproterenol relaxation by KT2-734 and that of KT2-734-relaxation by theophylline. KT2-734 caused increases in the level of cGMP without significantly affecting the cAMP level. These results suggest that KT2-734 may cause endothelium-independent relaxation mainly due to inhibition of cGMP-phosphodiesterase.
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PMID:Vasoinhibitory action of KT2-734, an antihypertensive agent, in isolated rat aorta. 813 65

Rat calcitonin gene-related peptide (rCGRP) causes endothelium-dependent vasorelaxations via a dual signal transduction mechanism involving elevations of both cyclic AMP and cyclic GMP levels in rat aorta. These responses are all dependent on de novo synthesis of nitric oxide (NO) in endothelial cells and appear to involve a mechanistic link between cyclic GMP and cyclic AMP responses in smooth muscle cells. The present study determined whether NO from an exogenous source (i.e. added nitroglycerin) could substitute for endogenous NO in rCGRP-induced responses in endothelium-denuded aorta. Nitroglycerin (1 microM) significantly elevated cyclic GMP levels by 20-fold and 3.3-fold and cyclic AMP levels by 26% and 22% at 1 and 2 min, respectively. By itself, rCGRP (100 nM) did not significantly elevate cyclic AMP levels. In combination, however, nitroglycerin and rCGRP caused more-than-additive cyclic AMP elevations (41% above basal at 1 and 2 min). Nitroglycerin also potentiated rCGRP-induced vasorelaxations in endothelium-denuded rings, thus uncovering a direct (endothelium-independent) relaxant effect of rCGRP in rat aorta. The data indicate that exogenous NO can substitute for endogenous NO in rCGRP-induced relaxant and cyclic AMP responses in aorta. This nitroglycerin-induced potentiation of CGRP effects likely involves inhibition of cyclic-GMP-inhibited-phosphodiesterase in smooth muscle cells, thus allowing cyclic AMP to accumulate and mediate the direct vasodilator effects of rCGRP.
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PMID:Nitroglycerin (exogenous nitric oxide) substitutes for endothelium-derived nitric oxide in potentiating vasorelaxations and cyclic AMP elevations induced by calcitonin gene-related peptide (CGRP) in rat aorta. 817 May 22

Following in vitro exposure of rat aortic rings to 550 microM nitroglycerin for 1 h, tolerance was demonstrated by a significant increase in EC50 values for nitroglycerin-induced relaxation. However, cross-tolerance to sodium nitroprusside was not observed. Co-incubation of aortic rings with the cGMP-phosphodiesterase (cGMP-PDE) inhibitor zaprinast (10 microM), during incubation with 550 microM nitroglycerin, did not prevent the development of tolerance. However, the addition of 0.30 or 10 microM zaprinast to tolerant aortic rings did restore responsiveness to nitroglycerin. The increase in cGMP in tolerant aortic rings in response to 300 nM nitroglycerin (2-4 fmol/micrograms) was significantly less than that observed for non-tolerant rings (6.6-12 fmol/micrograms), but cGMP levels were restored in tolerant rings by zaprinast (7-12 fmol/micrograms). These data suggest that inhibition of vascular cGMP-PDE activity does not prevent the development of tolerance in vitro, but does reverse the loss of vasorelaxant potency to nitroglycerin via restoration of intracellular cGMP levels.
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PMID:Reversal of nitroglycerin tolerance in vitro by the cGMP-phosphodiesterase inhibitor zaprinast. 827 63

The purpose of this study was to determine whether cross-tolerance develops between nitroglycerin and endothelium-derived relaxing factor (EDRF)-mediated vasoactive agents in vivo. Spontaneously hypertensive rats (SHR) were made tolerant by pretreatment with high doses of nitroglycerin (100 mg/kg s.c., 3 times/day, for 3 consecutive days). The hypotensive effect of challenge doses of nitroglycerin (1, 10, 300, 100 micrograms/kg i.v.) was completely abolished in nitroglycerin-pretreated SHR. To evaluate cross-tolerance, the effects of the following EDRF-dependent vasoactive agents on blood pressure were determined in groups of nitroglycerin-pretreated and vehicle-pretreated SHR: acetylcholine, bradykinin and L-arginine. In addition, the hypotensive effects of zaprinast (M & B 22,928), a cyclic guanosine monophosphate (cGMP) phosphodiesterase inhibitor, and the hypertensive effects of the nitric oxide-synthase inhibitor N omega-nitro-L-arginine were also evaluated. In all cases, there was no difference in the effects of these agents on blood pressure when compared in nitroglycerin-pretreated (tolerant) and vehicle-pretreated (non-tolerant) SHR. The use of a variety of agents which modulate EDRF release or its effects by several different mechanisms suggests that cross-tolerance does not occur between nitroglycerin and EDRF in vivo.
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PMID:Lack of cross-tolerance between nitroglycerin and endothelium-derived relaxing factor-mediated vasoactive agents in spontaneously hypertensive rats. 838 94

1. In isolated rat aortic rings, leminoprazole (2-[2-N-methyl-N-(2-methylpropyl)amino]benzylsulfinyl benzimidazole) (10(-6) - 10(-4) M) inhibited contractile responses to phenylephrine (PE), KCl and Ca2+ in KCl-depolarized tissues in a Ca2+ free medium. Leminoprazole also relaxed the aorta contracted by PE and KCl. 2. The relaxing effect of leminoprazole was markedly inhibited by nifedipine and verapamil (inhibitors of voltage operated Ca2+ channels). Relaxation induced by verapamil, but not by nifedipine, was inhibited by pre-treatment by leminoprazole. 3. The relaxing effect of leminoprazole was also inhibited by NG-monomethyl-L-arginine (a nitric oxide synthase inhibitor), methylene blue (a guanylate cyclase inhibitor) or endothelium removal but not by indomethacin (a cyclooxygenase inhibitor), glyburide (a KATP channel inhibitor) or iberiotoxin (a KCa channel inhibitor). 4. Zaprinast (a cGMP-phosphodiesterase inhibitor) also inhibited the relaxing action of leminoprazole. In addition, relaxation induced by nitroglycerin was potentiated by leminoprazole. 5. Further, in the presence of methylene blue, residual relaxation induced by leminoprazole was still potentiated by verapamil. 6. These results suggest that the vasoinhibitory effect of leminoprazole in rat aortic rings is due to the increased level of cGMP through inhibition of cGMP-phosphodiesterase and also due to inhibition of voltage operated Ca2+ channels.
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PMID:Vasoinhibitory effect of leminoprazole, a H+,K(+)-ATPase inhibitor, on rat aortic rings. 874 7


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