Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GR32191, a potent selective thromboxane receptor antagonist, has been shown to inhibit completely prostaglandin endoperoxide and thromboxane A2 (TxA2)-induced platelet aggregation, [14C]-serotonin secretion and beta-thromboglobulin secretion. Deposition of human platelets onto damaged rabbit aorta in vitro is reduced in the presence of GR32191 which appears to inhibit aggregation of platelets but not direct adhesion of platelets to subendothelium. The effects of non-prostanoid platelet activating agents whose mode of action requires the biosynthesis of TxA2 are also inhibited by GR32191. Prostanoids which inhibit platelet function, such as prostacyclin or PGD2, retain their inhibitory properties in the presence of GR32191 which does not inhibit phospholipase A2, prostaglandin cyclooxygenase, thromboxane synthase, 12-lipoxygenase or cAMP phosphodiesterase activity. The inhibitory action of GR32191 on platelet aggregation, mural thrombus formation and platelet protein storage granule secretion suggests that it has potential in treating thrombotic disease in man.
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PMID:The inhibitory effect of GR32191, a thromboxane receptor blocking drug, on human platelet aggregation, adhesion and secretion. 252 61

This study was designed to determine the in vivo effects of a phosphodiesterase inhibitor (HL 725) in combination with a thromboxane synthase inhibitor (CGS 13080) or prostacyclin (PGI2) as inhibitors of thrombin-induced changes in platelet function and prevention of sudden death. In anesthetized rabbits, the i.v. administration of thrombin reduced the circulating number of platelets from 256,000 +/- 32,000/microliter to 8 +/- 2% of the initial value, and produced a right ventricular thrombus of 285 +/- 52 mg. All animals died within 5 min. PGI2 (0.3 microgram/kg/min) or HL 725 (2 micrograms/kg/min) did not prevent the thrombin-induced fall in the number of circulating platelets, the formation of a right ventricular thrombus or death. Administration of 2 mg/kg of CGS 13080 reduced significantly the mass of the right ventricular thrombus, but did not prevent completely the reduction in the circulating platelet count or death. After the administration of the combination of CGS 13080 with HL 725, the thrombocytopenia was transient, the right ventricular thrombus was reduced (P less than .05), and survival increased to 75% (P less than .05). The combination of PGI2 with HL 725 was similar in benefit to the combination of CGS 13080 and HL 725. Survival for the group of the combination of CGS 13080 with 725 was significantly greater than survival in the CGS 13080 or HL 725 groups, indicating a synergistic effect for the combination. The decrease in blood pressure response to HL 725 was greater with PGI2, but not with CGS 13080.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of the effects of a thromboxane synthase inhibitor or prostacyclin in combination with a phosphodiesterase inhibitor for prevention of experimental thrombosis and sudden death in rabbits. 329 21

Ridogrel, a combined thromboxane receptor antagonist and thromboxane synthase inhibitor (1), inhibits platelet aggregation. Following stimulation with arachidonic acid, cAMP-levels are increased in human platelets preincubated with ridogrel, this is due to the known reorientation of the metabolism of the formed endoperoxides towards adenylate cyclase stimulating prostaglandins. Pretreatment of resting platelets with UDCG-212, a cAMP-phosphodiesterase inhibitor (2), also inhibits platele aggregation induced by arachidonic acid, concomitant with an increase in cAMP levels, due to an inhibition of its breakdown. Under basal conditions, cAMP also is increased. By combining the two drugs, a more than additive action was observed on platelet aggregation and on both resting and stimulated platelet cAMP content. The appropriate combination may result in a more effective antiplatelet strategy.
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PMID:Synergistic antiplatelet effect of ridogrel, a combined thromboxane receptor antagonist and thromboxane synthase inhibitor, and UDCG-212, a cAMP-phosphodiesterase inhibitor. 812 41

The antiplatelet effect of the pyridazinone analogue, 4, 5-dihydro-6-[4-[2-hydroxy-3-(3,4 dimethoxybenzylamino)propoxy]naphth-1-yl]-3(2H)-pyridazinone (HCL-31D), was investigated in vitro with rabbit platelets. HCL-31D dose-dependently inhibited the platelet aggregation and ATP release induced by collagen (10 microg/ml), arachidonic acid (100 microM) or thrombin (0.1 U/ml) with an IC(50) of about 0.95-5.41 microM. HCL-31D (0.5-5 microM) increased the platelet cyclic AMP level in a dose-dependent manner. Furthermore, HCL-31D potentiated cyclic AMP formation caused by prostaglandin E(1) but not that caused by 3-isobutyl-1-methylxanthine (IBMX). HCL-31D also attenuated phosphoinositide breakdown and intracellular Ca(2+) elevation induced by collagen, arachidonic acid or thrombin. HCL-31D inhibited the formation of thromboxane B(2) induced by collagen or thrombin but not by arachidonic acid. In addition, HCL-31D did not affect platelet cylooxygenase and thromboxane synthase activity. These data indicate that HCL-31D is an inhibitor of phosphodiesterase and that its antiplatelet effect is mainly mediated by elevation of cyclic AMP levels.
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PMID:Mechanism of inhibition of platelet aggregation by HCL-31D. 1065 Jan 52

The antiplatelet effect of a new synthetic compound, 8,9-dimethoxyl-1-(4-methoxy-phenyl)-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-2,3-dione (KW-7), was determined in rabbit platelets. KW-7 concentration-dependently prevented platelet aggregation caused by arachidonic acid, collagen, platelet-activating factor, and thrombin. KW-7 induced a substantial increase in cyclic AMP levels and a smaller increase in cyclic GMP levels in platelets. In platelet homogenates, KW-7 inhibited both cyclic AMP- and cyclic GMP-phosphodiesterase activities. The antiplatelet effect of KW-7 was reversed by SQ22536 (an inhibitor of adenylate cyclase) and H89 (an inhibitor of protein kinase A) but not by ODQ (an inhibitor of soluble guanylate cyclase). These data suggest that the antiplatelet effect of KW-7 is cyclic AMP-dependent, and is through inhibition of platelet phosphodiesterases. In addition, KW-7 inhibited arachidonic acid-stimulated thromboxane production; this effect was associated with an increase in prostaglandin D(2) levels indicating KW-7 is also an inhibitor of thromboxane synthase. The dual inhibition of KW-7 on phosphodiesterase and thromboxane synthase might provide an attractive target in developing antiplatelet drugs.
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PMID:Antiplatelet effects of KW-7, a new inhibitor of cyclic nucleotide phosphodiesterases. 1472 6

Vascular tone is tightly regulated by endothelium-derived factors. These include relaxing factors (EDRFs) such as nitric oxide (NO), hyperpolarizing factors (EDHFs), and contracting factors (EDCFs). Although EDHF is a prominent vasodilator, particularly in smaller arteries, little attention has been paid to the potential role of EDHF responses in diabetes. EDHF signaling may involve various factors, including several diffusible factors and non-diffusible factors (e.g., gap junctions). It has been demonstrated that the alterations in EDHF relaxation seen in mesenteric arteries from diabetic rats may be attributable to an increase in phosphodiesterase 3 (PDE3) activity, leading to a reduction in the action of adenosine 3',5'-cyclic monophosphate (cAMP), and consequently the activity of protein kinase A (PKA) is decreased in such arteries. Moreover, it has been suggested that the imbalance between EDRFs and EDCFs is present in mesenteric arteries from type 2 diabetic rats and the EDHF relaxation can be partly reversed by suppression of EDCF signaling. Indeed, chronic treatment with metformin, eicosapentaenoic acid, or thromboxane synthase inhibitor can reduce EDCF signaling and normalize EDHF signaling in mesenteric arteries from type 2 diabetic rats. Although the improvement or restoration of EDHF responses has not been the direct subject of any pharmaceutical effort, increasing cAMP/PKA signaling (e.g., by inhibiting PDE3 activity) or reducing EDCFs signaling has potential as an interesting therapeutic target in diabetic vasculopathy.
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PMID:[Therapeutic target for endothelium-derived hyperpolarizing factor signaling in diabetic vascular complication]. 2051 55