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

---

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

This study investigated the influence of NO, potassium (K+) channel blockade, and the phosphodiesterase inhibitors (PDEIs) theophylline (non-selective PDEI), siguazodan (PDE3I), rolipram (PDE4I), and zaprinast (PDE5I) on rat isolated main pulmonary artery hypoxic (95% N2 and 5% CO2) vasoconstriction. Hypoxic vasoconstriction increased by 27% (p < 0.01) in the presence of the NO synthase inhibitor L-NAME (10(-4) M), and by 15% (p < 0.05) in the presence of the K(ATP) channel blocker glibenclamide (10(-6) M), without potentiation by the combination of these two drugs. Hypoxic vasoconstriction decreased by 28% (p < 0.01) in presence of the Kv,-voltage-dependent channel blocker 4-aminopyridine (10(-3) M), whereas the other K+ channel blockers, charybdotoxin (BKCa, large-conductance Ca2+-sensitive K+ channels) and apamin (SKCa, small-conductance Ca2+-sensitive K+ channels) had no effect. The nonselective PDEI theophylline induced a concentration-dependent relaxation (pD2 = 4.05, Emax = 90% [expressed as a percentage of maximal relaxation induced by papaverine 10(-4) M]). Among the selective PDEIs, siguazodan was significantly (p < 0.01) more efficient than rolipram and zaprinast (Emax values were 84%, 67%, and 58%, respectively) and significantly (p < 0.05) more potent than zaprinast (pD2 values were 6.48, 6.34, and 6.16 for siguazodan, rolipram, and zaprinast). Glibenclamide and L-NAME significantly (p < 0.05) shifted the concentration-response curve (CRC) for zaprinast to the right, and L-NAME shifted the CRC significantly to the right for siguazodan. In the presence of L-NAME, glibenclamide had no effect on the CRC of zaprinast. We conclude that (a) NO exerts a permanent inhibitory effect against hypoxic vasoconstriction that might be mediated in part by an activation of K(ATP) channels; (b) a 4-aminopyridine-sensitive K+ channel is involved in vasoconstriction under hypoxic conditions; (c) PDEs 3 and 5 are the predominant PDE isoforms in rat pulmonary artery relaxation; and (d) NO and K(ATP), but neither BK(Ca), SK(Ca), nor Kv channels, are involved in the relaxant effect of PDEIs.
...
PMID:Hypoxic vasoconstriction of rat main pulmonary artery: role of endogenous nitric oxide, potassium channels, and phosphodiesterase inhibition. 1148 82

Experimental models to study the effect of agents on penile erection usually include electrical stimulation of peripheral nerves in anesthetized animals combined with systemic or intracavernous injection of drugs. The objective of this study was to demonstrate that conscious rabbits can be used as a simple and quantitative model for the assessment of compounds that show potential for the treatment of erectile dysfunction. Erection was assessed by measuring the length of uncovered penile mucosa before and after the intravenous (i.v.) administration of agents. Animals did not require anesthesia during the course of the study. The phosphodiesterase 5 (PDE5) inhibitors vardenafil x HCl (hereafter called vardenafil) and sildenafil were given intravenously, and measurements were taken for 0-5 h. The effects of phentolamine and milrinone were also evaluated. Vardenafil (0.1-3 mg/kg) induced dose-dependent penile erections in conscious rabbits following i.v. administration. The efficacy of vardenafil was potentiated, and the minimal effective dose was reduced significantly to 0.01 mg/kg by simultaneous administration of the nitric oxide (NO) donor sodium nitroprusside (SNP). Administration of the NO-synthase inhibitor L-NAME abolished the effect. Sildenafil was effective in this model after i.v. administration. The alpha-adrenergic receptor antagonist phentolamine (0.1, 0.3 and 1 mg/kg i.v.) induced erections with a slower t(max) compared with vardenafil and sildenafil. Intravenous administration of the PDE3 inhibitor milrinone (1 mg/kg i.v.) was less effective than the PDE5 inhibitor vardenafil. The conscious rabbit is a suitable and reliable model for the evaluation of compounds with potential for the treatment of erectile dysfunction. This was demonstrated using compounds that target different signaling pathways that induce smooth muscle relaxation in the penis.
...
PMID:A conscious-rabbit model to study vardenafil hydrochloride and other agents that influence penile erection. 1149 80

We studied the role of adenosine and P2 receptors in the pelvic nerve stimulation-induced penile tumescence in anesthetized dogs. A local intracavernous injection of adenosine induced the tumescence, which was abolished by intracavernous 8-(p-sulfophenyl)theophylline (8-SPT), an unspecific adenosine receptor antagonist, and by 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl amino]ethyl)phenol (ZM241385), an adenosine A(2A) receptor antagonist. ATP also induced the tumescence, which was diminished by 8-SPT, but not by reactive blue-2, a P2 receptor antagonist. Neither intracavernous beta, gamma-meATP nor ADP(beta)S, P2X and P2Y receptor agonists, induced tumescence. N(G)-nitro-L-arginine (L-NAME), a nitric oxide synthase inhibitor, and T-1032, a phosphodiesterase type V inhibitor, had no effects on the tumescence induced by adenosine. 8-SPT and reactive blue-2 had no effects on the tumescence induced by pelvic nerve stimulation. These results show that although exogenous adenosine and ATP induce tumescence, neither the adenosine nor the P2 receptor is involved in the tumescence induced by pelvic nerve stimulation in anesthetized dogs.
...
PMID:Role of adenosine and P2 receptors in the penile tumescence in anesthetized dogs. 1167 74

Endothelium-derived relaxing factor (EDRF) or nitric oxide (NO) biosynthesis from L-arginine occurs in the endothelium and platelets and may modulate platelet function and contribute to thromboresistance in the vessel wall. A rat model was used to evaluate selective accumulation of (III)In-labeled platelets in the pulmonary microcirculation following the administration of collagen, adenosine 5'-diphosphate (ADP) or thrombin. Platelet aggregation was monitored continuously over the thorax using a microcomputer-based system. Sodium nitroprusside, a stimulator of soluble guanylate cyclase and zaprinast, a phosphodiesterase V inhibitor, both known to cause accumulation of cyclic guanosine monophosphate, exhibited moderate inhibitory activity, which was shared by L-arginine. N(G)-monomethyl-L-arginine (L-NMMA; 1 mg/kg/min), an inhibitor of EDRF(NO), potentiated the aggregatory response to collagen at an intravenous dose of 100 &mgr;g/kg but not at one of 30 &mgr;g/kg. D-NMMA had no such effect. The augmenting effect of L-NMMA was abolished by L-arginine. N(G)-nitro-L-arginine methyl ester (L-NAME; 0.1 mg/kg/min) also markedly augmented the collagen-induced platelet response, and, at higher doses, all treated animals died upon collagen challenge. Both L-NMMA and L-NAME did not affect the responses to ADP and thrombin. The results suggest that in the intact vascular system, basal releae of EDRF(NO) is not critically involved in modulation of platelet function but becomes a significant factor when platelets are exposed to great amounts of collagen fibrils. Copyright 1994 S. Karger AG, Basel
...
PMID:EDRF(NO)-Mediated Modulation of Collagen-Induced Platelet Accumulation in Rat Pulmonary Microcirculation. 1172 5

The vasorelaxant effects of sildenafil and T-1032 [methyl-2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate], two phosphodiesterase type 5 inhibitors, were examined in the isolated rat aorta. Sildenafil and T-1032, both of which have almost the same potency and selectivity regarding phosphodiesterase type 5 inhibitory activity, produced a similar, moderate, relaxation at 10(-10) to 10(-7) M (sildenafil: 66.8 +/- 13.7%; T-1032: 77.9 +/- 10.8% at 10(-7) M). However, sildenafil, but not T-1032, produced further relaxation at the higher concentrations (sildenafil: 102.0 +/- 0.6%; T-1032: 81.0 +/- 7.2% at 10(-4) M, P < 0.05). Sildenafil also produced a more potent relaxation than did T-1032 at the high concentrations (10(-5) and 10(-4) M) in endothelium-denuded aortic rings and in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor (3 x 10(-4) M). Moreover, the high concentrations of sildenafil, but not of T-1032, caused a rightward shift of the concentration-response curve for calcium chloride in K(+)-depolarized endothelium-denuded preparations. In the ligand binding assay for the L-type Ca(2+) channels, the affinities of sildenafil at 10(-5) M for binding sites of nitrendipine and (--)-desmethoxyverapamil [(--)- D888] (35.2 +/- 3.3% and 35.8 +/- 1.9%, respectively) were higher than those of T-1032 (11.8 +/- 4.0% and -13.1 +/- 1.3%, respectively, P < 0.05). Regarding cyclic nucleotide levels, both phosphodiesterase type 5 inhibitors increased cGMP levels at 10(-6) M. However, sildenafil, but not T-1032, further increased cGMP levels at the higher concentrations (sildenafil: 15.7 +/- 2.7 pmol/mg protein; T-1032: 5.6 +/- 0.6 pmol/mg protein at 10(-4) M, P < 0.05). These results suggested that high concentrations of sildenafil had additional vasorelaxant properties through mechanisms other than phosphodiesterase type 5 inhibition. Sildenafil-induced relaxation appears to be due to inhibition of the external Ca(2+)-dependent cascade for contraction and/or to an increase in cGMP levels. In contrast, T-1032 only showed a vasorelaxant property due to phosphodiesterase type 5 inhibition. In conclusion, T-1032 appears to be a specific phosphodiesterase type 5 inhibitor compared with sildenafil and a useful compound to examine the physiological function of phosphodiesterase type 5.
...
PMID:Sildenafil and T-1032, phosphodiesterase type 5 inhibitors, showed a different vasorelaxant property in the isolated rat aorta. 1195 87

This study was designed to examine the pharmacological properties of evodiamine in isolated rabbit corpus cavernosum. In phenylephrine-precontracted cavernosal strips, evodiamine (0.01-10 microM) induced a concentration-dependent relaxation. Endothelium removal, N(G)-nitro-L-arginine methyl ester (L-NAME), or 1-H-[1,2,4]oxadiazolo [4,3-alpha] quinoxalin-1-one (ODQ) treatment did not affect this effect. In endothelium-denuded preparations, evodiamine-evoked response was significantly reduced in 60 mM KCl-precontracted strips and by charybdotoxin treatment, but not by glibenclamide. Higher-concentration evodiamine (> or =10 microM)-induced relaxation was also accompanied by an increase in cAMP and cGMP levels, but this effect was not affected by cis-N-(2-phenylcyclopentyl)-azacyclotridec-1-en-2-amine mono-hydrochloride (MDL-12,330A, an adenylyl cyclase inhibitor) or ODQ (a guanylyl cyclase inhibitor), respectively. Evodiamine significantly augmented both the corporal relaxation and the accumulation of cyclic nucleotides to sodium nitroprusside and forskolin, respectively. Evodiamine also enhanced electrical field stimulation-evoked relaxation, and this additive effect was significantly counteracted by zaprinast. In preparations obtained from aged rabbits, evodiamine still elicited complete relaxation; in contrast, acetylcholine- and sodium nitroprusside-evoked maximal response was significantly blunted. In summary, evodiamine possesses a potent corporal relaxing effect which is attributable to endothelium-independent properties probably linked to charybdotoxin-sensitive K(+) channel activation in the cavernosal vasculature and by nonselective interfering phosphodiesterase to prevent cyclic nucleotide degradation. Furthermore, the physiological effects of evodiamine on the aged animals may implicate a potential for the treatment of erectile dysfunction.
...
PMID:Pharmacological profile of evodiamine in isolated rabbit corpus cavernosum. 1209 97

Cilostazol, a potent inhibitor of guanosine 3':5'-cyclic monophosphate (cGMP)-inhibited adenosine 3':5'-cyclic monophosphate (cAMP) phosphodiesterase (PDE3), has been used clinically for the treatment of chronic peripheral arterial occlusive disease. The beneficial effect of cilostazol is attributed to both anti-platelet aggregating activity and vasodilation. However, the effect of cilostazol on resistance-sized vasculature is not well documented. Furthermore, mechanisms of vasodilation and influence on endothelium function are not fully understood. Thus, we investigated the vasodilator action of cilostazol using isolated, pressurized rabbit spinal arterioles with special reference to the functional endothelium. Cilostazol, acetylcholine (ACh), isocarbacyclin (prostacyclin analogue), and sodium nitroprusside (SNP) all produced concentration-dependent vasodilations of isolated spinal arterioles with endogenous myogenic tone. The order of potency of these agonists was isocarbacyclin>ACh>SNP>cilostazol. Indomethacin (10 micro M, a cyclo-oxygenase inhibitor), N(omega)-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor, 30 micro M), or chemical denudation of the endothelial cells did not significantly alter the cilostazol-induced arteriolar dilation. Furthermore, stimulating the release of endothelium-derived relaxing factors by administering ACh (100 nM), or treating with isocarbacyclin (1 nM) or SNP (3 nM) did not significantly modify the cilostazol-induced vasodilation. These results suggest that cilostazol produces the vasodilation of isolated, pressurized rabbit spinal arterioles independent of the functional endothelium. We infer that the vasodilator action of cilostazol in the spinal arterioles may be attributed to a yet unknown mechanism that is independent of the PDE3 inhibition.
...
PMID:Effects of cilostazol, a selective cyclic AMP phosphodiesterase inhibitor on isolated rabbit spinal arterioles. 1253 52

The effects of NCX 4050, a drug belonging to a new class of NO donors, was investigated in isolated preparations of human and rabbit corpus cavernosum (CC) and in human foetal corpora cavernosa (hfCC) smooth muscle cells. In strips of rabbit CC, NCX 4050 (0.001-100 microM) induced a concentration-dependent relaxation which was influenced neither by Nw-nitro-l-arginine-methyl-ester (l-NAME; 100 microm) nor by endothelium deprivation. The NCX 4050-induced relaxation was significantly reduced by the guanylate cyclase inhibitor 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 microm) and enhanced by a specific phosphodiesterase 5 inhibitor, sildenafil (300 nm). Moreover, NCX 4050 (0.01-1 microm), induced a concentration-dependent potentiation of the relaxant response induced by electrical field stimulation (EFS) in rabbit preparations pre-treated with guanethidine and indomethacin. The relaxant effect of NCX 4050 was similar to that obtained by increasing concentrations (0.001-100 microm) of sodium nitroprusside (SNP) in either rabbit or human preparations. To further investigate the activity of NCX 4050 on human corpora cavernosa, we exposed cultured hfCC smooth muscle cells to increasing concentrations of NCX 4050 and SNP. We found that both compounds dose-dependently reduced cell proliferation. The antiproliferative effect of all the concentration tested of NCX 4050 was completely blocked by ODQ (1 microm). These results suggest that in rabbit and human corpora cavernosa NCX 4050 acts by activating guanylate cyclase activity, induces smooth muscle relaxation and quiescence. Our results provide a rationale for a possible future use of NCX 4050 in the pharmacotherapy of erectile dysfunction linked to an impaired release of NO from the endothelium.
...
PMID:Effects of NCX 4050, a new NO donor, in rabbit and human corpus cavernosum. 1264 28

The interaction between the renin-angiotensin system and nitric oxide (NO) is undeniable, but its nature is not fully known. This study investigated the contribution of NO to the acute hypotensive effect of captopril in conscious normotensive rats and the effect on blood pressure of dual administration of captopril and the phosphodiesterase-5 inhibitor zaprinast. In two separate experiments, rats were pretreated with the NO inhibitor L-arginine methyl ester (L-NAME) and with the NO enhancer zaprinast. Pretreatment with L-NAME attenuated and pretreatment with zaprinast potentiated the hypotensive effect of captopril. The hypotensive effect of captoril was not associated with a significant change in the plasma level of cyclic guanosine monophosphate (cGMP). These findings suggest that NO contributes to the blood pressure-lowering effect of captopril. The inability of captopril to alter plasma cGMP levels is not consistent with this view, however, and leads to the conclusion that NO contributes to the acute hypotensive effect of captopril, although the mechanism is not fully understood. Zaprinast potentiates the hypotensive effect of captopril, and an adjustment in dose should be considered when this combination is administered.
...
PMID:Possible impact of nitric oxide on the antihypertensive effect of captopril and zaprinast. 1295 56

Most of the effects of the signalling molecule nitric oxide (NO) are mediated by the activation of NO-sensitive guanylyl cyclase (GC). Subsequent to the NO-induced stimulation of cGMP synthesis, the rise in the intracellular cGMP concentration induces the activation of the different cGMP effector molecules. Accumulating evidence has been presented that the sensitivity of the cGMP response is modulated by the amount of NO present, i.e., a lack of NO was shown to lead to an enhanced cGMP response in aortas in response to NO stimulation while preincubation with NO blunted this cGMP response. Here, we show that L-N-nitro-arginine-methyl ester (L-NAME) treatment of rats leads to a very much increased cGMP response toward sodium nitroprusside (SNP) in aortic tissue. In the aortic cytosolic fraction, enzyme activities of GC and phosphodiesterase (PDE) did not differ between the two animal groups. We did not detect any difference in the expression of NO-sensitive GC between L-NAME-treated and control animals, which could explain the enhanced NO response. The results show that a reduction of the endogenous NO production induced by long-term L-NAME treatment does not lead to an up-regulation of NO-sensitive GC on the level of protein expression.
...
PMID:The enhanced NO-induced cGMP response induced by long-term L-NAME treatment is not due to enhanced expression of NO-sensitive guanylyl cyclase. 1367 48


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---