Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prazosin (25 microM) was found to increase 125I-labeled rat atrial natriuretic peptide ([125I]rANP) receptor binding by 50% (SC50) in bovine adrenal zona glomerulosa membranes. A series of 2,4-disubstituted quinazolines was prepared in order to identify more potent analogues for additional in vitro testing. Compound 7 (N-[3-[[2-(diethyl-amino)-4-quinazolinyl]amino]propyl] guanidine dinitrate) from this series (3 microM) significantly decreased the EC50 for rANP-mediated inhibition of ACTH-stimulated aldosterone synthesis in rat adrenal glomerulosa cells. At a higher concentration (20 microM), compound 7 had no effect on particulate guanylate cyclase from rabbit glomeruli in either the presence or absence of rANP.
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PMID:Atrial natriuretic peptide receptor modulators: effects of disubstituted quinazolines on receptor binding and in vitro biological activity. 196 15

1. The mechanism by which neuropeptide Y (NPY) potentiates the vasoconstriction induced by alpha 1-adrenoceptor agonists was investigated in 3rd generation mesenteric arterioles of the rat. 2. At a maximally active concentration, nitrendipine (10(-6) M) displaced to the right the concentration-response curves to noradrenaline (pD2 decreased from 6.2 +/- 0.06 to 5.7 +/- 0.03) and phenylephrine (pD2 decreased from 5.6 +/- 0.03 to 5.3 +/- 0.03). Diltiazem (10(-5) M) also shifted to the right the concentration-response curve to phenylephrine (pD2 decreased from 6.0 +/- 0.06 to 5.5 +/- 0.04). In addition, the maximal response to phenylephrine was significantly decreased in the presence of either nitrendipine or diltiazem. 3. In the absence of a calcium channel blocking agent, NPY (100 nM) produced a leftward shift of the concentration-response curves to noradrenaline (pD2 increased from 6.2 +/- 0.06 to 6.5 +/- 0.05) and phenylephrine (pD2 increased from 5.6 +/- 0.03 to 6.0 +/- 0.06 and from 6.0 +/- 0.06 to 6.3 +/- 0.11). In the presence of either nitrendipine (10(-6) M) or diltiazem (10(-5) M), NPY (100 nM) did not alter the concentration-response curves to either noradrenaline or phenylephrine. 4. NPY was added to arterioles brought to the same level of tension (40% of the maximal contraction) either by phenylephrine alone (1.5 x 10(-6) M) or by a higher concentration of phenylephrine (3 x 10(-6) M) followed by the addition of prazosin (1.3 x 10(-9) M; a concentration at which it partially blocks alpha 1-adrenoceptors). In these conditions, the response to phenylephrine was completely abolished by nitrendipine (10-6 M) or by diltiazem (10-5M). Furthermore, NPY (10-1" to 10-7M) increased the arteriolar tension up to the maximal contractile capacity of the vessels with pD2 values of 8.6 + 0.02 and 8.7 + 0.01, in the absence and presence of prazosin, respectively. 5. Prazosin was replaced in the above protocol by other vasodilator agents acting through different mechanisms. Whether in the presence of 2 x 10-7M forskolin, 6 x 10-7M sodium nitroprusside (which stimulate adenylate cyclase or guanylate cyclase, respectively) or 2 x 10- 7M diltiazem (a concentration at which calcium entry is partially blocked), NPY enhanced phenylephrine-induced contraction to the maximum level with an identical potency (pD2 values of the peptide ranged from 8.3 to 8.7). 6. The results show that, in rat mesenteric arterioles, NPY potentiates only the calcium entry blockersensitive component of contraction induced by stimulation of alpha,-adrenoceptors. In addition, they provide evidence that the peptide counteracts with an equal potency the inhibitory effect of partial block of alpha,-adrenoceptors and of relaxing agents acting through different mechanisms. It is suggested that NPY enhances calcium entry induced by stimulation of alpha l-adrenoceptors in this tissue.
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PMID:Enhancement by neuropeptide Y (NPY) of the dihydropyridine-sensitive component of the response to alpha 1-adrenoceptor stimulation in rat isolated mesenteric arterioles. 197 Feb 70

1. Interactions between the synthesis of myo-inositol 1,4,5-trisphosphate (IP3) and guanosine 3':5'-cyclic monophosphate (cyclic GMP) in the smooth muscle cells of the rabbit aorta were investigated. 2. In the presence or absence of vascular endothelium, noradrenaline (NA; 5 microM) consistently reduced the amount of phosphatidylinositol 4,5-bisphosphate (PI-P2) and increased both phosphatidic acid (PA) and IP3. 3. In the presence or absence of endothelium, acetylcholine (ACh; 100 microM but not 5 microM) slightly increased the amount of IP3, but exposure to ACh (100 microM) 4 min after application of NA did not modify NA-induced synthesis of IP3. 4. ACh (100 microM) markedly enhanced the synthesis of cyclic GMP in the presence of endothelium but not in the endothelium-denuded tissues. 5. Prazosin (5 microM) but not dibutyryl cyclic GMP (db-cyclic GMP; 100 microM) blocked the hydrolysis of PI-P2 induced by 5 microM NA. Synthesis of IP3 induced by NA, as estimated with [3H]-inositol was not modified by application of 100 microM db-cyclic AMP or db-cyclic GMP. 6. alpha-Human atrial natriuretic peptide (alpha-hANP; 0.1 microM) increased cyclic GMP in the presence or absence of endothelium. alpha-hANP (0.1 microM) consistently inhibited the hydrolysis of PI-P2 induced by 5 microM NA. 7. The results indicate that synthesis of IP3 is inhibited neither by the synthesis of cyclic GMP in the cytosol nor by cyclic GMP itself. However, synthesis of IP3 through hydrolysis of PI-P2 may be inhibited by an interaction between some steps in the IP3 synthetic process and by the activation of the alpha-hANP-guanylate cyclase process at the sarcolemma.
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PMID:Inhibitory action of alpha-human atrial natriuretic peptide on noradrenaline-induced synthesis of myo-inositol 1,4,5-trisphosphate in the smooth muscle cells of rabbit aorta. 197 Apr 98

In this study the role of the endothelium was evaluated in the relaxation of rat aortic rings induced by a number of alpha adrenergic antagonists. Phentolamine, a nonselective alpha adrenergic antagonist, relaxed rat aortic rings that were previously contracted with an EC80 dose of phenylephrine, in a concentration-dependent manner. Removal of the endothelium significantly reduced the sensitivity but not the amplitude of the response. The presence of endothelium also enhanced the vascular relaxation induced by yohimbine, a specific alpha-2 adrenergic antagonist (10(-8)-10(-6) M), and by prazosin, a specific alpha-1 adrenergic antagonist (10(-11)-10(-9) M). Both methylene blue (10(-5) M), an inhibitor of soluble guanylate cyclase, and eicosatetraynoic acid (3.2 X 10(-5) M) blocked the endothelial augmentation of vascular relaxation to phentolamine. Vessels precontracted with potassium chloride were slightly relaxed by phentolamine (10(-8)-10(-6) M) only with the endothelium was intact. Both methylene blue and eicosatetraynoic acid also inhibited the response to phentolamine in the intact vessels precontracted with potassium chloride. Prazosin (10(-9)-10(-7) M) and yohimbine (10(-8)-10(-6) M), unlike phentolamine, failed to induce relaxation in potassium chloride-precontracted vessels. When the vessels were precontracted with the thromboxane analog U46619 none of the three alpha antagonists induced vascular relaxation. These results indicate that the endothelium has a significant role in promoting relaxation induced by the three alpha adrenergic antagonists tested.
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PMID:Endothelial potentiation of relaxation response to phentolamine in rat thoracic aorta. 283 42

Taking their lead from studies which have shown that endothelium-derived relaxing factor(s) (EDRF) mediates vasorelaxation by activating smooth muscle guanyl cyclase, the authors of the current article have examined the role of the endothelium in relation to the effects of the alpha-adrenoceptor antagonist prazosin. Prazosin acted as a non-competitive antagonist of norepinephrine- (NE-) induced contraction in rat aortic preparations with intact endothelium, but as a competitive antagonist in endothelium-denuded preparations. The affinity of NE for its smooth muscle receptor was the same in the presence or absence of endothelium, but its efficacy was 7 times lower in the presence than in the absence of endothelium. Other experiments showed that inhibition of guanyl cyclase by methylene blue in the presence of endothelium (like endothelium removal) led to competitive antagonism of NE responses by prazosin, and that increasing the tissue content of cyclic GMP by pre-incubating de-endothelialized preparations with 8-Br-cyclic GMP (as in intact preparations) led to non-competitive antagonism of NE responses by prazosin. The authors concluded that EDRF, by increasing the cyclic GMP content of vascular smooth muscle of rat aorta, can modify the efficacy of NE, and thereby alter the mode of antagonism of prazosin.
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PMID:Role of cyclic GMP in the modulation by endothelium of the adrenolytic action of prazosin in the rat isolated aorta. 285 49

The responses of the bovine retractor penis muscle to field stimulation of intramural nerves in vitro was investigated using micro-electrode and extracellular (sucrose gap) techniques. In the absence of tone single pulses or trains of stimuli (1-50 Hz 0.1-0.5 m.sec) produced e.j.p.s and a decrease in membrane resistance; spike potentials were not observed. E.j.p.s often small in amplitude (3-5 mV to single pulse) and accompanied by contractions in almost all preparations were noradrenergic, abolished by guanethidine (1-3 x 10(-5) M) and tetrodotoxin (3.5 x 10(-6) M) but not by prazosin (0.05 - 1.4 x 10(-6) M). Prazosin abolished the depolarization and contraction produced by added NA (0.02 - 2 x 10(-8) moles). TEA (10(-2) M) depolarized the membrane and initiated spontaneous activity; e.j.p.s and contractions were enhanced and prolonged but no spikes were observed. Atropine (0.5 x 10(-6) M) increased and physostigimine (1-5 x 10(-6) M) decreased e.j.p.s and contractions indicating a cholinergic regulatory component in the release of the excitatory transmitter. In the presence of tone, nerve stimulation produced i.j.p.s. and relaxations which were unaffected by apamin (5 x 10(-7) M), atropine (3 x 10(-6) M), guanethidine (3 x 10(-5) M), phentolamine (5 x 10(-6) M) and propranolol (4 x 10(-6) M) but were abolished by tetrodotoxin (3.5 x 10(-7) M) suggesting their mediation by non-adrenergic non-cholinergic (NANC) nerves. Sodium nitroprusside (10(-10) - 10(-8) moles), which increases cyclic GMP, also hyperpolarized the membrane and relaxed the BRP. Those responses and those to inhibitory nerve stimulation were antagonized by oxyhaemoglobin which inhibits guanylate cyclase. 2-O-propoxyphenyl-8-azapurin-6-one (M & B 22948 3-9 x 10(-6) M) which inhibits cGMP-specific phosphodiesterase, enhanced the relaxation but not the i.j.p. TEA (10(-2) M) initially depolarized the membrane potential and raised tone. In the sucrose gap inhibitory potentials were abolished; the mechanical relaxation was not and a small contractile component emerged. Electrical and mechanical inhibitory components in the bovine retractor penis may not be correlated.
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PMID:Electrical and mechanical responses of the bovine retractor penis to nerve stimulation and to drugs. 615 68

The effect of chloramphenicol (CAP) on the intestinal motility of mice was studied. Acute and chronic CAP treatment significantly increased the food transit time. CAP produced concentration-dependent inhibition of motility of the isolated ileum of mice. Prazosin, propranolol, atropine, ouabain and chlorpromazine all failed to modulate or counteract the CAP-induced inhibition of ileal motility. However, naloxone and hexamethonium slightly modified the inhibitory response of CAP. The inhibitory response of CAP was markedly counteracted by cystine, a guanylate cyclase inhibitor. CAP increased the activity of Ca(++)-ATPase in the ileum in all experiments. Our results suggest that the CAP-induced inhibition of the intestinal motility is not mediated through adrenergic, cholinergic and cAMP or through inhibition of the electrogenic pump. Compared to thiamphenicol (TAP), CAP, with a p-NO2 group in its structure, exhibited more pronounced alteration of both intestinal motility and Ca(++)-ATPase activity. We, therefore, suggest that greater inhibition of ileal motility induced by CAP is possibly a p-NO2-cGMP-Ca(++)-ATPase-mediated mechanism.
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PMID:Mechanism of chloramphenicol-induced modulation of mouse ileal motility. 747 3

The contribution of NO-cGMP dependent pathway to phentolamine mesylate-evoked nonadrenergic, noncholinergic relaxation of rabbit corpus cavernosum was investigated in vitro. Stimulation of nonadrenergic, noncholinergic neurons of the rabbit corpus cavernosum elicited frequency-related relaxation that was significantly attenuated by L-NAME (NO synthase inhibitor) or ODQ (an inhibitor of guanylate cyclase). Moreover, tetrodotoxin, a sodium channel blocker, abolished the electrical field stimulation-induced relaxation of rabbit corpus cavernosum, suggesting that neuronal release of NO mediates relaxation to electrical field stimulation. Phentolamine mesylate (30 and 100 nM) dose-dependently enhanced electrical field stimulation-induced relaxation of the rabbit corpus cavernosum. Prazosin (30 microM) and yohimbine (30 microM) failed to affect phentolamine mesylate-mediated nonadrenergic, noncholinergic rabbit penile smooth muscle relaxation, suggesting that phentolamine relaxes rabbit corpus cavernosum independent of alpha-adrenergic receptor blockade. In contrast, pretreatment of the rabbit cavernosal strips with L-NAME significantly-attenuated electrical field stimulation produced relaxations to phentolamine mesylate, suggesting that phentolamine mesylate relaxes rabbit corpus cavernosum by activating NO synthase. The data suggest that phentolamine mesylate relaxes nonadrenergic noncholinergic neurons of the rabbit corpus cavernosum by activating NO synthase and is independent of alpha-adrenergic receptor blockade.
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PMID:Phentolamine mesylate relaxes rabbit corpus cavernosum by a nonadrenergic, noncholinergic mechanism. 1146 7