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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was designed to characterize the antinociception produced by the administration of a muscarinic agonist, (+)-cis-methyldioxolane, into the rostral ventral medulla (RVM) of male Sprague-Dawley rats. Seven days after the implantation of 25-gauge stainless-steel guide cannulae, animals were injected with graded doses of (+)-cis-methyldioxolane, and antinociception was assessed by using the 52 degrees C hot-plate and tail-flick tests in a single-blind design. (+)-cis-Methyldioxolane produced dose-related hot-plate and tail-flick antinociception for 30 to 45 min peaking 5 to 10 min after RVM injection. The ED50 values of (+)-cis-methyldioxolane in the hot-plate and tail-flick tests were 2.4 and 1.7 nmol, respectively. Five-minute preinjections with 0.35 nmol of the muscarinic M1 receptor blocker pirenzepine competitively antagonized the antinociception produced by (+)-cis-methyldioxolane. The antinociception produced by RVM injections of the muscarinic M2 receptor blocker methoctramine was additive to the antinociceptive effects of (+)-cis-methyldioxolane when the two antinociceptive effects of (+)-cis-methyldioxolane when the two agents were combined. Twenty four-hour pretreatment of the RVM with the irreversible muscarinic receptor antagonist 4-diphenylacetoxy-N-[2-chloroethyl]-piperidine mustard blocked the antinociceptive effects of (+)-cis-methyldioxolane completely. Administration of 6 nmol of the nitric oxide synthase inhibitor L-NG-nitroarginine into the RVM competitively antagonized the antinociception produced by (+)-cis-methyldioxolane and (+)-muscarine in the hot-plate and tail-flick tests. Pretreatment with 100 nmol of L-arginine, but not D-arginine, significantly reversed the inhibitory effects of L-NG-nitroarginine on (+)-cis-methyldioxolane-produced antinociception. Pretreatment with 100 nmol of the guanylyl cyclase inhibitor methylene blue into the RVM profoundly antagonized the antinociception produced by (+)-cis-methyldioxolane. Neither buffer L-NG-nitroarginine, L-arginine-D-arginine or methylene blue altered hot-plate or tail-flick nociception when injected alone into the RVM. In contrast, either dibutyryl cyclic GMP or 8-bromo cyclic GMP, membrane-permeable cyclic GMP analogs, produced hot-plate and tail-flick antinociception when injected alone into the RVM. These data are consistent with the hypothesis that the antinociception produced by muscarinic stimulation of the RVM is mediated by an L-arginine/nitric oxide/cyclic GMP cascade.
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PMID:Pharmacological evidence that nitric oxide mediates the antinociception produced by muscarinic agonists in the rostral ventral medulla of rats. 751 22

We studied the role of cyclic guanosine monophosphate (cGMP) as a mediator of the reduction of L-type calcium current (ICa) induced by muscarinic receptor stimulation and by nitric oxide in isolated guinea-pig ventricular cells using the whole-cell patch-clamp technique. Our results show that when the level of cyclic adenosine monophosphate was increased by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX), stimulation of a pertussis-toxin (PTX)-sensitive muscarinic receptor by carbachol (1 microM) reduced the calcium current increase from 80.6 +/- 23.5% to 19.8 +/- 9.6% over the control and this effect was prevented by methylene blue (10 microM), an inhibitor of the soluble guanylate cyclase. Pipette solution containing 10 microM cGMP reduced the enhancement of ICa by IBMX from 121.9 +/- 11.6% to 14.2 +/- 5.4% above the control. Sodium nitroprusside (10 microM), a spontaneous donor of nitric oxide, and consequently a stimulator of soluble guanylate cyclase, also reduced IBMX-stimulated ICa from 115.2 +/- 13.2% to 32.2 +/- 6.9% above control and the sodium nitroprusside effect was also suppressed by methylene blue. The latter two reagents were ineffective on basal ICa.
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PMID:Guanylate-cyclase-mediated inhibition of cardiac ICa by carbachol and sodium nitroprusside. 751 32

To determine whether nitric oxide (NO) modifies cardiomyocytes directly or indirectly via peripheral autonomic neurons, the effects of NO were studied in long-term (3-6 wk) cultures of adult guinea pig ventricular myocytes alone as well as in cocultures with adult extracardiac (stellate ganglion) or intrinsic cardiac neurons. NADPH diaphorase was associated histochemically with cultured intrinsic cardiac and, to a lesser extent, stellate ganglion neurons. The beating frequency of ventricular myocytes cocultured with intrinsic cardiac neurons (M-intrinsic) or stellate ganglion neurons (M-stellate) increased by 20-30% (P < 0.001) after administration of the NO donor S-nitroso-N-acetylpenicillamine (SNAP); this effect was abolished by the guanylate cyclase inhibitor LY-83583. The beating frequency of noninnervated myocyte cultures was not affected by SNAP. The precursor of NO, L-arginine, also increased the beating rate (approximately 20%; P < 0.05) of M-intrinsic cocultures, not affecting that of M-stellate cocultures or noninnervated myocyte cultures. Augmentor effects induced by SNAP were no longer elicited in the presence of tetrodotoxin and were unaffected by beta-adrenergic or muscarinic receptor blockade. It is concluded that 1) NO-sensitive neurons are present in stellate and intrinsic cardiac ganglia, and these neurons increase the beating rate of cardiomyocytes in the presence of NO; 2) more NO-synthesizing neurons are present in M-intrinsic than M-stellate cocultures, since L-arginine increased the beating frequency of myocytes significantly only in M-intrinsic cocultures; and 3) the beating rate of noninnervated myocyte cultures is not directly affected by NO.
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PMID:Nitric oxide modulates signaling between cultured adult peripheral cardiac neurons and cardiomyocytes. 765 33

1. The effects of acute inhibition of nitric oxide (NO) synthase on cardiovascular responses to vasodilator challenges have already been described. We now report the responses to vasodilators during and after chronic NO synthase inhibition. 2. In conscious Brattleboro rats, the regional haemodynamic effects of 3 min infusions of acetylcholine (4 micrograms min-1), sodium nitroprusside (15 micrograms min-1) or adrenaline (0.2 micrograms min-1) were assessed (from areas under or over curves (AUC, AOC)) under control conditions, 6 and 72 h after the addition of the NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA) to the drinking water (1 mg ml-1), and 6, 24 and 48 h after the withdrawal of L-NMMA. In a separate group of Brattleboro rats, responses to acetylcholine, sodium nitroprusside and adrenaline were assessed before and 6 h after the onset of oral ingestion of the more potent nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 0.05 mg ml-1). 3. Acetylcholine caused renal vasodilation (87 +/- 11 units) and mesenteric vasoconstriction (-31 +/- 5 units), sodium nitroprusside caused vasodilatation in renal (96 +/- 12 units), mesenteric (222 +/- 13 units) and hindquarters (49 +/- 15 units) vascular beds, whereas adrenaline caused hindquarters vasodilatation (92 +/- 8 units). Seventy two h after the onset of oral ingestion of L-NMMA, acetylcholine had a decreased renal vasodilator (59 +/- 9 units) effect, sodium nitroprusside had an increased renal vasodilator (142 +/- 23 units) action, while adrenaline had a decreased hindquarters vasodilator (55 +/- 6 units) influence. Twenty four h after withdrawal of L-NMMA, the renal vasodilator effect of acetylcholine was greater than the control response (106 +/- 14 units), but the regional haemodynamic effects of sodium nitroprusside and adrenaline were not different from those under control conditions. Hence, the increased renal vasodilator response to acetylcholine was probably due to changes in muscarinic receptor-mediated mechanisms rather than to any increase in guanylyl cyclase or its sensitivity to NO.
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PMID:Effects of chronic treatment with nitric oxide synthase inhibitors on regional haemodynamic responses to vasodilators in conscious Brattleboro rats. 768 4

We investigated the effects of lithium ion (Li+) on muscarinic receptor-mediated nitric oxide (NO) generation, and guanylate cyclase (GCase) activation using the mouse neuroblastoma clone, N1E-115. The levels of released NO were determined by measuring the levels of nitrite/nitrate in the incubation medium, and the activity of GCase was measured with an assay for cellular cyclic [3H] GMP levels. We determined that Li+ had no effects on muscarinic receptor-activated elevation of nitrite/nitrate levels, which were significantly inhibited by 100 microM L-NG-monomethylarginine, although it has been reported that Li+ inhibits muscarinic receptor-activated cyclic GMP formation in the cells. In addition, Li+ inhibited the cyclic GMP formation induced by an NO donor, sodium nitroprusside (SNP), in both intact cells and a crude cellular homogenate; thus, the inhibition by Li+ of muscarinic receptor-mediated cyclic GMP synthesis appeared to be at the level of GCase, but not NO synthase.
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PMID:Inhibition by lithium of cyclic GMP formation without inhibition of nitric oxide generation in the mouse neuroblastoma cell (N1E-115). 784 Aug 63

The ability of muscarinic receptor antagonists to compete with (-)-[3H]quinuclidinyl benzilate ([3H]QNB) binding was compared with their ability to block carbachol-mediated stimulation of particulate guanylate cyclase activity in rat colonocytes. The binding of [3H]QNB to membranes was inhibited by antagonists with the following rank order of potencies (inhibitory constants, nM): atropine (2.5) approximately 4-diphenylacetoxy-N-methylpiperidine iodide (4-DAMP) [4.6] >> pirenzepine (121) > methoctramine (385). 4-DAMP (IC50 = approximately 10 nM) was also more potent in blocking carbachol-induced stimulation of guanylate cyclase activity than either pirenzepine (IC50 = approximately 700 nM) or methoctramine (IC50 = approximately 1500 nM).
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PMID:M3 muscarinic receptors on rat colonocytes are coupled to particulate guanylate cyclase activation. 810 94

We studied the effect of fentanyl on the endothelium-dependent vascular responses in isolated rat aortic strips. Fentanyl depressed the endothelium-dependent relaxation induced by acetylcholine but not that induced by the calcium ionophore, A23187. Endothelium-independent relaxation in response to sodium nitroprusside (SNP), a soluble guanylate cyclase activator, was not depressed by fentanyl. On the other hand, fentanyl depressed the increase in cyclic GMP level stimulated by acetylcholine but not that stimulated by A23187 or SNP. Furthermore, fentanyl depressed the vasocontraction by acetylcholine but not that by histamine or KCl in isolated pig coronary artery strips without endothelium, suggesting that fentanyl can inhibit endothelium-independent contraction via muscarinic receptor on smooth muscle cells. These results suggest that fentanyl can inhibit endothelium-dependent vasorelaxation via endothelium-derived relaxing factor (EDRF) by acting on endothelial cells but not on smooth muscle cells. The inhibitory effect of fentanyl on the relaxation probably occurs at the level of muscarinic receptor on endothelial cells or at a site before biochemical pathways converting L-arginine to EDRF.
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PMID:[Inhibitory effect of fentanyl citrate on endothelium-dependent relaxation in rat aorta]. 830 61

We have investigated the effects of (a) the cholinesterase inhibitor physostigmine and (b) drugs that are known to change intracellular cyclic GMP levels on the autoinhibition of acetylcholine release from rat hippocampal slices. Autoinhibition was triggered by submaximal electrical stimulation in both the absence and presence of physostigmine. The results obtained indicate that an unusual increase in the extracellular acetylcholine content, such as that induced by cholinesterase inhibition, is not essential for autoinhibition triggering. Dibutyryl cyclic GMP reduced significantly the stimulation-evoked acetylcholine release in the presence, but not in the absence, of atropine. Neither sodium nitroprusside nor glyceryl trinitrate exerted a dibutyryl cyclic GMP-like effect. NG-Nitro-L-arginine did not lessen the autoinhibition. These results indicate that an increase in the intracellular cyclic GMP level reduces acetylcholine release, and that the muscarinic receptor stimulation-nitric oxide synthesis-(soluble) guanylyl cyclase activation pathway is not involved in the cholinergic autoinhibition process.
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PMID:Effects of physostigmine and some nitric oxide-cyclic GMP-related compounds on muscarinic receptor-mediated autoinhibition of hippocampal acetylcholine release. 838 37

We examined the effects of acetylcholine (ACh) on coronary perfusion pressure (CPP) and force of cardiac contraction (FCC) in isolated rat hearts. Perfusion of hearts with ACh increased both CPP and the FCC, whereas cardiac contraction rate fell. These effects of ACh were abolished by atropine but were not affected by the beta 1-adrenergic antagonist metoprolol. The nonselective beta-adrenergic antagonist propranolol decreased ACh-mediated increase in FCC but did not affect the rise in CPP. Pretreatment of hearts with cyclooxygenase inhibitor indomethacin or thromboxane (Tx) A2-endoperoxide receptor antagonist SQ 29,548 decreased ACh-mediated increase in CPP and FCC, suggesting release of TxA2 in the microvasculature, which may partially account for the increase in CPP and FCC with ACh infusion. In contrast to the effect of indomethacin and SQ 29,548, pretreatment of hearts with endothelium-derived relaxing factor (EDRF) synthetase inhibitor NG-monomethyl-L-arginine (L-NMMA) or guanylate cyclase inhibitor methylene blue potentiated ACh-mediated increase in CPP and attenuated the increase in FCC, suggesting that ACh-mediated increase in CPP is modified by basal EDRF release. Thus the cardiac effects of ACh are related to muscarinic receptor activation, and the release of prostaglandins and EDRF modulates the effects of ACh in isolated rat heart.
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PMID:Cardiac effects of acetylcholine in rat hearts: role of endothelium-derived relaxing factor and prostaglandins. 849 52

1. In this paper we have determined the different signalling pathways involved in muscarinic acetylcholine receptor (AChR)-dependent inhibition of contractility in rat isolated atria. 2. Carbachol stimulation of M2 muscarinic AChRs exerts a negative inotropic response, activation of phosphoinositide turnover, stimulation of nitric oxide synthase and increased production of cyclic GMP. 3. Inhibitors of phospholipase C, protein kinase C, calcium/calmodulin, nitric oxide synthase and guanylate cyclase, shifted the dose-response curve of carbachol on contractility to the right. These inhibitors also attenuated the muscarinic receptor-dependent increase in cyclic GMP and activation of nitric oxide synthase. In addition, sodium nitroprusside, isosorbide, or 8-bromo cyclic GMP, induced a negative inotropic effect, increased cyclic GMP and activated nitric oxide synthase. 4. These results suggest that carbachol activation of M2 AChRs, exerts a negative inotropic effect associated with increased production of nitric oxide and cyclic GMP. The mechanism appears to occur secondarily to stimulation of phosphoinositides turnover via phospholipase C activation. This in turn, triggers cascade reactions involving calcium/calmodulin and protein kinase C, leading to activation of nitric oxide synthase and soluble guanylate cyclase.
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PMID:Endogenous nitric oxide signalling system and the cardiac muscarinic acetylcholine receptor-inotropic response. 856 14


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