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)

Coculture of endothelial cells with atrial cells (R. A. Lew and A. J. Baertschi. Biochem. Biophys. Res. Commun. 163: 701-709, 1989) increased atrial natriuretic factor (ANF) release to 205 +/- 15% (n = 33 experiments) of basal secretion (2.02 +/- 0.33 ng/ml). Stimulation of ANF release by endothelial cells was significantly reduced (P < 0.05) by addition of the calcium channel antagonist nicardipine (Nic, 100 nM; by 69 +/- 4%), the guanylate cyclase activator sodium nitroprusside (SNP, 1 microM; by 97 +/- 27%), or acetylcholine (ACh, 10 microM; by 55 +/- 13%). Endothelial cell-conditioned medium elicited a 62 +/- 10% (n = 10) increase in ANF release. Rat and porcine endothelin (0.1-100 nM) each elicited a dose-dependent increase in ANF release [up to 84 +/- 14% (n = 18) over baseline]. The activity of conditioned medium was not affected by heat or trypsin treatment, but was significantly reduced by addition of Nic or SNP and was attenuated by ACh. Stimulation of ANF by 1 nM synthetic rat or porcine endothelin was also unaffected by heat or trypsin but was significantly reduced by Nic, SNP, and ACh. Addition of endothelin-specific antiserum abolished the ANF stimulatory activity of endothelial cell-conditioned medium. Neither inhibition of superoxide anion by superoxide dismutase nor inhibition of endothelium-derived nitric oxide production by NG-monomethyl-L-arginine affected the ANF release from coculture. Thus endothelial cells release a heat-stable, diffusible ANF stimulatory factor, which is not endothelium-derived relaxing factor or superoxide anion but is biologically and immunologically similar to endothelin.
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PMID:Endothelium-dependent ANF secretion in vitro. 141 54

We have examined the depressor effects of L- and D-arginine on the diastolic blood pressure of pithed normotensive Wistar (NW), Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats after the administration of a single bolus injection of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA). A single bolus intravenous injection of L-NMMA, 30 mg/kg, produced an increase in both the systolic and diastolic blood pressure of pithed rats. Injections of bolus doses, 1-300 mg/kg, of D-arginine did not lead to sustained reductions of the blood pressure in pithed NW rats although slight decreases in the blood pressure of WKY and SH rats were observed, and these transient effects of D-arginine appeared to be more pronounced in the WKY strain. Immediately following the bolus injections of the higher doses of D-arginine a transient decrease in both the systolic and diastolic pressure occurred. In contrast to the actions of D-arginine single bolus injections of L-arginine, 1-300 mg/kg, produced a dose-dependent sustained reduction in both the systolic and diastolic blood pressures of all rats. The threshold for the depressor actions of L-arginine was the same for NW, WKY and SH rats. The final dose of L-arginine (300 mg/kg), produced a significantly greater depressor effect in WKY and SH rats as compared to NW rats. The blood pressure remained elevated after the dose-response curve to D-arginine and, in order to determine whether D-arginine-treated rats are sensitive to the effects of other vasodilators and whether differences in vasoactive actions exist for vasodilators acting other than via nitric oxide synthesis, a dose-response curve to the calcium channel antagonist verapamil was constructed. Injections of verapamil, 0.1-1000 micrograms/kg, produced a dose-dependent reduction in blood pressure with no difference in either threshold or sensitivity to the actions of verapamil among the three strains of rats. Our results suggest that strain differences exist between the depressor actions of L-arginine and that it is possible that these differences may be due to an alteration in the endogenous levels of nitric oxide synthase and/or the activity of guanylate cyclase, however, no relationship to the hypertensive state of the spontaneously hypertensive rats was apparent.
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PMID:Actions of L- and D-arginine and NG-monomethyl-L-arginine on the blood pressure of pithed normotensive and spontaneously hypertensive rats. 160 Jun 43

We believe that the mechanisms through which nitric oxide and guanylate cyclase produce relaxation are fully functional in cerebral arteries at term in the fetal sheep and probably also in the term human infant. The relation between cGMP levels and the degree of relaxation varies both with age and with the relaxant used in a vessel specific manner. The factors underlying this variability constitute a fruitful area for future research and include possible age-related changes in membrane potential, calcium channel density and currents, and the participation of cGMP-independent mechanisms, to name only a few. Between fetal and newborn life, the biotransformation of nitroglycerin appears to improve significantly, particularly in the smaller more distal cerebral arteries. This improvement may be a clue to other important vascular metabolic and enzymatic changes that occur during the perinatal period. At the endothelial level, responses to A23187, an index of maximum endothelial vasodilator capacity, are relatively stable across the perinatal period and do not change consistently with age across all arteries. More importantly, large arteries, such as the common carotid, appear to relax better than the smaller cerebral arteries, and this difference is greater in fetal than in adult arteries. Responses to ADP disappear with age in the common carotid, but remain or even become enhanced in the cerebral arteries, thus illustrating the key role played by changes in receptor type and distribution in development and maturation.
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PMID:Developmental aspects of endothelial function. 164 68

In previous studies we have determined that both cultured neuronal and astrocyte glial cells prepared from the hypothalamus and brain stem of 1-day-old rats contain specific receptors for angiotensin II (ANG II). Astrocyte glial receptors are coupled to inositol phospholipid hydrolysis, but there is little indication of the intracellular messengers or signal transduction mechanisms coupled to the neuronal ANG II receptors. In the present study, we have determined that ANG II decreases cellular guanosine 3',5'-cyclic monophosphate (cGMP) levels in neuronal but not in astrocyte glial cultures. This effect is both time and concentration dependent and is inhibited by the ANG II-receptor antagonist [Sar1,Ile8]ANG II, showing the involvement of specific ANG II receptors. ANG II has no effects on particulate or soluble guanylate cyclase activities or on efflux of cGMP from neuronal cultures. However, the effects of ANG II on cellular cGMP content are abolished by pretreatment with the calcium channel blockers cadmium and nifedipine, and by the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. These results suggest that calcium entry and possibly activation of a phosphodiesterase enzyme are involved in this ANG II-induced effect. This represents the first demonstration of a receptor-mediated effect of ANG II on an intracellular messenger in neuronal cultures. The functional role of cGMP as an intracellular messenger coupled to ANG II receptors in cultured neurons remains to be determined.
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PMID:Angiotensin II decreases cGMP levels in neuronal cultures from rat brain. 170 34

The cardiovascular effects of endothelin-1 (ET-1) in trout were examined in unanesthetized fish, perfused tissues, and isolated vascular rings. In vivo, a bolus of 500 ng/kg body wt ET-1 transiently lowered arterial (postgill) blood pressure (BP) by nearly 30%; 1,500 ng/kg body wt produced a triphasic, pressor-depressor-pressor, response. Continuous infusion of 0.1, 1, 10, and 30 ng.kg-1.min-1 progressively lowered BP but did not affect heart rate (HR), urine flow, or electrolyte excretion. In the in situ perfused heart ET-1 (10(-11) to 10(-8) M) had no effect on HR or power output. ET-1 produced dose-dependent increases in vascular resistance in the perfused gill, renal-skeletal muscle, and splanchnic circulations, and increased tension, independent of endothelium, in vascular rings from celiacomesenteric (CA) and coronary arteries and anterior cardinal veins (CV). Ventral aortas were refractory to ET-1. In vitro, ET-1 effects were slow in onset and long lasting. External calcium was required for maximal ET-1 responses in gill and CA. ET-1 effects on CA but not CV were partially inhibited by calcium channel blockers, diltiazem, and D 600, and by the guanylate cyclase activators, atrial natriuretic factor, and sodium nitroprusside. [3H]water flux across the perfused gill was stimulated by ET-1 through what appeared to be a vascular-independent mechanism. These experiments show that the trout vasculature is exquisitely sensitive to ET-1, and they suggest that the physiological expression of this peptide has been highly conserved during the course of vertebrate evolution.
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PMID:Cardiovascular effects of endothelin in trout. 182 12

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

Maitotoxin (MTX) activates calcium channels and stimulates phosphoinositide breakdown in pheochromocytoma PC12 cells, while having no effect on basal levels of the cyclic nucleotides cAMP and cGMP. Atrial natriuretic factor (ANF) induces a dose-dependent accumulation of cGMP in PC12 cells through the activation of a membrane bound guanylate cyclase. Effects of ANF on cGMP are independent of extracellular concentrations of calcium. Since agents that activate phosphoinositide breakdown can indirectly affect cyclic nucleotide formation, the effects of MTX on ANF-mediated accumulation of cGMP was studied. MTX induces a dose-dependent inhibition of ANF-mediated accumulation of cGMP. The inhibition by MTX requires the presence of extracellular calcium, but is unaffected by the calcium channel blocker nifedipine. The inhibitory effect of MTX is not mimicked by the calcium ionophore ionomycin. A phorbol ester, PMA, which stimulates protein kinase C, also inhibits ANF-mediated accumulation of cGMP. Sodium nitroprusside induces large accumulations of cGMP in PC12 cells through the stimulation of a soluble guanylate cyclase. Neither MTX nor PMA inhibit nitroprusside-mediated accumulation of cGMP. The results indicate that in PC12 cells, protein kinase C activation, either directly with PMA, and indirectly with MTX through phosphoinositide breakdown and formation of diacylglycerol, leads to inhibition of ANF-mediated, but not nitroprusside-mediated accumulation of cGMP.
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PMID:Effects of maitotoxin on atrial natriuretic factor-mediated accumulation of cyclic GMP in PC12 cells. 215 21

1. In the isolated perfused, noradrenaline (NA)-constricted mesenteric arteries of the rat, acetylcholine (0.003-1 nmol), histamine (0.01-10 nmol) and the calcium ionophore A23187 (0.01-1 nmol), caused endothelium-dependent vasodilatation while the vasodilatation by the K+ channel activator BRL 34915 (0.1-1 nmol) was independent of endothelium. 2. The guanylate cyclase inhibitor, methylene blue at 10 microM did not inhibit the action of any of the vasodilators but at 50 microM reduced the vasodilator effect of acetylcholine (ACh), histamine and A23187. 3. Infusion of ouabain or perfusion with K(+)-free or excess K+ (50 mM) Krebs solution reduced the vasodilator effect of ACh, histamine and A23187, suggesting the action of these agents involves, at least in part, activation of Na+/K(+)-ATPase. The vasodilator effect of BRL 34915 was not affected by ouabain, but abolished during perfusion with Krebs solution containing excess K+ or depleted of K+. 4. Five structurally distinct K+ channel blockers (apamin, crude scorpion venom, procaine, quinidine and tetraethylammonium) attenuated the vasodilator effect of ACh, histamine and A23187. The K+ channel blockers, except apamin and crude scorpion venom, also inhibited the vasodilatation produced by BRL 34915. 5. The vasodilator effect of ACh, histamine or A23187 was not altered in mesenteric vessels of pertussis toxin-treated rats, suggesting that the K+ channels associated with the endothelium-dependent vasodilator effect of these agents are either not coupled to G-proteins or are coupled to G-proteins that are insensitive to pertussis toxin. 6. The calcium channel blockers, diltiazem (0.1 or 1 microM), nifedipine (0.01 or 0.1 microM) or nitrendipine (1 nM) attenuated the vasodilatation produced by ACh, histamine, A23187 and also that by BRL 34915. 7. We conclude that endothelium-dependent vasodilatation induced by ACh, histamine and A23187 is mediated via activation of membrane K+ channels and Na+/K+-ATPase. The K+ channels involved in the vasodilator action of these agents are not coupled to pertussis toxin-sensitive G-proteins and appear to be regulated by Ca2 +.
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PMID:Endothelium-dependent and BRL 34915-induced vasodilatation in rat isolated perfused mesenteric arteries: role of G-proteins, K+ and calcium channels. 216 32

The 1,4-dihydropyridine BAY-K-8644 [methyl-1,4-dihydro-2, 6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate] acts as both a calcium channel agonist and antagonist by stimulating or inhibiting inward calcium current. In AtT-20 mouse pituitary tumor cells, BAY-K-8644 both stimulates and blocks adrenocorticotropin (ACTH) secretion. Because in several cell systems the cytoplasmic enzyme guanylate cyclase is activated, presumably by calcium entry, the effect of BAY-K-8644 on cyclic GMP (cGMP) synthesis in AtT-20 cells was assessed. BAY-K-8644 increased cGMP accumulation in a time-dependent manner. The concentrations of BAY-K-8644, however, required to increase cGMP formation were not associated with its stimulatory effects on secretion but rather with its ability to antagonize basal and (-)-isoproterenol-induced ACTH secretion. The inhibitory effect of BAY-K-8644 on ACTH secretion was not mimicked by 8-Br-cGMP. The cGMP response to BAY-K-8644 was not mimicked by the cationophore, A-23187, or depolarizing concentrations of K+. Other calcium channel antagonists such as nifedipine or verapamil had markedly smaller effects on cGMP formation compared to BAY-K-8644. Sodium nitroprusside and sodium azide both increased cGMP synthesis in AtT-20 cells and both inhibited, to a lesser extent than BAY-K-8644, both basal- and (-)-isoproterenol-stimulated ACTH release. The data suggest that BAY-K-8644 stimulates cGMP synthesis by binding to sites less accessible or poorly activated by other dihydropyridines, and that stimulation of guanylate cyclase is independent of inward calcium current.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:BAY-K-8644-stimulated cyclic GMP synthesis in mouse pituitary tumor cells. 241 44

Bradykinin, which activates polymodal nociceptors, increased cyclic GMP (cGMP) in a capsaicin-sensitive population of cultured sensory neurones from rat dorsal root ganglia (DRG) by stimulating guanylate cyclase, but had no effect on cyclic AMP (cAMP). In nonneuronal cells from DRG, bradykinin increased cAMP, but not cGMP. The bradykinin-induced increase in cGMP in the neurones was completely blocked by removal of extracellular Ca2+, or by incubation of the cells with the calcium channel blockers nifedipine and verapamil. Pretreatment of the neurones with either dibutyryl cGMP or sodium nitroprusside (which elevates cGMP) inhibited bradykinin-induced formation of inositol phosphates. It is possible that cGMP could be involved in the regulation of polyphosphoinositide turnover in DRG neurones.
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PMID:Activation of guanylate cyclase by bradykinin in rat sensory neurones is mediated by calcium influx: possible role of the increase in cyclic GMP. 247 84


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