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 hypothesis that c GMP and sodium nitroprusside (NP), an activator of guanylate cyclase which elevates levels of c GMP, have antiarrhythmic activity was tested in the barium chloride (BaCl2) model of arrhythmias. Electrocardiograms were recorded continuously on tape in unanesthetized New Zealand white rabbits weighing approximately 2.0 kg. BaCl2, 4 mg/kg i.v. bolus, induced frequent ventricular ectopic beats. These ventricular arrhythmias were abolished by 8-bromo-c GMP, 5 mg/kg, injected into the left ventricle (5/6 rabbits), NP 25.0 microgram/kg/min i.v. (6/6), NP 10 micrograms/kg/min i.v. (3/6), and markedly reduced in frequency by NP 10 micrograms/kg/min (3/6). In temporal association with NP, 4 fold increases in c GMP levels in blood and significant increases in myocardial GMP were found compared to control animals (n = 6). In this model, c GMP and NP have significant antiarrhythmic properties. NP effect may be mediated by alterations in c GMP metabolism.
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PMID:Antiarrhythmic effects of cyclic guanosine 3' :5'-monophosphate and sodium nitroprusside on barium chloride arrhythmias in rabbits. 628 53

Using the method of isometric tension measurement in isolated blood vessels, we investigated some mechanisms of action of high calcium concentrations (>3 mM) on the mechanical activity of small branches of the rat mesenteric artery. Calcium in concentrations up to 30 mM caused relaxation of the arteries (calcium relaxation). The amplitude of the effect decreased in the presence of ouabain (10(-4) M), tetraethylammonium (10(-3) M), charibdotoxin (10(-7) M) and in the potassium-free external solution in intact and denuded rings. Glibenclamide (10(-6) M), 4-aminopyridine (10(-3) M), barium (10(-3) M) and cesium (2.10(-2) M) were inefficient. Calcium relaxation of intact vessels was impaired in the presence of N(omega)-nitro-L-arginine (10(-4) M) or methylene blue (10(-4) M) but not in the presence of indomethacin (10(-5) M). The attenuation of calcium relaxation to the same extent was observed in denuded mesenteric arteries. We conclude that calcium can cause relaxation of vascular smooth muscle cells by two mechanisms. The first is mediated via the cell membrane hyperpolarization due to the activation of Na+/K(+)-ATPase and Ca(2+)-activated potassium channels. The second mechanism is endothelium-mediated and depends on the nitrogen monoxide-guanylate cyclase pathway.
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PMID:Mechanisms of vascular wall calcium relaxation. 1036 63

1. The contribution of an endothelium-derived hyperpolarizing factor (EDHF) was investigated in saphenous and mesenteric arteries from endothelial nitric oxide synthase (eNOS) (-/-) and (+/+) mice. 2. Acetylcholine-induced endothelium-dependent relaxation of saphenous arteries of eNOS(-/-) was resistant to N(omega)-nitro-L-arginine (L-NNA) and indomethacin, as well as the guanylyl cyclase inhibitor, 1H-(1,2,4)oxadiazolo(4,3-a) quinoxalin-1-one(ODQ). 3. Potassium (K(+)) induced a dose-dependent vasorelaxation which was endothelium-independent and unaffected by either L-NNA or indomethacin in both saphenous and mesenteric arteries from eNOS(-/-) or (+/+) mice. 4. Thirty microM barium (Ba(2+)) and 10 microM ouabain partially blocked potassium-induced, but had no effect on acetylcholine-induced vasorelaxation in saphenous arteries. 5. Acetylcholine-induced relaxation was blocked by a combination of charybdotoxin (ChTX) and apamin which had no effect on K(+)-induced relaxation, however, iberiotoxin (IbTX) was ineffective against either acetylcholine- or K(+)-induced relaxation. 6. Thirty microM Ba(2+) partially blocked both K(+)- and acetylcholine-induced relaxation of mesenteric arteries, and K(+), but not acetylcholine-induced relaxation was totally blocked by the combination of Ba(2+) and ouabain. 7. These data indicate that acetylcholine-induced relaxation cannot be mimicked by elevating extracellular K(+) in saphenous arteries from either eNOS(-/-) or (+/+) mice, but K(+) may contribute to EDHF-mediated relaxation of mesenteric arteries.
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PMID:Potassium- and acetylcholine-induced vasorelaxation in mice lacking endothelial nitric oxide synthase. 1072 68

1. In phenylephrine (PHE) (1 micro M)-precontracted superior mesenteric arteries from adult rats, low concentration of hydrogen peroxide (H(2)O(2), 10-100 micro M) caused only contraction, while high concentration of H(2)O(2) (0.3-1 mM) caused a biphasic response: a transient contraction followed by a relaxation response. 2. Endothelium removal did not affect the biphasic response. 7,7-Dimethyl-(5Z,8Z)-eicosadienoic acid, diclofenac, furegrelate, or SQ 29548 greatly inhibited the contraction but did not affect the relaxation. 17-Octadecynoic acid, eicosatriynoic acid, ICI 198615, SQ 22536, or ODQ did not inhibit the biphasic response. 3. KCl at 40 mM inhibited the relaxation response to H(2)O(2) by 98+/-24%. 4-Aminopyridine (4-AP) inhibited while tetraethylammonium chloride (TEA), charybdotoxin, or glibenclamide attenuated the relaxation response. A combination of 4-AP, TEA and glibenclamide mimicked the effects of 40 mM KCl. Iberiotoxin, apamin, or barium chloride did not inhibit the relaxation response. 4. H(2)O(2) at 1 mM hyperpolarized membrane potential and reversibly augmented K(+) current in smooth muscle cells of mesenteric artery. These effects of H(2)O(2) were attenuated significantly by 4-AP. 5. In summary, in PHE-precontracted rat mesenteric artery: (1) the response to H(2)O(2) shifted qualitatively from contraction to a biphasic response as H(2)O(2) increased to 0.3 mM or higher; (2) the relaxation response is caused by the activation of K(+) channels, with voltage-dependent K(+) channels playing a primary role; and the contraction is likely to be mediated by thromboxane A(2); (3) the K(+) channel activation by H(2)O(2) is independent of phospholipase A(2), cyclooxygenase, lipoxygenase, cytochrome P450 monooxygenase, adenylate or guanylate cyclase.
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PMID:Mechanisms of hydrogen-peroxide-induced biphasic response in rat mesenteric artery. 1268 64

The effect of histamine on the pressure-induced constriction was characterized in rat cerebral arteries and mechanisms were investigated. Rat cerebral arteries were pressurized to 70 mm Hg in an arteriograph and the effect of histamine on myogenic tone was studied. Histamine and amthamine, a selective histamine H(2)-receptor agonist, concentration-dependently decreased myogenic tone, which was unchanged in the absence of endothelium. 2-(2-aminoethyl) pyridine, a selective histamine H(1)-receptor agonist, produced concentration-dependent constriction of arteries that was significantly increased in the absence of endothelium. Imetit, a selective histamine H(3)-receptor agonist, has no effect on myogenic tone. The dilation to histamine was antagonized by tiotidine, a selective antagonist of histamine H(2)-receptor subtype, giving a pK(B) of 7.86 that was not altered in the absence of endothelium. The histamine-mediated dilation was significantly antagonized by NF 449, a reversible inhibitor of Gs-protein activation but was not affected by ODQ and SQ 22536. Dilations to histamine and amthamine were accompanied by a decrease in arterial wall calcium measured by fura-2 ratios. The dilation to histamine was significantly reduced by partial depolarization of smooth muscle by 25 mM KCl (control 91+/-5%, 25 mM KCl 53+/-5%, P<0.002) and was not observed in the presence of strongly depolarizing 60 mM KCl. The histamine dilation was not affected by iberiotoxin, barium chloride and glibenclamide but was strongly antagonized by 4-aminopyridine (0.3 mM) and tetraethylammonium chloride (10 mM) (pEC(50): control: 5.6+/-0.1, 4-aminopyridine: 4.1+/-0.1 (P<0.001); tetraethylammonium chloride: 3.2+/-0.2 (P<0.0001)). These results suggest that histamine-mediated reversal of myogenic tone in rat cerebral arteries is endothelium-independent, mediated by histamine H(2)-receptor subtype with no involvement of guanylyl cyclase or adenylyl cyclase activation and most likely involves activation of K(V) potassium channels.
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PMID:Histamine decreases myogenic tone in rat cerebral arteries by H2-receptor-mediated KV channel activation, independent of endothelium and cyclic AMP. 1692 98

The role of C-type natriuretic peptide (CNP) in the gastrointestinal tract is still unclear. This study was designed to investigate the effect of CNP on barium current (I(Ba)) through the L-type calcium channel in gastric antral myocytes of guinea pigs. The whole-cell patch clamp technique was performed in gastric antral myocytes isolated by collagenase in guinea pigs. CNP significantly inhibited I(Ba) in a dose-dependent manner at the concentrations of 0.001, 0.01, and 0.1 micromol/l, CNP inhibited I(Ba) to 81.56 +/- 2.48 %, 73.64 +/- 3.65 %, and 57.77 +/- 4.93 % of control at 0 mV, respectively. The values of steady-state half-inactivation voltage (33.6 +/- 2.6 mV and 33.8 +/- 3.4 mV, in control and CNP groups, respectively) or the half-activation voltage (-12.6 +/- 2.2 mV and 12.4 +/- 1.8 mV) of I(Ba) were not significantly changed (p > 0.05, n = 6). 8-br-cGMP (1 mmol/l) mimicked the effect of CNP on I(Ba), and the peak current of I(Ba) was inhibited from -403.84 +/- 61.87 pA to 318.94 +/- 67.17 pA (p < 0.05, n = 5). In the presence of LY83583 (0.1 micromol/l), a nonspecific inhibitor of guanylate cyclase, CNP (0.1 micromol/l)-induced inhibition of I(Ba) was partially blocked (n = 13, p < 0.05 ). However, when the cell was pretreated with zaprinast (0.1 micromol/l), an inhibitor of cyclic guanosine monophosphate (cGMP) sensitive phosphoesterase, the inhibitory effect of CNP on I(Ba) was significantly potentiated (n = 11, p < 0.05). KT5823 (1 micromol/l), a cGMP-dependent protein kinase (PKG) inhibitor, almost completely blocked CNP-induced inhibition of I(Ba). The results suggested that CNP can inhibit L-type calcium channel currents, and the inhibitory effect is mediated by pGC-cGMP-PKG-dependent signal pathway in gastric antral myocytes of guinea pigs.
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PMID:Inhibitory effect of C-type natriuretic peptide on L-type calcium channel currents in gastric antral myocytes of guinea pigs. 1735 30

The ability of agmatine, formed from L-arginine by the enzyme arginine decarboxylase (ADC), to modulate vasomotor function in rat aorta was investigated in the present study. Agmatine-mediated modulation of vasomotor tone was studied in organ chambers, protein expression quantified by Western blot analysis and cyclic guanosine 5'-monophosphate (cGMP) levels measured by radioimmunoassay. Agmatine (10(-10) to 10(-3) M) produced concentration-dependent relaxations (82+/-5%) in phenylephrine-contracted endothelium intact rat aorta. Relaxations to agmatine were diminished on denudation of endothelium and nitric oxide synthase (NOS) inhibition by L-Nomega-nitro arginine or soluble guanylate cyclase inhibition by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (P<0.001) abolished agmatine-mediated relaxations, while relaxations were insensitive to inducible NOS inhibition by 1400W. Agmatine-treated aorta demonstrated increased protein expression of phosphorylated S473-Akt and phosphorylated S1177-endothelial nitric oxide synthase (eNOS), and elevated the levels of cyclic GMP (P<0.01). Agmatine-mediated potentiation of relaxations and elevation of cGMP levels was sensitive to phosphatidylinositol 3'-kinase inhibitor, wortmannin. Relaxations to agmatine were also affected by pre-treatment with tetraethylammonium (P<0.01) or apamin (P<0.05), and were not affected by charybdotoxin. Relaxations to agmatine were partially affected by pre-treatment of aortic rings with barium chloride (P<0.05), and glybenclamide (P<0.05). Results obtained suggest that agmatine activates protein kinase B/Akt to phosphorylate eNOS and elevate cyclic GMP levels to produce vasodilatation of aorta. Agmatine-mediated relaxations in rat aorta seems to be mediated mainly by endothelial NO-mediated activation of small conductance Ca2+-activated K+ channels, and partly by ATP-sensitive and inward rectifying K+ channels.
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PMID:Activation of protein kinase B/Akt and endothelial nitric oxide synthase mediates agmatine-induced endothelium-dependent relaxation. 1764 Jun 32

1-Hydroxy-2, 3, 5-trimethoxyxanthone (HM-1) is a xanthone isolated from Halenia elliptica, a Tibetan medicinal herb. HM-1 (0.33-42.1 microM) produced a concentration-dependent relaxation in rat coronary artery rings pre-contracted with 1 microM 5-hydroxytryptamine (5-HT), with an EC(50) of 1.67+/-0.27 microM. Removal of the endothelium significantly affected the vasodilator potency of HM-1, resulting in 46% decrease in E(max) value. The endothelium-dependent effects of HM-1 was confirmed when its vasorelaxant effect was inhibited after addition of nitric oxide synthase (NOS) inhibitor N(omega)-nitro-l-arginine methyl ester (100 microM) or the soluble guanylate cyclase inhibitor 1H-[1, 2, 4] oxadiazolo [4,3-alpha] quinoxalin-1-one (ODQ, 10 microM). Atropine (100 nM), flurbiprofen (10 microM), propranolol (100 microM), pyrilamine (10 microM), cimetidine (10 microM) and SQ22536 (100 microM) had no effect on the vasorelaxant activity of HM-1 indicated the non-involvement of other receptor/enzyme systems. In endothelium-denuded coronary artery rings, the vasorelaxant effect of HM-1 was unaffected by potassium channel blockers such as tetraethylammonium (10 mM), iberiotoxin (100 nM), barium chloride (100 microM) and 4-aminopyridine (1 mM). The involvement of Ca(2+) channel in 5-HT-primed artery ring preparations incubated with Ca(2+)-free buffer was confirmed when HM-1 (9.93 microM) partially abolished the CaCl(2)-induced vasoconstriction (87% inhibition in intact-endothelium artery rings; 50% inhibition in endothelium-denuded rings). In the KCl-primed preparations incubated with Ca(2+)-free buffer, HM-1 (9.93 microM) produced a 27.3% inhibition in endothelium-denuded rings. HM-1 (3.31-33.1 microM) had minimal relaxant effects (14.4%-20.3%) on the contractile response generated by 10 microM phorbol 12,13-diacetate (PDA) in Ca(2+)-free solutions, suggesting minimal effects on intracellular Ca(2+) mechanisms. These findings suggest the vasodilator action of HM-1 involved both an endothelium-dependent mechanism involving NO and an endothelium-independent mechanism by inhibiting Ca(2+) influx through L-type voltage-operated Ca(2+) channels; a minor contribution to the effects of HM-1 may be related to inhibition of the protein kinase C-mediated release of intracellular Ca(2+) stores.
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PMID:Mechanisms of the vasorelaxant effect of 1-hydroxy-2, 3, 5-trimethoxy-xanthone, isolated from a Tibetan herb, Halenia elliptica, on rat coronary artery. 1782 18

We previously reported that piceatannol isolated from the rhizome extract of RHEUM UNDULATUM has a potent vasorelaxant activity. In the present study, the mechanisms underlying the direct vascular relaxant effect of piceatannol were investigated in isolated rat aorta. Piceatannol induced a concentration-dependent relaxation in aortic preparations precontracted with phenylephrine (EC (50) : 2.4 +/- 0.4 microM), which was completely inhibited by endothelial removal, N(omega)-nitro- L-arginine (nitric oxide synthase inhibitor), methylene blue and 1 H- oxadiazolo [4,3- A]quinoxalin-1-one (guanylyl cyclase inhibitor). The piceatannol-induced relaxation was also blocked by raising the extracellular K (+) (45 mM), 4-aminopyridine (voltage-sensitive K (+) channel blocker) and tetraethylammonium [the non-selective Ca (2+)-activated K (+) (K (Ca)) channel blocker] but not by indomethacin (cyclooxygenase inhibitor), atropine (muscarinic receptor antagonist), propranolol (beta-adrenoceptor antagonist), verapamil and nifedipine (L-type voltage-gated Ca (2+) channel blocker), barium chloride (inward rectifier K (+) channel inhibitor) and glibenclamide (ATP-sensitive K (+) channel blocker). In further studies investigating the role of Ca (2+)-activated K (+) (K (Ca)) channels, piceatannol-induced relaxant responses were decreased by charybdotoxin [large (BK (Ca))- and intermediate (IK (Ca))-conductance K (Ca) channel blocker], iberiotoxin (selective BK (Ca) channels blocker), but not by apamin [small-conductance K (Ca) (SK (Ca)) channel blocker], TRAM-34 [intermediate-conductance K (Ca) (IK (Ca)) channel blocker]. The present results demonstrate that piceatannol-induced vascular relaxation in rat aorta may be mediated by an endothelium-dependent nitric oxide signaling pathway, at least partially, through the activation of BK (Ca).
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PMID:Large conductance Ca2+-activated K+ (BKCa) channels are involved in the vascular relaxations elicited by piceatannol isolated from Rheum undulatum rhizome. 1796 May 14

1, 5-Dihydroxy-2, 3-dimethoxy-xanthone (HM-5) is one of the naturally-occurring xanthones of a Tibetan medicinal herb Halenia elliptica. Recently, it has been shown that HM-5 is one of the phase I metabolites of 1-hydroxy-2, 3, 5-trimethoxy-xanthone (HM-1), the major active component of H. elliptica with potent vasorelaxant actions. This study investigated the vasorelaxant effect of HM-5 and its mechanism(s). HM-5 (0.35-21.9 microM) produced a concentration-dependent relaxation in rat coronary artery rings pre-contracted with 1 microM 5-hydroxytryptamine (5-HT), with an EC(50) of 4.40+/-1.08 microM. Unlike HM-1, the effect of HM-5 was endothelial-independent such that removal of the endothelium did not affect its vasodilator potency. Nitric oxide synthase (NOS) inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME, 100 microM), the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-alpha] quinoxalin-1-one (ODQ, 10 microM) did not affect the vasodilatory effects of HM-5, thus confirming the non-involvement of endothelium related mechanisms. In endothelium-denuded coronary artery rings, the vasorelaxant effect of HM-5 was inhibited by a potassium channel blocker, TEA (10 mM), and 4-aminopyridine (4-AP, a K(v) blocker; 1 mM) but not by other K+ channel blockers such as iberiotoxin (100 nM), barium chloride (100 microM) and glibenclamide (10 microM). The involvement of Ca2+ channel was studied in artery rings pre-incubated with Ca2+-free buffer (intact endothelium or endothelium-denuded) and primed with 1 microM 5-HT or 60 mM KCl prior to the addition of CaCl2 to elicit contraction. In the 5-HT-primed preparations, HM-5 (34.7 microM) significantly inhibited the CaCl(2)-induced vasoconstriction (89.9% inhibition in intact endothelium artery rings; 83.3% inhibition in endothelium-denuded rings). In the KCl-primed preparations, HM-5 (34.7 microM) produced a 34% inhibition in endothelium-denuded rings. The same concentration of HM-5 inhibited (by 62.3%) the contractile response to 10 microM phorbol 12, 13-diacetate (PDA), a protein kinase C activator, in Ca2+-free solutions. Taken together, this study showed that the mechanisms of the vasorelaxant effects of HM-5 were distinctly different from those of its parent drug HM-1. The vasorelaxant effect of HM-5 was mediated through opening of potassium channel (4-AP) and altering intracellular calcium by partial inhibition of Ca2+ influx through L-type voltage-operated Ca2+ channels and intracellular Ca2+ stores.
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PMID:Mechanisms of the vasorelaxant effect of 1, 5-dihydroxy-2, 3-dimethoxy-xanthone, an active metabolite of 1-hydroxy-2, 3, 5-trimethoxy-xanthone isolated from a Tibetan herb, Halenia elliptica, on rat coronary artery. 1804 22


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