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

Nitric oxide (NO) caused a potent, marked, and transient relaxation of precontracted strips of corpus cavernosum isolated from humans and rabbits. The relaxation response elicited by NO was very similar to the relaxation evoked by electrical field stimulation via the nonadrenergic-noncholinergic pathway. Sodium nitroprusside, nitroglycerin, and S-nitroso-N-acetylpenicillamine, which are nitrovasodilators known to generate NO, also caused marked concentration-dependent relaxation of corpus cavernosum. Relaxant responses to NO were enhanced by the cyclic GMP phosphodiesterase inhibitor M&B 22,948 and inhibited by oxyhemoglobin. Similarly, relaxation of corpus cavernosum in response to electrical field stimulation or acetylcholine was enhanced by M&B 22,948 and inhibited by oxyhemoglobin. NO stimulated cyclic GMP formation in corpus cavernosum and a close positive correlation was found between the magnitudes of relaxation and cyclic GMP formation. The data suggest that NO-elicited activation of guanylate cyclase and cyclic GMP formation represents the signal transduction mechanism responsible for relaxation and nonadrenergic-noncholinergic-mediated penile erection. These observations indicate that NO is a potent relaxant of human and rabbit corpus cavernosum and support our hypothesis that endogenous NO is the principal mediator of penile erection caused by nonadrenergic-noncholinergic stimulation.
...
PMID:Nitric oxide is a potent relaxant of human and rabbit corpus cavernosum. 131 69

1. Relaxant responses to nitroprusside were examined on U46619-contracted pulmonary artery ring preparations from rats exposed to hypoxia, in chambers containing 10% oxygen, for 1, 3, or 14 days, or for 14 days followed by 12 days in room air. Control rats were housed in room air. 2. After 3 days of hypoxia (but not 1 day), rats had elevated pulmonary artery pressure, right ventricular hypertrophy and polycythemia. After 14 days of hypoxia there was, in addition, hypertrophy of the pulmonary artery. In rats returned to room air for 12 days after 14 days of hypoxia, there was still some right ventricular and vascular hypertrophy but no increase in pulmonary artery pressure or polycythemia. 3. The potency (neg log EC50) of nitroprusside on pulmonary arteries taken from rats after 3 or 14 days of hypoxia was significantly less than on preparations from control rats (3 and 11 fold, respectively). This was not seen after 1 day of hypoxia or after 14 days of hypoxia followed by 12 days in room air. Removal of the endothelium from the preparations had no effect on the potency of nitroprusside in control or hypoxic rats (14 days). 4. In preparations from hypoxic, but not control, rats (14 days), the maximum response to nitroprusside was > 100% (177% reversal of the U46619 contraction) in the absence, but not in the presence, of the endothelium, indicating that pulmonary arteries from hypoxic rats had inherent tone which could be counteracted by a relaxing factor from the endothelium. 5. Exposure of rats to hypoxia (14 days) did not affect the potency of nitroprusside on aorta or trachea.6. It is concluded that exposure of rats to hypoxia results in reversible desensitization of the vascular smooth muscle of pulmonary artery to nitroprusside. The time course of this desensitization suggests that it is probably associated with the elevated pulmonary artery pressure or maintained hypoxaemia rather than with the vascular hypertrophy.7. It is postulated that the increase in pulmonary artery pressure and/or the maintained hypoxaemia may cause chronic release of nitric oxide from the pulmonary vascular endothelium or smooth muscle resulting in desensitization of soluble guanylate cyclase to the action of nitroprusside.
...
PMID:Reduced relaxant potency of nitroprusside on pulmonary artery preparations taken from rats during the development of hypoxic pulmonary hypertension. 142 89

1. Relaxant responses to six vasodilator drugs, with different mechanisms of action, were examined on noradrenaline (0.1 microM)-contracted ring preparations of pulmonary artery and aorta taken from rats with pulmonary hypertension induced by monocrotaline or chronic hypoxia. 2. On pulmonary artery preparations from monocrotaline-treated rats, compared with controls, (a) the maximum relaxation to pinacidil and cromakalim was significantly increased, but their potency (negative log EC50) was unchanged, (b) the potencies of nitroprusside and sodium nitrite were significantly reduced (10 fold and 3 fold respectively), but there was no change in the maxima, (c) for nicorandil there was an increase in maximum relaxation and a decrease in potency (3 fold), and (d) for atriopeptin II there was no change in potency or maximum. 3. The increase in maximum relaxation for pinacidil and the decrease in potency for nitroprusside were also demonstrated in pulmonary artery preparations from rats with chronic hypoxic pulmonary hypertension. The other four drugs were not examined in preparations from hypoxic rats. 4. In both models of pulmonary hypertension, no change in maximum response or potency was seen on aortic preparations for any of the vasodilator drugs. 5. In control preparations, none of the drugs was more potent on pulmonary artery than on aorta (i.e. they were not pulmonary-selective). In preparations from pulmonary hypertensive rats, pinacidil was selective for pulmonary artery, in contrast to nitroprusside which was selective for aorta.6. It is concluded that the development of pulmonary hypertension in rats is accompanied by changes in the responsiveness of the pulmonary arteries to some vasodilator drugs; whether or not these changes occur depends on the mechanism of action of the vasodilator drug, but they are independent of the method of inducing pulmonary hypertension.7. It is postulated that the reduction in potency seen for nitroprusside, sodium nitrite and nicorandil may be due to desensitization of soluble guanylate cyclase in pulmonary vascular smooth muscle in pulmonary hypertension.
...
PMID:Responses to vasodilator drugs on pulmonary artery preparations from pulmonary hypertensive rats. 159 77

Vasodilatory responses to sodium nitroprusside were compared with those to nitroglycerin in helical strips of blood vessels isolated from dogs, humans, monkeys, rats and guinea-pigs. Sodium nitroprusside relaxed arterial and venous strips contracted with prostaglandin F2 alpha in a dose-related manner, as did nitroglycerin. Relaxant responses to sodium nitroprusside and nitroglycerin were significantly greater in dog coronary arteries than in the mesenteric arteries. Tachyphylaxis developed upon repeated applications of nitroglycerin but not of sodium nitroprusside. In rat and guinea-pig aortae, relaxant responses to sodium nitroprusside and nitroglycerin were markedly suppressed by treatment with methylene blue or oxyhemoglobin. In dog arteries and veins, treatment with oxyhemoglobin significantly inhibited relaxant responses to sodium nitroprusside and nitroglycerin. On the other hand, treatment with methylene blue did not inhibit responses to sodium nitroprusside but markedly suppressed those to nitroglycerin in dog blood vessels as well as in human gastroepiploic and monkey mesenteric arteries. It is concluded that dog and primate blood vessels do not develop tolerance to repeated applications of sodium nitroprusside and that sensitivity of soluble guanylate cyclase to methylene blue may differ in blood vessels from different mammals (dog and primate vs rat and guinea-pig).
...
PMID:Influence of methylene blue and oxyhemoglobin on mammalian vascular responses to sodium nitroprusside and nitroglycerin. 178 9

Hydrogen peroxide produces concentration-dependent relaxation of precontracted isolated bovine intrapulmonary arterial rings by a mechanism which is independent of the endothelium or prostaglandin mediators. Relaxant responses to hydrogen peroxide concentrations of up to 100 microM were markedly attenuated by the inhibitor of soluble guanylate cyclase activation, methylene blue (10 microM). Micromolar concentrations of hydrogen peroxide elicit time- and concentration-dependent increase in arterial levels of guanosine 3',5'-cyclic monophosphate that are associated with decreases in force. Soluble guanylate cyclase activity is markedly activated by enzymatically generated hydrogen peroxide in a manner that is most closely associated with the concentration of catalase present in the assay, by a mechanism that is inhibited by superoxide anion and the inactivation of catalase. Our data are most consistent with the involvement of compound I, a species of catalase formed during the metabolism of peroxide, in the mechanism of guanylate cyclase activation. The nature of this mechanism of arterial relaxation suggests that it could contribute to the regulation of pulmonary vascular tone by oxygen tension.
...
PMID:Hydrogen peroxide elicits pulmonary arterial relaxation and guanylate cyclase activation. 288 94

1. The putative role of vasoactive intestinal polypeptide (VIP) as the relaxant neurotransmitter in human cavernosal smooth muscle has been studied in isolated tissue preparations. 2. Consistent neurogenic relaxations were evoked by electrical field stimulation (EFS; 2-64 pulses/train, 0.8 ms pulse duration, 10 Hz). VIP (0.1-3 microM) relaxed cavernosal smooth muscle in a dose-dependent fashion. Relaxant responses to both EFS and VIP were reduced in tissue from impotent men. 3. Neurogenic relaxant responses were not diminished in the presence of the VIP-inactivating peptidase, alpha-chymotrypsin (alpha-CT, 2 units ml-1). In contrast VIP-induced relaxations were completely abolished. 4. Inhibition of nitric oxide synthase by NG-nitro-L-arginine (30 microM), and of guanylate cyclase by methylene blue (50 microM) caused highly significant reductions of neurogenic relaxant responses whereas VIP-evoked relaxations were unaffected. 5. It is concluded that VIP-evoked relaxations are not mediated by the NO-guanosine 3':5'-cyclic monophosphate (cyclic GMP) pathway and that VIP release is not essential for neurogenic relaxation of human cavernosal smooth muscle. VIP does not therefore act as the major relaxant neurotransmitter in this tissue.
...
PMID:Evidence against vasoactive intestinal polypeptide as the relaxant neurotransmitter in human cavernosal smooth muscle. 809 18

We studied the nitric oxide-cGMP pathway in endothelium-dependent relaxation in femoral arterial rings from piglets at different postnatal ages. Responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were examined in phenylephrine-precontracted rings from newborn (10-22-h) and 7 d (7-10-d)-old piglets. Relaxant responses were investigated in endothelium-denuded rings and endothelium-intact controls, and in endothelium-intact rings incubated with the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine acetate (L-NMMA), indomethacin, or the superoxide anion generator 6-anilinoquinoline-5,8-quinone (LY83583). Arterial rings from both age groups relaxed to a similar degree in response to ACh. Relaxation in rings from newborn piglets was insensitive to NOS inhibition by L-NMMA, whereas in artery rings from 7-d-old piglets, the relaxant response was significantly inhibited by L-NMMA. Incubation with LY83583 gave an inhibition of ACh-induced relaxation very similar to that of L-NMMA. Incubation with indomethacin had no significant effect on ACh-induced relaxation in either age group. Artery rings from both age groups relaxed 100% to SNP; the 7-d-old group was more sensitive than the newborn. NOS inhibition potentiated SNP-induced relaxation in both groups, but the potentiating effect was of greater magnitude in the newborn. Our results indicate a difference in the mechanism(s) underlying ACh-induced relaxation in the femoral artery from newborn and 7-d-old piglets, with an intact relaxant response in rings from the newborn despite NOS inhibition. The SNP results indicate a down-regulated soluble guanylate cyclase in the newborn, possibly related to a difference in basal NO release between the two age groups.
...
PMID:Postnatal changes in mechanisms mediating acetylcholine-induced relaxation in piglet femoral arteries. 912 94

1. Anaesthetized dogs were subjected to 1 h occlusion of the left circumflex coronary artery followed by 2 h of reperfusion. Relaxant responses were examined in coronary artery rings removed proximal (nonischaemic) or distal (ischaemic) to the site of occlusion. 2. Relaxant responses to acetylcholine (ACh) were similar in nonischaemic and ischaemic artery rings. In addition ACh-induced relaxation of nonischaemic and ischaemic artery rings was equally susceptible to inhibition of nitric oxide (NO) synthase using L-N(G)-nitroarginine (L-NOARG, 10(-4) M), or to inhibition of soluble guanylate cyclase using 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 10(-5) M). 3. In nonischaemic arteries, the relaxation to ACh was unaffected by high K+ (67 mM) but in ischaemic arteries, the maximum relaxation to ACh was significantly reduced from 113+/-6 to 60+/-2% (ANOVA, P<0.05). Tetraethylammonium (TEA, 10(-3) M), an inhibitor of large conductance calcium activated potassium (BK(Ca)) channels did not inhibit the response to ACh in nonischaemic arteries but in ischaemic arteries TEA significantly shifted the concentration response curve to ACh to the right (pEC(50); nonischaemic, 7.07+/-0.25; ischaemic, 6.54+/-0.21, P<0.01, ANOVA) without decreasing the maximum relaxation. TEA did not affect the responses to sodium nitroprusside in either nonischaemic or ischaemic arteries. 4. In conclusion, ischaemia/reperfusion did not change the sensitivity of endothelium-dependent relaxation to L-NOARG or ODQ indicating that ischaemia did not affect the contribution of NO or cyclic GMP to ACh-induced relaxation. However, in ischaemic arteries the opening of the BK(Ca) channels contributed to relaxation caused by ACh whereas TEA had no effect in nonischaemic arteries. The factor responsible for the opening of this potassium channel was a factor other than NO and may be endothelium derived hyperpolarizing factor (EDHF).
...
PMID:Enhanced role for the opening of potassium channels in relaxant responses to acetylcholine after myocardial ischaemia and reperfusion in dog coronary arteries. 1019 72

Bradykinin (BK) induced endothelium- and concentration-dependent relaxations in segments of porcine posterior descending coronary arteries submaximally precontracted with the thromboxane A2 mimetic, U-46619. The effects of BK were reduced by L-NG-monomethylarginine (L-NMMA) and 6-anilinoquinoline-5,8-quinone (LY-83583), respective inhibitors of nitric oxide (NO) synthase and guanylate cyclase, but were unaffected by the cytochrome P450 monoxygenase blocker, thiopentone sodium; however, BK effects were slightly reduced by dimethyl sulfoxide (DMSO), an hydroxyl radical scavenger. Relaxant responses were reduced markedly by ouabain, a sodium pump inhibitor but only slightly by tetraethylammonium (TEA) and charybdotoxin, respective blockers of Ca-activated (KCa) and large-conductance (BKCa) K+ channels. However, BK responses were practically abolished by TEA + L-NMMA + ouabain while unaffected by apamin, 4-aminopyridine and glibenclamide, blockers of small-conductance KCa voltage-sensitive and ATP-sensitive K+ channels, respectively. In segments submaximally precontracted with K+, BK-induced relaxation was lower than that of those precontracted with U-46619, and was further reduced by L-NMMA, LY-83583 and especially, ouabain; L-NMMA + ouabain + TEA abolished the effect. Precontraction of segments with higher K+ concentrations almost abolished the relaxation. These results suggest that the relaxation to BK is mediated: 1) by endothelial NO release which activates guanylate cyclase of smooth muscle cells; 2) by hydroxyl radicals; and 3) by an endothelial hyperpolarizing factor, that does not seem to be a metabolite derived from cytochrome P450 monoxygenases and that relaxes activating K+ channels (mainly BKCa), and especially, the sodium pump.
...
PMID:Mechanisms of bradykinin-induced relaxation in pig coronary arteries. 1039 30

Although gender and oestrogen treatment influence production of the vasorelaxant, NO, their influence on factors downstream in the NO signal-transduction pathway, specifically protein kinase G (PKG), remains unknown. We aimed to study the influence of sex hormones on PKG, along with the endothelial modulation of these effects, in rat thoracic aortic rings in two separate groups, control male and female rats and ovariectomized female rats after treatment with oestrogen or vehicle. Vessel preparations were preconstricted with phenylephrine (0.1 microM). Constrictions were greater in male than female aortas. This differential effect was attenuated by endothelium removal, addition of the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 microM) and the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 100 microM), supporting the role of NO in maintenance of basal relaxation and vascular tone in females. We have examined the relative activity of the specific PKG subtypes 1 alpha and 1 beta in vascular smooth muscle, based on relaxation of rat aortas by two cGMP analogues with different selectivity, beta-phenyl-l-N(2)-ethano-8-bromo-cGMP (8-Br-PET-cGMP) and 8-(2-aminophenylthio)cGMP (8-APT-cGMP). 8-Br-PET-cGMP was more potent than 8-APT-cGMP in both sexes, suggesting that PKG 1 alpha is the primary subtype involved in vasorelaxation. The gender differences in PKG activity were examined based on relaxation responses in male and female rat aortas. Both 8-Br-PET-cGMP and 8-APT-cGMP were more potent in aortas from male than female rats. In further studies on the endothelial modulation of relaxation with 8-APT-cGMP, the differential gender-vasorelaxation response was negated by endothelium removal and addition of the guanylate cyclase inhibitor ODQ (1 microM), but not by the NOS inhibitor L-NMMA (100 microM), suggesting that an endothelial-dependent factor other than NO may be responsible for the observed differential PKG-mediated vasorelaxation between the sexes. To further investigate oestrogen influence on PKG, treated female rats were studied. Contrary to our hypothesis, in the presence of 1 microM ODQ, there were no differences in either the phenylephrine constriction, or the relaxation with 8-APT-cGMP from either sham-operated, vehicle-treated or oestrogen-treated ovariectomized rats. In conclusion, female rat aortas have greater basal NO production compared with males. Relaxant responses to PKG activation are greater in aortas from male compared with female rats. These findings suggest hormonal regulation of PKG; however, oestrogen treatment of ovariectomized rats did not affect PKG activity, suggesting factors other than oestrogen may be responsible for the gender differences noted in this study.
...
PMID:Gender differences in protein kinase G-mediated vasorelaxation of rat aorta. 1129 86


1 2 Next >>

---