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)

Endothelium-dependent relaxation of mesenteric resistance arteries of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats was studied. Acetylcholine-induced relaxation of SHR vessels precontracted with 10 microM norepinephrine was endothelium dependent and attenuated compared with WKY vessels. The impaired response of SHR vessels was normalized by inhibition of cyclooxygenase with indomethacin. Blockade of nitric oxide synthetase with NG-nitro L-arginine methyl ester (L-NAME) or inhibition of guanylate cyclase with methylene blue attenuated acetylcholine-induced relaxation of norepinephrine-contracted SHR vessels but had no effect on WKY vessels. When vessels were precontracted with 30 nM arginine vasopressin, acetylcholine induced similar degrees of relaxation in both strains. A similar response was detected when lysine vasopressin was used to induce tone. Indomethacin had no effect on relaxation responses of SHR and WKY vessels precontracted with either form of vasopressin. L-NAME and methylene blue partially inhibited acetylcholine-induced relaxation of vasopressin-contracted vessels from both strains. Acetylcholine added at baseline did not induce contraction of vessels from either strain. It is concluded that endothelium-dependent relaxation of SHR resistance arteries is not impaired under all circumstances. Acetylcholine-induced relaxation may be suppressed in SHR resistance arteries when norepinephrine is used to induce contraction as a result of catecholamine-induced production of an endothelium-derived contracting factor. Vasopressin, on the other hand, does not elicit production of this contracting factor and may enhance the vasorelaxant action of acetylcholine in resistance arteries of both strains via actions on endothelial or vascular smooth muscle cells.
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PMID:Endothelium-dependent relaxation of hypertensive resistance arteries is not impaired under all conditions. 841 84

Microinjection of N-methyl-D-aspartate (NMDA; 1 and 2.5 nmol) or kainate (KA; 50 pmol) into the deep prepiriform cortex elicited behavioral signs of seizure activity. No epileptiform activity was observed after deep prepiriform cortex microinjection of either L-arginine (L-Arg, 5 and 10 nmol) or its D-enantiomer, D-arginine (D-Arg, 2.5-10 nmol). However, both the seizure score and the incidence of electroencephalographic (EEG) epileptic discharges elicited by NMDA (1 and 2.5 nmol) and KA (50 pmol) were significantly increased by L- but not D-Arg. The facilitatory effects of L-Arg on seizure activity elicited by both NMDA and KA were dose-dependent and could be prevented by co-administration of L-Arg (10 nmol) and the nitric oxide (NO) synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 20 nmol). Motor and electrocortical seizures were observed after microinjection of the NO donor sodium nitroprusside (SNP; 5 to 20 nmol) into the deep prepiriform cortex. Infusion of methylene blue (20 nmol), a soluble guanylate cyclase inhibitor, protected against SNP-induced seizures. Furthermore, prior infusion of a subconvulsant dose of SNP into the deep prepiriform cortex significantly potentiated the seizure activity elicited by either NMDA (1 and 2.5 nmol) or KA (50 pmol). These results support the proposal that NO is formed from L-Arg upon excitatory amino acid receptor activation within the deep prepiriform cortex, thereby contributing to the genesis of seizure activity.
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PMID:L-arginine potentiates excitatory amino acid-induced seizures elicited in the deep prepiriform cortex. 842 97

1. The dependence on extracellular L-arginine of vascular hyporeactivity induced by bacterial lipopolysaccharide (LPS) was studied in vivo in rats infused with LPS and in vitro in endothelium-denuded rat thoracic aortic rings exposed to LPS. 2. Infusion of LPS during 50 min at a dose of 10 mg kg-1 h-1 produced a significant impairment of the pressor effect of noradrenaline, while in tissues collected 60 min after the start of LPS infusion, no significant alteration in either plasma arginine concentration or aortic arginine content was found compared to saline-infused controls (where plasma arginine was 78.5 +/- 7 microM and aortic arginine 394 +/- 124 nmol g-1 tissue). 3. Incubation of isolated, endothelium-denuded aortic rings with LPS (10 micrograms ml-1) in the absence of L-arginine for 4 h at 37 degrees C produced a 6 fold (P < 0.01) rightward shift in the noradrenaline concentration-effect curve compared to polymyxin B (1 micrograms ml-1, a LPS neutralizing agent) and reduced by 15% the maximum observed tension. 4. The presence of L-arginine (100 microM) during the incubation with LPS and throughout the following contraction experiments caused a 15 fold (P < 0.01) increase in the EC50 of noradrenaline and greater depression (45%) of the maximum observed tension compared to polymyxin B-treated controls. Responses in control, non LPS-treated rings were unaffected by the presence of L-arginine. 5. The addition of L-arginine to rings incubated with LPS in the absence of L-arginine and maximally precontracted with noradrenaline (10 microM) induced a dose-dependent relaxation. The EC50 of L-arginine was 8.0+/-0.3mu.6. The reactivity of LPS-treated rings to noradrenaline both in the absence and presence of L-arginine was restored to control levels by N0-nitro-L-arginine methyl ester (L-NAME, 300 mu), an inhibitor of NO production and by methylene blue (3 JAM), an inhibitor of guanylate cyclase.7. Incubation of isolated aortae in the absence of L-arginine did not significantly decrease the tissue arginine content, whether LPS (10 fg ml-') was present or not. Similarly, the presence of L-arginine(100 mu) in the incubation medium did not modify the tissue arginine content.8. These results show that the LPS-induced impairment of vasoconstriction elicited by noradrenaline is dependent on extracellular L-arginine, although the tissue arginine content is not depleted after LPS pretreatment, and that circulating L-arginine is sufficient to activate maximally the vascular L-arginine/NO pathway in endotoxaemic rats.
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PMID:Dependence of endotoxin-induced vascular hyporeactivity on extracellular L-arginine. 842 12

The contribution of nitric oxide to mesenteric arterial vasodilator responses was investigated in the isolated perfused mesenteric arterial bed of cirrhotic rats (carbon tetrachloride/phenobarbitone; n = 6). Age-matched (n = 9) and phenobarbitone-treated rats (n = 9) served as controls. Responses to the endothelium-dependent dilators acetylcholine and adenosine 5'-triphosphate (ATP) and the smooth muscle dilator (NO donor) sodium nitroprusside were investigated after tone was raised by continuous infusion of methoxamine, before and during infusion of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 30 mumol/L) +/- L-arginine (1 mmol/L). A significant hyporesponsiveness to methoxamine infusion in cirrhotic preparations (P < .05) was not fully corrected by L-NAME. There was no difference in the percentage vasodilator response to acetylcholine in the cirrhotic group compared with controls; L-NAME significantly and reversibly inhibited the dilator response in all groups. ATP elicited dose-dependent vasodilation that, in the absence of L-NAME, did not differ between the groups. By contrast, in the presence of L-NAME, ATP (5 x 10(-8) mol) produced pronounced, reversible vasoconstriction only in cirrhotic animals (P < .02). Vasodilatation attributable to sodium nitroprusside (5 x 10(-8) mol) was significantly attenuated in cirrhotic rats. The methoxamine data support the concept of mesenteric hyposensitivity to vasoconstrictor agents in cirrhosis that may be at least partly NO mediated. Increased NO activity in smooth muscle leading to decreased guanylate cyclase availability may account for the diminished vasodilator responses to sodium nitroprusside in cirrhotic preparations. The unchanged responsiveness to vasodilatation by acetylcholine (ACh) and the vasoconstriction to ATP observed during NO blockade in cirrhotic animals indicate that mesenteric endothelial NO is unchanged or possibly diminished.
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PMID:Mesenteric vasodilator responses in cirrhotic rats: a role for nitric oxide? 855 32

Ephedrine is the preferred vasoconstrictor for the treatment of hypotension after epidural and spinal anesthesia in obstetrics because it preserves uterine perfusion better than pure alpha-adrenergic agonists. Previous studies of uterine vascular rings in vitro suggested that direct uterine vasoconstriction from ephedrine is reduced during pregnancy. This study examined the hypothesis that nitric oxide synthase (NOS) is up-regulated in uterine arteries during pregnancy, and that ephedrine stimulates NOS to release nitric oxide (NO) and diminish direct vasoconstriction. Uterine arterial vessels were obtained from 12 pregnant and 9 nonpregnant ewes, and vessel tension was monitored in vitro in response to escalating concentrations of ephedrine or metaraminol. In some experiments, vascular endothelium was mechanically removed, while in others antagonists of NO synthesis (N omega-nitro-L-arginine methyl ester [L-NAME], NO diffusion (hemoglobin [Hgb]), or guanylate cyclase (methylene blue [MB]) were included. In other experiments, solutions containing ephedrine were superfused over uterine arteries from pregnant ewes onto uterine arteries from nonpregnant ewes. Finally, NOS activity, determined by 14C-citrulline generation, was determined in uterine arteries from pregnant and nonpregnant ewes. Both ephedrine and metaraminol caused concentration-dependent constriction of uterine arterial rings from pregnant and nonpregnant animals. Pregnancy reduced maximum constriction from ephedrine more than metaraminol. Similarly, ephedrine-induced constriction was increased more than that of metaraminol in uterine arteries from pregnant animals treated to diminish the effects of nitric oxide (L-NAME, Hgb, MB, endothelium removal). Ephedrine's constriction of uterine arteries from nonpregnant animals was reduced when it was superfused over uterine arteries from pregnant animals. NOS activity was increased in uterine arteries from pregnant compared to nonpregnant animals. These studies confirm decreased direct uterine arterial vasoconstriction during pregnancy from ephedrine and support the hypothesis of increased release of an endogenous vasodilator (NO), either from the vascular endothelium or the vessel wall, as the cause for this decreased vasoconstriction.
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PMID:Pregnancy and ephedrine increase the release of nitric oxide in ovine uterine arteries. 856 28

This study was designed to explore the effect of ginsenosides, saponins from Panax ginseng, on the vasodilator nerve actions in the rat perfused mesentery and the mechanism of this effect. In the rat perfusion mesentery, when adrenergic nerves were blocked by guanethidine (5 x 10(-6) M) and vascular muscle tone was increased with methoxamine (5 x 10(-6)-10(-5) M), transmural field stimulation produced a frequency-dependent vasodilator response, which is due to the release of calcitonin gene-related peptide; ginsenosides significantly suppressed this vasodilator response in a concentration-dependent manner (3-30 micrograms mL-1). After pretreatment with saponin (50 micrograms mL-1, 3 min) to damage endothelial cells, this suppressing effect of ginsenosides was unaltered. However, the effect was abolished by N omega-nitro-L-arginine methyl ester (L-NAME) (10(-4) M), an inhibitor of nitric oxide synthesis and addition of L-arginine (3 x 10(-4) M) restored this suppressing effect. Methylene blue (10(-5) M), an inhibitor of guanylate cyclase, also abolished the suppressing effect of ginsenosides. However, ginsenosides did not alter the relaxation responses caused by exogenous calcitonin gene-related peptide administration. We conclude that ginsenosides can produce an inhibitory effect on the vasodilator response prejunctionally in the rat perfused mesentery and that this effect of ginsenosides may be mediated by nitric oxide released from non-adrenergic, non-cholinergic nerves.
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PMID:Effects of ginsenosides on vasodilator nerve actions in the rat perfused mesentery are mediated by nitric oxide. 856 31

Recent reports suggest that endothelial-dependent relaxant factor, recognized as nitric oxide (NO), reduces myocardial contractility. Here, we showed that both exposures to acetylcholine and bradykinin for 30 min increased cyclic guanylate monophosphate (cyclic GMP) in isolated rat cardiomyocytes. These increases in cyclic GMP were blunted by NW-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase. Hypoxia augmented the cyclic GMP accumulation due to exposures to acetylcholine and bradykinin, which were blunted by L-NAME. The increases in cyclic GMP due to acetylcholine and bradykinin during normoxic and hypoxic conditions were not blunted by aminoguanidine, an inhibitor of inducible NO synthase. These findings revealed that NO is produced in cardiomyocytes due to stimulation of NO synthase and modulates their own guanylate cyclase, which was augmented by hypoxia. NO production, through NO synthase in cardiomyocytes, may constitute autocrine regulations of myocardial contractility and paracrine regulations of coronary vasodilation and platelet aggregation.
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PMID:Evidence for nitric oxide generation in the cardiomyocytes: its augmentation by hypoxia. 857 31

Previous studies from our laboratory have shown that an extrinsic nitric oxide (NO) donor (i.e., nitroprusside) caused vasodilatation and negative inotropy by activating guanylate cyclase and increasing myocardial cyclic GMP. We tested the hypothesis that endogenous myocardial NO production would limit myocardial oxygen consumption and function in vivo. We used the NO synthase inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA) in nine open-chest anesthetized mongrel dogs. Either L-NAME (6 mg/kg) or L-NMMA (3 mg/kg) were infused into the left anterior descending coronary artery (LAD). The circumflex (CFX) coronary artery region served as a control. Regional segment work was calculated as the integrated product of local force (miniature transducer) and segment shortening (ultrasonic crystals). Local myocardial O2 consumption was determined using an ultrasonic LAD flow probe and local arterial-venous O2 content difference (oximetry). Cyclic GMP levels were obtained via a radioimmunoassay. Both L-NAME and L-NMMA caused a local decrease in coronary blood flow (LAD flow: 80 +/- 8 to 69 +/- 7 ml/min/100 g [means +/- SEM]) and increased O2 extraction (9.1 +/- 0.6 to 10.2 +/- 0.7 ml O2/100 ml). However, this led to no change in local O2 consumption. LAD segment force was not altered (12.1 +/- 0.7 to 11.6 +/- 0.9 g), nor was the percent shortening changed (10.8 +/- 1.8% to 10.0 +/- 1.4%) by L-NAME or L-NMMA, leading to no net change in segment work. Myocardial cyclic GMP levels were not different in a comparison between the LAD (1.7 +/- 0.4 pmoles/g) and control (1.7 +/- 0.2) regions with either L-NAME or L-NMMA. We conclude that blockade of endogenous NO production with L-NAME and L-NMMA is sufficient to cause vasoconstriction in the heart of anesthetized dogs. However, this dose did not lead to alteration in local myocardial function, O2 consumption, or cyclic GMP levels.
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PMID:Endogenous basal nitric oxide production does not control myocardial oxygen consumption or function. 861 38

1. The aims of this study were to compare in the rat isolated perfused lung preparation, the dilator actions of nicorandil, pinacidil and nitroglycerin on the hypoxic pulmonary pressure response with or without hypercapnic acidosis and to investigate the possible involvement of K channels and EDRF in these effects. 2. Isolated lungs from male Wistar rats (260-320 g) were ventilated with 21%O2 + 5%CO2 + 74%N2 (normoxia) or 5%CO2 + 95%N2 (hypoxia) and perfused with a salt solution supplemented with ficoll and gassed with 40%CO2 + 60%N2 to produce hypercapnic acidosis. Glibenclamide (1 microM), charybdotoxin (0.1 microM), NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) and methylene blue (30 microM) were used to block KATP channels, KCa channels, EDRF synthesis and guanylate cyclase, respectively. 3. Hypoxic pressure response was significantly increased by hypercapnic acidosis (+115%, P < 0.001), L-NAME (+111%, P < 0.001), methylene blue (+100%, P < 0.05) but not by glibenclamide or charybdotoxin. In contrast none of these inhibitors affected the hypoxic hypercapnic acidosis response. 4. Nicorandil, pinacidil and nitroglycerin caused relaxation during the hypoxic pressure response and hypoxic hypercapnic acidosis response. Nicorandil was more potent in the latter. Glibenclamide inhibited the relaxant effects of nicorandil and pinacidil but not those of nitroglycerin during hypoxia alone. In contrast, glibenclamide inhibited the relaxant effects of the three drugs during hypoxia + hypercapnia. Charybdotoxin inhibited the relaxant effect of pinacidil during normocapnia and hypoxia but not those of nicorandil or nitroglycerin. Methylene blue inhibited partially the dilator response to pinacidil but did not modify the effects of nitroglycerin or nicorandil. 5. It is concluded that in the rat isolated lung preparation, EDRF limits hypoxic pulmonary vasoconstriction but not hypoxic vasoconstriction potentiated by hypercapnic acidosis, whereas KATP or KCa channels are not involved in either case. Nicorandil and pinacidil dilate pulmonary vessels mainly through KATP channels but the effects of pinacidil may also involve an additional mechanism of action through KCa channels. Finally it is suggested that nitroglycerin may partly exert its relaxant effects through KATP channels.
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PMID:Comparison of the effects of nicorandil, pinacidil and nitroglycerin on hypoxic and hypercapnic pulmonary vasoconstriction in the isolated perfused lung of rat. 864 7

1. The effects of the sodium salt of the weak acid lactate on tension and intracellular pH (pH1) were studied in rat mesenteric small arteries mounted on a wire myograph. Sodium lactate was substituted iso-osmotically for sodium chloride. 2. At a concentration of 50 mM, both L- and D-stereoisomers of lactate markedly relaxed arteries preconstricted with noradrenaline (NA) within 10 min. The concentration-response relationship for L-lactate showed that the NA contracture was relaxed by 50% at approximately 26 mM. L-Lactate did not, however, relax arteries preconstricted with high-K+(45 mM) solution. 3. L-Lactate did not alter extracellular pH (pHo) but caused a small but significant decrease in pH1, measured using the pH-sensitive fluorochrome, 2',7'-bis(carboxyethyl)-5-(6)-carboxyfluorescein (BCECF). Relaxation to L-lactate was unaffected when this change in pHi was offset by the simultaneous addition of NH4Cl to the solution. 4. Sodium pyruvate (50 mM) caused a significant intracellular acidosis but did not relax arteries preconstricted with NA. 5. L-Lactate-induced relaxations were unaffected by removal of the endothelium or when the synthesis of nitric oxide (NO) was inhibited by 10(-4) M N omega-nitro-L-arginine methyl ester (L-NAME). 6. The potassium channel blockers glibenclamide (10 microM), 4-aminopyridine (3 mM) and tetraethylammonium chloride (10 mM) did not affect L-lactate-induced relaxation in arteries preconstricted with NA. Inhibition of guanylate cyclase with Methylene Blue, or cyclooxgenase with indomethacin, also did not affect relaxation to L-lactate. 7. The Rp stereoisomer of adenosine-3',5'-cyclic monophosphothioate (Rp-cAMPS), an analogue of cAMP which inhibits competitively stimulation of protein kinase A, reduced significantly L-lactate-induced relaxation at a concentration of 25 microM. Rp-cAMPS also significantly reduced forskolin-induced relaxation of the NA contracture. 8. It is concluded that L-lactate-induced relaxation in this vascular bed is pHi-1 endothelium-, and nitric oxide-independent. It is not mediated by inhibition of voltage-gated Ca2+ channels, opening of K+ channels, prostacylin or cyclic GMP. cAMP may however play a role in L-lactate-induced relaxation.
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PMID:Mechanism of lactate-induced relaxation of isolated rat mesenteric resistance arteries. 868 76


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