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)

Bradykinin (BK) and its analogues induce a typical biphasic response (relaxation followed by contraction) in the isolated rat duodenum. We studied the role of B1 and B2 BK receptors and nitric oxide (NO) in relaxation and contraction of the isolated rat duodenum. Both effects are concentration-dependent: BK has shown an EC50 (contraction) of 3.8 +/- 1.9 x 10(-7) M and an IC50 (relaxation) of 3.0 +/- 0.7 x 10(-9). Similar results were obtained with the selective B2 receptor agonists [Hyp3,Tyr(Me)8]-BK and [Phe8 psi (CH2-NH)Arg9]-BK, showing an EC50 of 9.6 +/- 1.9 x 10(-7) M and 5.6 +/- 2.9 x 10(-7) M and an IC50 of 3.5 +/- 0.6 x 10(-10) M and 6.8 +/- 1.7 x 10(-10) M, respectively. Furthermore, the effects induced by these three agonists were not altered when tissues were treated with 42.1 microM Mergetpa, a carboxypeptidase N inhibitor. While the relaxant and contractile effects elicited by BK were significantly inhibited in the presence of Hoe 140 (0.7 microM), a selective B2 receptor antagonist, those induced by the selective B1 receptor agonist desArg9-BK were not. Furthermore, [Leu8]-desArg9-BK (2.6 microM), which is both a pure and selective B1 receptor antagonist, acted as an agonist on the rat duodenum, inducing a biphasic relaxant and contractile effect. These relaxant and contractile effects were not altered by drugs that inhibit or stimulate NO production, such as L-NAME (200 microM), a combination of L-NAME (200 microM) and indomethacin (2.5 microM), L-arginine (1 mM), or superoxide dismutase (20 U/ml). However, the contractile effect was significantly reduced when tissues were preincubated with methylene blue (100 microM), which inhibits activation of guanylate cyclase. We conclude that 1) BK and its analogues selectively activate a B2 receptor, producing a biphasic effect (relaxation and contraction); 2) DesArg9-BK may either acts via a different receptor which might be another B1 receptor subtype or a typical B1 receptor where [Leu8]-desArg9-BK acts as a partial agonist; and 3) neither NO nor the prostaglandin pathway mediates BK-induced relaxation in the isolated rat duodenum.
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PMID:Role of B1 and B2 receptors and of nitric oxide in bradykinin-induced relaxation and contraction of isolated rat duodenum. 752 22

Endothelium-dependent modulation of vascular tone was investigated in isolated porcine and bovine basilar arteries. L-Nitro-arginine (NO synthase inhibitor) and methylene blue (soluble guanylate cyclase inhibitor) increased, but indomethacin (cyclooxygenase inhibitor) decreased the vascular tone in the basilar arteries from both species. Bradykinin evoked relaxation of precontracted porcine basilar artery, but not bovine basilar artery. Sodium fluoride (endothelial G-protein activator) produced relaxation of precontracted basilar arteries from both species. The effects of bradykinin and sodium fluoride were completely abolished by endothelial denudation and markedly inhibited by L-nitro-arginine and methylene blue, but not by indomethacin. Sodium nitroprusside (guanylate cyclase activator) evoked relaxation of precontracted endothelium-denuded basilar arteries from both species. These results suggest that there is species variation in endothelium-dependent modulation of vascular tone in the basilar artery.
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PMID:Endothelial modulation of vascular tone in isolated porcine and bovine basilar arteries. 753 39

To determine whether chronic angiotensin-converting enzyme (ACE) inhibition produces functional changes in the aorta normotensive rats, four groups of rats were studied in parallel for 6 weeks. Group 1 orally received ramipril and beta 2-kinin antagonist HOE140 500 micrograms/kg per day s.c. by injection for the remaining 2 weeks; group 3, hydralazine 100 mg/kg per day PO for 6 weeks; group 4 (control), subcutaneous injections of saline solution during the last 2 of 6 weeks. In aorta isolated from group 1 the relaxations induced by bradykinin, acetylcholine, and histamine were significantly potentiated compared with those of group 4. In group 3, despite a decrease in systolic blood pressure similar to that induced by ramipril treatment, the responses to these three endothelium-dependent vasodilators were not different from those of group 4. In group 2, bradykinin-induced relaxations were completely abolished whereas acetylcholine-induced and histamine-induced relaxations were to those of group 4. The inhibitory effect of the endothelium on serotonin-induced contractions was significantly increased in preparations of group 1 compared with those of groups 2 through 4. Indirect measurements of nitric oxide formation such as contractions evoked by NG-monomethyl-L-arginine (L-NMMA) and aortic cGMP content were also significantly enhanced in preparations from group 1 compared with those of groups 2 through 4. Moreover, because the relaxations to nitroglycerin and nitroprusside were similar in groups 1, 2, and 4 an alteration of the guanylate cyclase activity by ramipril treatment is quite unlikely. Thus long-term treatment with ramipril potentiates the endothelium-dependent responses in the rat aorta by enhancing nitric oxide availability.
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PMID:Chronic angiotensin-converting enzyme inhibition and endothelial function of rat aorta. 759 Oct 12

Increasing evidence points to an important role for nitric oxide in the regulation of pulmonary functions and in pulmonary disease. In the respiratory tract, sensory nerves, endothelial cells, vascular and airway smooth muscle cells, inflammatory cells and the airway epithelium are sources of nitric oxide. Different nitric oxide synthases have been isolated, cloned and sequenced. Functionally, there are constitutive and inducible forms of nitric oxide synthase. A number of cytokines have been shown to inhibit or induce the expression of the inducible nitric oxide synthase. In human airways, endogenous nitric oxide appears to account for the bronchodilator nonadrenergic and noncholinergic response. Nitric oxide-containing vasodilators, such as glyceryl trinitrate and sodium nitroprusside, induce relaxation of the isolated airway smooth muscle, activate guanylate cyclase and raise c-GMP levels. Nitric oxide (constitutive), produced by the epithelial layer, appears to be important in blunting the histamine contractile response of the airway tissue. Furthermore, tracheal relaxation by, e.g., bradykinin or potassium chloride, is mediated by the release of nitric oxide. The virus (Parainfluenza type 3)-induced airway hyperreactivity in guinea-pigs is correlated with a deficiency in endogenous constitutive nitric oxide production by the airways and can be blocked by low doses of L-arginine. In inflamed tissue, nitric oxide quickly reacts with superoxide anion, resulting in the formation of the toxic peroxynitrite which promotes lipid and sulfhydryl oxidation. Asthmatic patients have higher amounts of nitric oxide in the expired air, possibly due to the inflammation. This increased nitric oxide production can be inhibited by inhaled corticosteroids. The effect of inhaled nitric oxide on the lung function of asthmatic patients is variable. In contrast, low doses of inhaled nitric oxide are effective in reversing the pulmonary vasoconstriction. These results point to an important role for nitric oxide in modulating airway reactivity.
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PMID:Nitric oxide and bronchial hyperresponsiveness. 763 22

Responses to substance P were investigated in the pulmonary vascular bed of the cat with controlled pulmonary blood flow and constant left atrial pressure. Under baseline conditions, intralobar injections of substance P caused small, inconsistent reductions in lobar arterial pressure (AP) and significant reductions in mean systemic AP without affecting left atrial pressure. Decreases in lobar AP were significant and dose related when lobar vascular resistance was increased with U-46619, a thromboxane A2 mimetic. When compared with other vasodilator agents, the order of potency was substance P approximately bradykinin > pituitary adenylate cyclase activating polypeptide (PACAP) > acetylcholine (in nmol). Pulmonary vasodilator responses to substance P were unchanged by administration of atropine, glibenclamide, or sodium meclofenamate or when airflow to the left lower lung lobe was interrupted by bronchial occlusion. The NO synthesis inhibitor, N omega-nitro-L-argininemethyl ester (L-NAME), and the soluble guanylate cyclase inhibitor, methylene blue (MB), selectively inhibited pulmonary vasodilator responses to substance P and to acetylcholine. MB or L-NAME had no significant effect on pulmonary vasodilator responses to albuterol, lemakalim, or PACAP, whereas MB inhibited and L-NAME enhanced vasodilator responses to NO and sodium nitroprusside. The present investigation demonstrates that, when tone is increased experimentally, substance P has potent pulmonary vasodilator activity, and responses are not dependent on changes in bronchomotor tone, on the activation of muscarinic receptors or ATP-sensitive K+ channels, or on the release of a dilator prostaglandin but do involve, at least in part, endothelium-derived NO release and soluble guanylate cyclase activation.
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PMID:Analysis of responses to substance P in the pulmonary vascular bed of the cat. 768 May 35

We previously reported that angiotensin II (Ang II) increases cGMP content through a new Ang II receptor subtype that is distinct from both the AT1 and AT2 subtypes in differentiated Neuro-2A cells. In this study, the mechanism of the Ang II-stimulated cGMP increase was investigated in comparison with bradykinin- and atrial natriuretic factor (ANF)-stimulated cGMP increases in differentiated Neuro-2A cells. Ang II increased cGMP in differentiated Neuro-2A cells rapidly, with a maximal effect in 30 sec and a return to basal levels in 60 sec. Removal of extracellular Ca2+ or pretreatment with a membrane-permeable Ca2+ chelator [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester] attenuated Ang II-stimulated cGMP accumulation. Both the time course and Ca2+ dependency of the effect of Ang II were similar to those of the effect of bradykinin, which activates soluble guanylyl cyclase, but distinct from those of the effect of ANF, which activates particulate guanylyl cyclase. Methylene blue, an inhibitor of soluble guanylyl cyclase, attenuated the effects of Ang II and bradykinin but not that of ANF. LaCl3, a nonspecific Ca2+ blocker, prevented Ang II-stimulated cGMP accumulation. L-type Ca2+ channel blockers, nifedipine and diltiazem, or an N-type Ca2+ channel blocker, omega-conotoxin, failed to inhibit the effect of Ang II. Ang II had no effect on formation of 1,4,5-inositol trisphosphate or cAMP content, whereas bradykinin stimulated 1,4,5-inositol trisphosphate formation in differentiated Neuro-2A cells. Further, the nitric oxide synthase inhibitors NG-monomethyl-L-arginine and NG-nitro-L-arginine attenuated Ang II- and bradykinin-stimulated elevation of cGMP content but not that stimulated by ANF. The Ca2+ ionophore A23187 also stimulated cGMP formation and the effect was inhibited by the nitric oxide synthase inhibitors. These results indicate that the newly found Ang II receptor mediates cGMP formation through activation of soluble guanylyl cyclase and that the activation is mediated by nitric oxide, which is increased by Ca2+ influx via an ion channel distinct from the L-type and N-type Ca2+ channels.
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PMID:New signaling mechanism of angiotensin II in neuroblastoma neuro-2A cells: activation of soluble guanylyl cyclase via nitric oxide synthesis. 768 50

Interactions between human glomerular endothelial cells and atrial natriuretic peptide (ANP) were studied with 125I-alpha-human-ANP binding and intracellular accumulation of cGMP. Uptake for alpha-hANP (1-28 or 5-28) by homogeneous cultures of human glomerular endothelial cells was dose and time dependent with optimal uptake occurring after 30 min of incubation at 37 degrees C. Scatchard analysis of the specific binding data with a two-compartmental model identified both high (Kd = 0.3 nM)- and low (Kd = 10 nM)-affinity receptors, with a binding site density of 12,000 and 18,060 receptors per cell, respectively. alpha-hANP markedly stimulated glomerular endothelial cell-associated cGMP. After a 2-min incubation, cGMP increased 1.3-fold (from 17.88 +/- 1.29 to 23.33 +/- 3 pmol/mg of protein), in the presence of 1 nM ANP, to more than threefold (from 21 +/- .1 to 80.5 +/- 14.5 pmol/mg of protein) with 1 microM ANP (P < 0.05). In contrast, a 10 microM concentration of the clearance receptor C-ANP4-23 increased cGMP by 1.6 +/- 0.6 fold. ANP stimulation of intracellular cGMP was 100 times more sensitive in human glomerular endothelial than in mesangial cells. In comparison, higher doses of bradykinin were necessary to evoke similar responses in glomerular endothelial cells. In the presence of 10 microM bradykinin, cellular cGMP increased by 1.75 +/- 0.6-fold versus control cells. However, unlike ANP, bradykinin-stimulated cGMP synthesis was significantly inhibited by prior treatment with oxyhemoglobin (10(-5) M), an inhibitor of soluble guanylate cyclase, and NG-nitro-L-arginine (NO2Arg), a specific inhibitor of endothelial-derived relaxing factor (EDRF).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Uptake of atrial natriuretic peptide and production of cGMP in cultured human glomerular endothelial cells. 784 48

Bradykinin-induced activation of peripheral sensory fibres was studied using an in vitro preparation of the neonatal rat spinal cord with attached tail. Noxious heat stimulation, as well as the applications of bradykinin and capsaicin, to the tail evoked reproducible responses recorded as a depolarization of a lumbar ventral root. Prolonged administration of a supramaximal concentration of bradykinin invariably induced a complete but selective desensitization to a subsequent bradykinin challenge. Bradykinin-induced desensitization was significantly attenuated by concanavalin-A and the effect of concanavalin-A was prevented by alpha-methyl mannoside. Both cyclic GMP and sodium nitroprusside induced a long lasting reduction of bradykinin responsiveness in peripheral fibres. The effect of nitroprusside was prevented by concanavalin-A, and by methylene blue, an inhibitor of guanylyl cyclase. Methylene blue also reduced bradykinin-induced desensitization. L-arginine, but not D-arginine, induced a desensitization to bradykinin. On the other hand, 7-nitroindazole (7-NI, 200-500 nM), an inhibitor of NOS, reduced the desensitization of bradykinin responses but higher concentrations of 7-NI (IC50 = 6.7 +/- 0.9 microM) selectively attenuated responses to bradykinin. The effects of 7-NI were attenuated by L-arginine pretreatment. These data suggest that bradykinin-induced desensitization of peripheral sensory fibres is mediated in part via NO and cyclic GMP dependent mechanisms: possibly NO production is required for guanylate cyclase activation.
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PMID:Regulation of bradykinin sensitivity in peripheral sensory fibres of the neonatal rat by nitric oxide and cyclic GMP. 786 49

1. The oral administration of a benzothiazolinone derivative (benzoyl-6 dihydro-2,3 benzothiazole), S14080, caused dose-dependent antinociception in the rat paw pressure test, which represents a model of mechanical hyperalgesia. S14080 had no significant effect on the inflammatory oedema induced by carrageenin or on the tail flick test, nor did it possess a notable antipyretic effect. 2. Post-treatment with S14080 dose-dependently antagonized the hyperalgesia induced by prostaglandin E2, bradykinin, dopamine and by the hyperalgesic cytokines reported to be released by carrageenin (tumour necrosis factor alpha, interleukin-1 and interleukin-8). 3. The blockade of prostaglandin E2-induced paw hyperalgesia by oral pretreatment of the rats with S14080 was abolished by prior intraplantar administration of either naloxone or NorBNI which are non-specific and specific kappa opioid antagonists, respectively. 4. Adrenalectomy abolished the oral antinociceptive effect of S14080. 5. Five consecutive daily injections of S14080 did not produce tolerance such as that seen with the central antinociceptive action of morphine. 6. As with peripherally acting opiates, the antinociceptive activity of S14080 was abolished by the intraplantar injection of agents which inhibit either arginine synthetase (NG-monomethyl-L-arginine) or the activation of guanylate cyclase (methylene blue). 7. We conclude that S14080 is a new type of peripheral antinociceptive which, in rats, acts mainly by releasing an endogenous, opioid-like substance from the adrenal glands.
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PMID:S14080, a peripheral analgesic acting by release of an endogenous circulating opioid-like substance. 788 29

In perinatal lungs, veins contribute substantially to total pulmonary vascular resistance. The present study was designed to determine the role of endothelium-derived nitric oxide (EDNO) in modulating the responsiveness of pulmonary veins and arteries in newborn lambs. Fourth-order pulmonary arterial and venous rings of newborn lambs were suspended in organ chambers filled with modified Krebs-Ringer bicarbonate solution (95% O2/5% CO2, 37 degrees C), and their isometric force was measured. Nitro-L-arginine had no effect on the resting tension of pulmonary arteries but caused an endothelium-dependent contraction of pulmonary veins. During contraction to endothelin-1 or U46619, acetylcholine, bradykinin, and calcium ionophore A23187 induced larger endothelium-dependent relaxation in pulmonary veins than in arteries. The endothelium-dependent relaxation of pulmonary vessels was abolished by nitro-L-arginine. In vessels without endothelium, nitric oxide induced significantly greater relaxation in pulmonary veins than in arteries. All vessels relaxed similarly to 8-bromo-cGMP. Radioimmunoassay showed that the basal level of intracellular cGMP of pulmonary veins with endothelium was higher than that of arteries with endothelium. Acetylcholine, bradykinin, and calcium ionophore A23187 induced a significantly larger endothelium-dependent increase in the intracellular content of cGMP in pulmonary veins than in arteries. In vessels without endothelium, nitric oxide induced a larger increase in cGMP content in pulmonary veins than in arteries. The present study suggests that EDNO may play a larger role in modulation of pulmonary venous than arterial reactivity, which may be mainly due to a difference in the activity of soluble guanylate cyclase in vascular smooth muscle.
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PMID:Endothelium-derived nitric oxide plays a larger role in pulmonary veins than in arteries of newborn lambs. 789 31


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