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)

Nicorandil relaxes coronary vascular smooth muscle by stimulating guanylyl cyclase and increasing cyclic GMP (cGMP) levels (as shown first in our laboratory) as well as by a second mechanism resulting in activation of K+ channels and hyperpolarization. Therefore, we studied the relative contributions of either mechanism to the overall response in bovine circular strips of coronary arteries by simultaneously measuring changes in length and in cGMP levels through radioimmunoassay. Blockade by 10 microM methylene blue of the cGMP increases in strips precontracted by 1 microM of the thromboxane A2 analogue U46619 reduced nicorandil-induced relaxation to 30-50%, and there were no significant changes in cGMP levels. Suppression of the hyperpolarizing component of nicorandil by 80.4 mM K+ or 1 microM glibenclamide in precontracted strips reduced nicorandil relaxation to 50% (K+) or shifted the dose response to the right by a factor of two (glibenclamide) without alteration of increases in cGMP. A quantitative separation of both mechanisms of action was obtained by comparing the correlation between increases in cGMP and relaxation under conditions of inhibited versus noninhibited hyperpolarization. The results indicate that cGMP contributes to the total relaxing effect of nicorandil by 30-40% at low concentrations and 80-90% at high concentrations of nicorandil. From the experiments with glibenclamide, it can be concluded that the probable mechanism by which nicorandil hyperpolarizes is opening glibenclamide-sensitive K+ channels in coronary vascular smooth muscle and that this latter effect mimics those of other K+ channel openers such as cromakalim or pinacidil.
J Cardiovasc Pharmacol 1992
PMID:Molecular mechanism of action of nicorandil. 128 68

Three agents with K(+)-channel-opening activity--nicorandil, bimakalim (EMD 52692), and EMD 56431--were tested for vasorelaxation abilities in human coronary artery and human arteria mammaria. The potency orders were bimakalim = EMD 56431 >> nicorandil for relaxation in human coronary artery and bimakalim = EMD 56431 >> nicorandil in human arteria mammaria. These data demonstrate that K(+)-channel openers are effective vasorelaxant agents in human coronary artery and human arteria mammaria. Bimakalim and EMD 56431 were more potent than nicorandil, a drug that also activates guanylate cyclase.
J Cardiovasc Pharmacol 1992
PMID:Relaxation of human coronary artery and arteria mammaria by K(+)-channel openers. 128 70

Inducible nitric oxide (NO) synthase in vascular smooth muscle cells (SMCs) appears to play a major role for the diminished responsiveness to vasoconstrictors observed in endotoxemia. However, cardiovascular dysfunctions associated with septic shock are also observed in the absence of endotoxin (LPS). Similar hemodynamic changes are produced either by a gram-negative bacteria (Escherichia coli) or by a gram-positive bacteria (Staphylococcus aureus), a microorganism without LPS, suggesting a common pathway leading to cardiovascular abnormalities. In the present study, we describe the induction of NO synthase in vascular SMCs by lipoteichoic acid (LTA), a component of the membrane of gram-positive bacteria. In cultured vascular SMCs, a 24-h incubation with LTA produced an increase in intracellular cyclic GMP. This effect was inhibited by methylene blue (MB), an inhibitor of guanylate cyclase. Incubation with a specific inhibitor of L-arginine, i.e., NG-nitro-L-arginine methyl ester (L-NAME), or depletion of L-arginine attenuated the LTA-induced cGMP production. A 5-h incubation of endothelium-free rings of rat aorta in the presence of LTA induced a loss of tonicity to the contractile response of phenylephrine. The contractions were restored by MB and by L-NAME. The effect of L-NAME was reversed by L-arginine. These results show that LTA, like LPS, expresses NO synthase in vascular SMCs.
J Cardiovasc Pharmacol 1992
PMID:Lipoteichoic acid: a new inducer of nitric oxide synthase. 128 52

The aim of the present experiments was to test the possible involvement of nitric oxide (NO) in cytokine-induced enhancement of tumor cell (TC) adhesion to endothelial cells (ECs). Exposure of EA hyb 926 cells to TNF (500 U/ml) plus IFN (100 U/ml) for 24 h significantly enhanced their adhesivity for the 51Cr-labeled GLC1 (small cell lung carcinoma) TCs. Conversely, exposure of TCs to cytokines did not result in an increased adhesion of these cells to ECs. TC-stimulated adhesion to EA hyb 926 was abrogated by the glucocorticoid dexamethasone (Dex, 10(-7) M), the NO synthase inhibitors N omega-nitro-L-arginine methyl ester (L-NAME, 10(-5) M) and NG-monomethyl-L-arginine (L-NMMA, 10(-5) M) and the protein synthesis inhibitor cycloheximide (Cex, 10(-6) M). Furthermore, GLC1-stimulated adhesion to EA hyb 926 was reversed following removal of L-arginine from the medium or pretreatment with the guanylate cyclase inhibitor methylene blue. TC-stimulated adhesion was also prevented when TCs were pretreated with the monoclonal antibody CD15 directed against the endothelial-leukocyte adhesion molecule (ELAM-1) ligand or following exposure of ECs to anti-ELAM-1 monoclonal antibody. Although suppressing TC-stimulated adhesion, L-NMMA failed to modify significantly cytokine-induced ELAM-1 expression in EA hyb 926. These results (a) provide evidence for the NO-inducible pathway contributing to cytokine-induced enhancement of tumor cell adhesion to the vascular endothelium and (b) demonstrate the involvement of the ELAM-1/CD15 adhesion system in tumor cell-stimulated adhesion to ECs.
J Cardiovasc Pharmacol 1992
PMID:Involvement of nitric oxide in tumor cell adhesion to cytokine-activated endothelial cells. 128 56

The arterial vasodilator activity of endothelium-derived relaxing factor (EDRF) is mediated by activation of the soluble form of guanylate cyclase, causing increased levels of guanosine-3',5'-cyclic monophosphate (cGMP). Because of its extreme lability, the actions of EDRF are local. The ability to monitor changes in renal interstitial fluid cGMP would be of great advantage in clarification of local mechanisms controlling renal function. Utilizing a renal interstitial microdialysis technique, we investigated changes in renal interstitial and urinary cGMP in response to right intrarenal arterial administration of the EDRF inhibitor, NG-monomethyl-L-arginine (L-NMMA), in anesthetized dogs (n = 5) in metabolic balance at a sodium intake of 40 mEq/day. Urine was collected directly from the right and left ureter. L-NMMA at 20-60 micrograms/kg/min significantly decreased right renal interstitial and right urinary cGMP levels (p < 0.01) without changing left renal interstitial and urinary cGMP levels (p < 0.01). L-NMMA at 100 micrograms/kg/min decreased both right and left renal interstitial and urinary cGMP levels (p < 0.01). These data demonstrate the ability to monitor renal interstitial cGMP in vivo. There was a dose-dependent decrease in renal interstitial and urinary cGMP in response to intrarenal EDRF inhibition. Additionally, they suggest that EDRF acts as a renal paracrine substance through the modulation of renal interstitial cGMP.
J Cardiovasc Pharmacol 1992
PMID:Endothelium-derived relaxing factor modulates renal interstitial cyclic GMP. 128 58

The distribution of guanylate cyclase, phosphodiesterase, and NADPH-diaphorase [nitric oxide (NO) synthase] was studied in rat brain both at the light and electron microscopic level with special emphasis on the vascular system. We showed that the cGMP-generating enzyme is located in cells (glial cells and pericytes) surrounding cerebral vessels, but not in the endothelium. For NO synthase, a dual localization was observed. The enzyme is present in parts of the endothelium and in nerve endings apparently innervating larger brain vessels. We propose, therefore, that NO acts on guanylate cyclase both from a "synaptic" and endothelial source.
J Cardiovasc Pharmacol 1992
PMID:Histochemistry of guanylate cyclase, phosphodiesterase, and NADPH-diaphorase (nitric oxide synthase) in rat brain vasculature. 128 93

The properties of brain capillary endothelial cells (BCECs) have been analyzed. BCECs express two types of receptor sites for endothelins (ETs), and ETA-like receptor, and an ETB-like receptor that is not coupled to phospholipase C but whose occupancy activates Na+/H+ exchange activity. The ETA receptor is positively coupled to phospholipase C and negatively coupled to adenylate cyclase. BCECs, unlike aortic endothelial cells, express high-affinity receptor sites for C-type natriuretic peptide. They respond to exogenous nitric oxide (NO) and to NO donor molecules by large activations of soluble guanylate cyclase. They produce little cGMP in response to A23187 or to agonists of phospholipase C but do so after an exposure to interleukin-1. The physiological consequence of the high reactivity of BCECs to vasoactive factors is discussed.
J Cardiovasc Pharmacol 1992
PMID:Function of vasoactive factors in the cerebral microcirculation. 128 98

Seven-month-old, lean male SHHF/Mcc-cp rats, a model of spontaneous hypertension, progressive renal dysfunction, and congestive heart failure (CHF), were treated with either clonidine (CL) or enalapril (EN) or received no treatment (CON) for 20 weeks. CL significantly decreased systolic blood pressure (SBP), kidney weights, and severity of renal lesions as compared with untreated CON. EN produced a decrease in SBP comparable to that in CL. Kidney weights and severity of renal histologic changes in the EN group were intermediate between those of the CL and CON groups. Despite similar plasma atrial natriuretic peptide (ANP) concentrations, CL treatment resulted in a significant increase in the density of guanylate cyclase-linked glomerular ANP receptors, whereas EN treatment resulted in a significant decrease in the total number of ANP receptors and in the number of nonguanylate cyclase-linked receptors and an increase in overall binding affinity. These findings demonstrate that antihypertensive agents will slow progression of renal injury in SHHF/Mcc-cp rats and that CL is more effective than EN in alleviating progressive kidney damage in this model. Furthermore, different classes of antihypertensive drugs may alter the density or ratio of biologically active and clearance ANP receptor sites in the glomerulus.
J Cardiovasc Pharmacol 1992 Mar
PMID:Effects of enalapril and clonidine on glomerular structure, function, and atrial natriuretic peptide receptors in SHHF/Mcc-cp rats. 137 31

Cicletanine is an antihypertensive/vasorelaxant/natriuretic agent of unknown mechanism. We wished (a) to determine if cicletanine interacts with guanylate cyclase activators that modulate vasomotor tone and sodium balance [i.e., atriopeptin II (AP II), endothelium-derived relaxing factor (EDRF), and sodium nitroprusside (SNP)], and (b) to define the subcellular basis for this interaction by quantitating the effects of cicletanine on low Km cyclic GMP phosphodiesterase (PDE) activity. In phenylephrine-contracted rat aortic smooth muscle, the vasorelaxant potency of cicletanine was increased twofold in the presence of a threshold-relaxant concentration of AP II, and functional cyclic GMP PDE inhibition was also evident from the three- to sixfold potentiation by cicletanine of AP II- or SNP-induced vasorelaxation. Vasorelaxation produced by cicletanine was not endothelium dependent, however. In further studies, intravenous (i.v.) administration of cicletanine or the low Km cyclic GMP PDE inhibitor, zaprinast, decreased blood pressure (BP) greater than or equal to 20% in conscious spontaneously hypertensive rats (SHR). These results are consistent with the additional finding that cicletanine inhibited Ca2(+)-calmodulin (CaM) cyclic GMP PDE and zaprinast-sensitive cyclic GMP specific PDE over a concentration range (10-600 microM) similar to that for vasorelaxation. Thus, inhibition of low Km cyclic GMP PDEs by cicletanine may be partly responsible for the vasorelaxant effect of cicletanine as well as the potentiation by cicletanine of the vasorelaxant actions of guanylate cyclase activators. The extent to which this mechanism contributes to the antihypertensive efficacy of cicletanine has not yet been fully determined.
J Cardiovasc Pharmacol 1990 Sep
PMID:Inhibition of low Km cyclic GMP phosphodiesterases and potentiation of guanylate cyclase activators by cicletanine. 170 Feb 24

SIN1 (the active metabolite of molsidomine), nitroglycerin, and endothelium-derived relaxing factor (EDRF) produce vasodilation by activation of soluble guanylate cyclase. Therefore, prolonged exposure to SIN1 might affect not only the responses to SIN1 itself and to nitroglycerin but also to EDRF. In vivo treatment of rats consisted of subcutaneous injections of either SIN1 (60 mg/kg) for the treated group or placebo for the control group, twice daily for 3 days. Thoracic aortas from the treated group were threefold and sixfold less sensitive to nitroglycerin and SIN1, respectively. The endothelium-dependent relaxations to acetylcholine were, nevertheless, similar in both groups. Moreover, the concentration-response curves to phenylephrine, which are known to be modulated by the endothelium, were similar in both groups. In addition, incubation with methylene blue (10 microM for 30 min), which blocks the vasodilator action of EDRF, potentiated in the same way the contractions to this alpha-adrenergic agonist. The increase in resting tone induced by methylene blue incubation was also equivalent in the two groups. The present results show that SIN1 treatment for several days in rats is associated with slight tolerance development not only to SIN1 itself but also to nitroglycerin, while the endothelial function remains operative. We conclude that the mechanisms involved in the activation of guanylate cyclase by SIN1 and nitroglycerin are probably different than those of EDRF-mediated responses.
J Cardiovasc Pharmacol 1990 Oct
PMID:Effects of in vivo SIN1 treatment on nitrovasodilator relaxation and on EDRF-mediated responses in rat aorta. 170 6


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