Biomedical subjects

C Romanin

Publications and source records attributed to C Romanin.

38 records · Page 3Linked to original sources

PubMed1988

Guanylate cyclase activation by organic nitrates is not mediated via nitrite.

Nitrovasodilators relax vascular smooth muscle by stimulating guanylate cyclase. Ignarro et al. (1981) proposed a mechanistic scheme according to which organic nitrates release nitrite in the presence of thiols. The corresponding nitrous acid would decay leading to nitric oxide, which then would react with another thiol to nitrosothiol. Dose-response relations with regard to guanylate cyclase stimulation of organic nitrates and sodium nitrite were compared in the presence of cysteine and its closely related methylester. Nitrite formation from ED95 concentrations of organic nitrates was also measured and compared with that present under an equi-effective concentration of sodium nitrite. In addition, the proposed formation of nitrosothiol from nitric oxide was re-examined. In the presence of cysteine, organic nitrates as well as sodium nitrite stimulated guanylate cyclase, but nitrite formation under ED95 concentrations of organic nitrates was 1000-fold smaller than that present under an equi-effective concentration of sodium nitrite. In the presence of cysteinemethylester, liberation of nitrite from organic nitrates was similar but no stimulation of guanylate cyclase was obtained. Sodium nitrite, however, showed a stimulating activity similar to that in the presence of cysteine. These results clearly demonstrate that guanylate cyclase stimulation by organic nitrates is not mediated by nitrite and subsequent formation of nitrosothiol. Since nitrous acid did not decay to nitric oxide in the pH range studied, the formation of nitrosothiol is apparently due to a direct reaction of nitrous acid with thiol.

Enzyme Activation↗

PubMed1987

Mechanism of vasodilation by nitrates: role of cyclic GMP.

Nitrovasodilators relax vascular smooth muscle by stimulating soluble guanylate cyclase (GC). The resulting rise in cGMP probably initiates Ca extrusion from the smooth muscle cell which causes relaxation. Since repeated administration of organic nitrates, particularly nitroglycerin, leads to tolerance, i.e. a decrease in the vasodilator effect, it was studied whether (a) tolerance was a peripheral phenomenon occurring in the vascular smooth muscle, and (b) was due to an impairment of GC activation. In isolated circular strips of bovine coronary arteries, 90 min pretreatment with nitroglycerin greatly lowered the relaxing as well as the cGMP increasing response to nitroglycerin, indicating tolerance induction. Tolerance, although to a lesser extent, was also obtained with other organic nitrates under similar conditions, including IS 5-MN. Little (nitroprusside Na) to negligible tolerance was obtained with sodium nitrate and SIN-1, the active metabolite of molsidomine. The latter group of drugs stimulated soluble GC in vitro in the absence of cysteine whereas organic nitrates required the presence of this thiol. Preincubation with nitroglycerin almost completely inactivated GC whereas other organic nitrates had little effect. The results indicate that tolerance is caused by an impairment of GC function in the smooth muscle cell, particularly when elicited by nitroglycerin, and that differences in the degree of tolerance development by various nitrovasodilators are possibly due to different mechanisms of activation and inactivation of GC as well as differences in cysteine requirement.

Animals↗