cyclic-gmp and isosorbide-2-mononitrate

Nitrates are used in the treatment of coronary heart disease and heart failure. The major drawback of their therapeutic use is the rapid development of tolerance.. To investigate the effect of different nitrates on isolated rabbit hearts and aortic strips and the mechanism responsible for nitrate tolerance, using nitroglycerine (NTG), isosorbide dinitrate (ISDN), 5-mononitrate (5MN) and 2-mononitrate (2MN).. Preparations were stimulated by different spasmogenic agents: KCl, angiotensin II and noradrenaline; nitrates were administered on the plateau contraction, at the concentration of maximum inhibitory effect. In another series of experiments, preparations were preincubated with the maximum inhibitory concentration of each nitrate to evaluate the induction of tolerance.. Nitrates produced the following maximum inhibitions on noradrenaline-induced contraction: NTG 90% (10(-6) mol/l), ISDN 60% (10(-4) mol/l), 5MN 55% (10(-4) mol/l) and 2MN 80% (10(-4) mol/l). After incubation a loss of vasodilator effect of nearly 50-60% was observed for all the nitrates considered except 2MN, whose loss of effect was significantly lower (36%). The cyclic guanosine monophosphate (cGMP) levels measured in the preparations were lower in the presence of 2MN than the other compounds.. These data suggest that 2MN is able to induce a lower cGMP increase and less tolerance induction; since these observations seem to be correlated, the vasodilator effect of 2MN probably also involves mechanisms other than stimulation of guanylate cyclase.

Topics: Animals; Aorta; Coronary Circulation; Coronary Vessels; Cyclic GMP; Dose-Response Relationship, Drug; Drug Tolerance; Female; In Vitro Techniques; Isosorbide Dinitrate; Male; Muscle, Smooth, Vascular; Nitroglycerin; Perfusion; Rabbits; Vasodilation; Vasodilator Agents

Isosorbide-5-mononitrate and isosorbide-2-mononitrate, the metabolites of isosorbide dinitrate, were studied for their effects on the contractile and electrical activity and on the content of cyclic nucleotides in isolated heart muscles of guinea-pig and dog. Isosorbide-5-mononitrate at all concentrations tested and isosorbide-2-mononitrate at low concentrations did not produce significant changes in the mechanical activity of guinea-pig heart preparations. Isosorbide-2-mononitrate in concentrations above 10(-4) M inhibited the contractility and shortened the action potential of guinea-pig and dog heart muscle. Neither mononitrate had an effect on cAMP concentration but both induced a significant elevation of cGMP content in guinea-pig heart tissue, the effect of isosorbide-2-mononitrate being greater.

Topics: Animals; Cyclic AMP; Cyclic GMP; Dogs; Guinea Pigs; Heart; In Vitro Techniques; Isosorbide Dinitrate; Myocardial Contraction; Vasodilator Agents