pirsidomine and linsidomine

The systemic and coronary hemodynamic effects of the nitrovasodilator, pirsidomine, were compared with SIN-1, nitroprusside, and nitroglycerin. Four groups consisting of 32 experiments were performed in 17 conscious dogs chronically instrumented for measurement of aortic and left ventricular pressure, left ventricular dP/dtmax, diastolic coronary blood flow velocity, cardiac output, and subendocardial segment length. On separate experimental days, systemic and coronary hemodynamics were recorded during control conditions and after intravenous administration of pirsidomine (1.0, 2.0, and 4.0 mg.kg-1), SIN-1, (50, 100, and 200 micrograms.kg-1), nitroprusside (0.5, 1.0, and 2.0 micrograms.kg-1.min-1), or nitroglycerin (1.0, 2.0, and 4.0 micrograms.kg-1.min-1). Pirsidomine decreased mean arterial, left ventricular systolic and end-diastolic pressures, stroke volume and systemic vascular resistance. Diastolic coronary blood flow velocity and heart rate were increased and coronary vascular resistance decreased by pirsidomine. SIN-1, nitroprusside and nitroglycerin caused similar decreases in preload (evaluated by left ventricular end-diastolic pressure) and afterload (indirectly assessed by mean arterial pressure and systemic vascular resistance) as compared to pirsidomine. However, equihypotensive doses of SIN-1, nitroprusside, and nitroglycerin improved ventricular performance as assessed by increases in left ventricular dP/dtmax, cardiac output and segment shortening, in contrast to those findings during comparable doses of pirsidomine (4 mg.kg-1). Despite similar loading conditions, high doses of pirsidomine did not enhance left ventricular function, suggesting that pirsidomine may have direct negative inotropic effects.

Topics: Animals; Blood Pressure; Dogs; Heart Rate; Hemodynamics; Injections, Intravenous; Molsidomine; Nitric Oxide; Nitroglycerin; Nitroprusside; Sydnones; Vasodilator Agents

The molecular mechanism(s) underlying the vasodilator activity of CAS 936 (3-(cis-2,6-dimethylpiperidino)-N-(4-methoxybenzoyl)-sydn oni mine) and its metabolites 3-(cis-2,6-dimethylpiperidino)-sydnonimine (C87 3754) and N-(cis-2,6-dimethylpiperidino)-N-nitroso-2-aminoacetonitrile (C873786) was investigated. These compounds were tested for their relaxant activity in isolated rabbit arterial segments, activation of purified soluble guanylyl cyclase and release of nitric oxide (NO) in vitro and in vivo. C873754 and C873786 inhibited the noradrenaline-induced contraction and increased the cyclic GMP content of endothelium-denuded rabbit aortic and femoral segments, whereas CAS 936 was without effect. Similarly, both metabolites, but not CAS 936, activated purified soluble guanylyl cyclase (EC50 about 30 microM) and released NO in buffered aqueous solutions, as detected by electron spin resonance (esr) spectrometry. Both in vitro and in vivo an accumulation of NO was detected by esr spectrometry in vascular tissues exposed to the metabolites of CAS 936, whereas a significant release of NO from CAS 936 was only detected in the isolated rabbit liver, but not in vascular tissue. It is conceivable, therefore, that the metabolites of CAS 936 appearing in the systemic circulation after hepatic biotransformation induce vasodilatation by release of NO and activation of soluble guanylyl cyclase in vascular smooth muscle. Moreover, the activation of soluble guanylyl cyclase in vitro by the metabolites of CAS 936 was significantly enhanced by co-incubation with certain particulate fractions from bovine aortic endothelial and smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Vessels; Cattle; Cyclic GMP; Electron Spin Resonance Spectroscopy; Endothelium, Vascular; Female; In Vitro Techniques; Male; Molsidomine; Muscle, Smooth, Vascular; Nitric Oxide; Nitroso Compounds; Piperidines; Rabbits; Swine; Sydnones; Vasodilator Agents