Differential effects of the novel NO-donating drug pirsidomine and isosorbide dinitrate on the venous vascular bed

Abstract

Sixteen healthy male subjects were investigated on four occasions when they received either placebo, 10 mg isosorbide dinitrate (ISDN), or 2.5 or 10 mg pirsidomine, a novel NO-donating drug.A constant-rate iv. infusion of a subsystemic dose (average 42 ng. min -~, SD 20.5) of noradrenaline in a dorsal hand vein was begun i h before drug treatment. It did not cause systemic changes but reduced the venous hand vein diameter by about 50%. This venoconstrictor response was approximately halved by 10 mg ISDN. Pirsidomine, in contrast, did not affect the in situ venoconstrictor responses to noradrenaline.ISDN and pirsidomine reduced systemic resting blood pressure. ISDN and 10rag pirsidomine were approximately equipotent in reducing systolic blood pressure, both in terms of the duration and the extent of the effect (maximum average reduction of ISDN-6.7, 95 % CI-10.3 to -3.0; and 10 mg pirsidomine -7.6, 95% CI -11.3 to -4.0 mmHg, respectively); 2.5 mg pirsidomine was less effective (-4.1, 95 % C1-7.8 to -0.5). ISDN and 10 mg pirsidomine were also similarly effective in reducing diastolic blood pressure (ISDN -8.4 mmHg, 95 % C1-10.5 to -6.2; 10 mg pirsidomine -6.0 mmHg, 95 % CI -8.2 to -3.9; 2.5 mg pirsidomine -2.8 mmHg, 95 % C1-5.0 to -0.6) but the effects of ISDN were longer lasting.Although similar with regard to their putative mechanism(s) of action and likely arterial/arteriolar effects, pirsidomine and ISDN seem to affect the venous vascular bed in distinctly different ways.For over a century, nitroglycerin and other organic nitrates have been widely used in the treatment of angina pectoris. They yield NO, which stimulates guanylate cyclase to form cGMP [1], thus causing an increase in smooth muscle CGMP which promotes vascular relaxation. Since the classic nitrates are hampered by their short duration of action and the development of tolerance on chronic usage, there has been a continuous search for new NO-donating compounds. Sidnonimines stimulate guanylate cyclase in a sulfhydryl (SH) group-independent fashion [2, 3] and so may not induce tolerance. Pirsidomine [CAS 936, 3-(cis-2.6-dimethylpiperidino)-N-(4-methoxybenzoyl)-sidnonimine] is a prodrug which, like sidnonimine, yields deacylated metabolites that liberate NO in an SH-independent fashion.The haemodynamic actions underlying the therapeutic efficacy of NO-donating drugs in angina pectoris are not yet completely clear and are considered to be mediated by one or more of the following effects: 1, venodilatation which increases the systemic venous capacity and reduces preload; 2, systemic arterial/arteriolar dilatation which reduces afterload; and 3, dilatation of epicardial coronary arteries, which directly enhances coronary blood flow [4]. Human pharmacology studies have helped to assess the nature, time course and dose-dependency of the haemodynamic effects of organic nitrates. They reduce blood pressure, peripheral vascular resistance and change systolic time intervals as a consequence of their arterial/arteriolar effects [5,6]. Their venous vasodilatory...