Vascular and cardiac effects of HP 406 and nifedipine in vitro and in conscious spontaneously hypertensive rats and renal hypertensive dogs

The cardiovascular effects of the calcium antagonists HP 406 and nifedipine were assessed in a series of in vitro and in vivo studies. HP 406 was found to display moderate affinity for dihydropyridine binding sites, as determined by the inhibition of [3H]-nitrendipine binding on rat ventricular membranes. HP 406 was found to have an IC50 of 1.3 × 10−7 M as compared to nifedipine with an IC50 of 7.0 × 10−9 M. Additional in vitro studies were conducted with isolated spontaneously contracting and electrically paced guinea pig atria and rabbit aortic rings. HP 406 was found to have minimal effects on cardiac chronotropic and inotropic activity in isolated guinea pig atria. In contrast, nifedipine caused significant dose-related reductions in heart rate and myocardial contractile force. Rabbit aortic rings were precontracted with potassium chloride (KCI) or norepinephrine (NE), and HP 406 or nifedipine was added to tissue baths in a cumulative dose range. HP 406 and nifedipine both caused dose-related relaxation of KCI- and NE-contracted rings; however, the IC50's against KCI were found to be significantly lower than those against NE for both compounds. The IC50's against NE were found to be 4.8 × 10−8 M and 5.9 × 10−8 M for HP 406 and nifedipine, respectively. The IC50's against NE were 1.9 × 10−5 M for HP 406 and 4.4 × 10−5M for nifedipine. Finally, the antihypertensive activity of HP 406 and nifedipine were compared in the spontaneously hypertensive rat (SHR) and renal hypertensive dog. Both compounds produced significant reductions in mean arterial pressure at 1 mgikg p.o. in the SHR and at 3 mgikg p.o. in the renal hypertensive dog. Nifedipine was also found to cause a significantly greater tachycardia compared to HP 406. The results of this study show that HP 406 is a potent antihypertensive agent with minimal direct or reflex-mediated chronotropic effects. The mechanism of this antihypertensive activity appears to result from calcium-channel antagonism and vascular dilation.