Increased Vasodilator Responsiveness to BRL 34915 in Spontaneously Hypertensive versus Normotensive Rats: Contrast with Nifedipine

Abstract

Abstract

The blood pressure-lowering potency and activity of BRL 34915, a new vasodilator and putative stimulator of potassium efflux from vascular smooth muscle, was investigated in conscious spontaneously hypertensive rats (SHR) and normotensive rats (NTR) after intravenous administration and compared with that of the calcium channel blocker, nifedipine. In SHR, BRL 34915 (3–100 μg/kg) or nifedipine (10–3000 μg/kg) produced similar reductions in mean arterial pressure of 58 ± 3% and 55 ± 3%, respectively. BRL 34915 (ED_30% = 13.8 μg/kg) was 15.3 times more potent than nifedipine (ED_30% = 207 μg/kg) in SHR. In contrast, only a 1.7-fold difference in potency was observed in NTR between BRL 34915 (ED_30% = 123 μg/kg) and nifedipine (ED_30% = 182 μg/kg). The potency ratio (ED_30% NTR/ED_30% SHR) for BRL 34915 was 8.83 whereas nifedipine had a ratio of 0.88, reflecting the greater responsiveness of the SHR to BRL 34915. Systemic hemodynamics were monitored in anesthetized SHR and NTR to determine the basis for the reductions in blood pressure. BRL 34915 (3–100 μg/kg iv) lowered mean arterial pressure in both groups solely by decreasing total peripheral vascular resistance, since no changes in cardiac output were observed. Relaxation responses were also obtained in phenylephrine-contracted isolated aortic strips from both strains of rat to ascertain whether differences in responsiveness existed at this level of the vasculature. No significant difference in the potency of BRL 34915 (3–10 μM) as a vasodilator was found in aortas from SHR or NTR. These results indicate that, unlike nifedipine, BRL 34915 is a more potent vasodepressor agent in SHR than in NTR and suggests that the potassium efflux stimulator may preferentially relax resistance vessels in the hypertensive rat.