Study of the in vivo and in vitro cardiovascular effects of a hydralazine-like vasodilator agent (HPS-10) in normotensive rats.

Abstract

1. In this work, the cardiovascular effects of HPS-10, a new vasodilator agent, were studied in rats. 2. In conscious normotensive rats, oral administration of HPS-10 (4-9 mg kg-1) produced a dose-related and long-lasting fall in systolic arterial blood pressure (ED30 of 5.32 mg kg-1), accompanied by an increase in heart rate (ED30 of 8.43 mg kg-1). This tachycardia was totally inhibited by pretreatment with (+/-)-propranolol (10 mg kg-1, p.o.). 3. In anaesthetized normotensive rats, HPS-10 (0.3-0.6 mg kg-1, i.v.) produced a gradual, dose-dependent and sustained decrease in systolic, diastolic and mean arterial pressure (MAP) (ED30 for MAP of 0.41 mg kg-1, i.v.), accompanied by a significant bradycardia at high doses (> 0.4 mg kg-1; ED20 of 0.61 mg kg-1, i.v.). HPS-10 (0.5 mg kg-1, i.v.) did not modify the positive chronotropic effects induced by intravenous administration of noradrenaline (NA; 5 micrograms kg-1), angiotensin II (AII; 0.2 microgram kg-1) and nicotine (200 micrograms kg-1) but markedly inhibited the hypertensive response produced by these agents. 4. In rat isolated rubbed aorta, HPS-10 (0.1-1 mM) non-competitively and with almost equal effectiveness antagonized the contractions induced by NA, AII (in normal Krebs solution) and Ca2+ (in depolarizing Ca(2+)-free high-K+ 50 mM solution). In the experiments in Ca(2+)-free medium, HPS-10 (1 mM) considerably inhibited the contractions induced by NA, AII and caffeine in rat aorta. 5. Furthermore, in the studies with radioactive Ca2+, HPS-10 (1 mM) did not modify the basal uptake of 45Ca2+ but strongly decreased the influx of 45Ca2+ induced by NA, AII and K+ in rat aortic rings. 6. In rat isolated atria, HPS-10 (1 mM) produced a positive inotropic/negative chronotropic effect. 7. HPS-10 (0.3 mM) significantly inhibited the sustained and transient Ba2+ inward current (IBa) recorded in whole-cell clamped rat aortic myocytes. 8. These results indicate that the non-selective vasorelaxant effects of HPS-10 in rat aortic rings can be attributed to transmembrane Ca(2+)-antagonist activity and an intracellular action on smooth muscle cells. The direct vasodilator action of HPS-10 observed in rat isolated aorta may be responsible for the HPS-10 hypotensive activity in anaesthetized normotensive rats.