Effects of cadralazine on contractions induced by Ca2+ and norepinephrine in isolated rabbit aortic strips

Antagonistic effects of the new antihypertensive agent cadralazine (ethyl(+/-)-6-[ethyl(2-hydroxypropyl)-amino]-3-pyridazinecarbazate ) and its metabolite ISF-2405 [+/-)-6-[ethyl(2-hydroxypropyl)amino]-3-hydrazinopyridazine) on contractile responses to CaCl2 in K+-depolarised medium and to norepinephrine (NE) in Ca2+-free medium were compared with those of hydralazine using isolated rabbit abdominal aortic strips. Even at high doses of cadralazine (10(-4) mol/l), ISF-2405 (10(-5) mol/l) and hydralazine (10(-5) mol/l), only less than 10% inhibition was observed on dose-dependent contractions induced by CaCl2, 0.05 to 6.4 mmol/l, in K+ 40 mmol/l medium. NE produced dose-dependent contractions even in Ca2+-free medium at concentrations of 10(-9) to 3 X 10(-5) mol/l, and the maximal response was diminished to about 45% of the response in the presence of Ca2+. Cadralazine 10(-4) mol/l exerted no effect on Ca2+-free NE-induced contractions, while ISF-2405 and hydralazine at concentrations of 10(-7) to 10(-5) mol/l were equipotent, showing marked dose-dependent, non-competitive inhibition on NE-induced contractions. These results suggest that ISF-2405 and hydralazine show vasodilating effect through the inhibition of the Ca2+-release from intracellular storage but not via inhibition of the potential dependent Ca2+ influx.