Effect of the novel calcium antagonist AE0047 on responses of isolated dog blood vessels to vasoconstricting agents and to nerve stimulation

Abstract

The effect of AE0047 on contractile responses to high K+ and agonists and to perivascular nerve stimulation was investigated using isolated dog cerebral, coronary and mesenteric arteries and mesenteric veins. AE0047 inhibited concentration-dependent contractions induced by KCl, norepinephrine, prostaglandin (PG) F2 alpha and serotonin. The inhibition of contractions caused by PGF2 alpha and serotonin was greater in cerebral arteries than in mesenteric arteries. The inhibitory effect of AE0047 on norepinephrine-induced mesenteric arterial contraction persisted for 24 hr or longer even though the strips were repeatedly washed. Greater inhibition was obtained in the arteries contracted with K+ than in those contracted with agonists. AE0047 reduced Ca(2+)-induced contraction in K(+)-depolarized mesenteric artery strips to a greater extent than those in PGF2 alpha-stimulated strips. The relaxation induced by transmural electrical stimulation in coronary arteries treated with phenotolamine was reduced by AE0047, whereas the norepinephrine-induced relaxation was unaffected. In cerebral arteries treated with superoxide dismutase, AE0047 reduced nicotine-induced relaxation but not NO-induced relaxation. These findings suggest that AE0047 selectively inhibits vasocontractions via voltage-dependent Ca channels and preferentially inhibits cerebroarterial contraction, these actions being long-lasting. AE0047 appears to reduce the release of neurotransmitter from adrenergic and nitroxidergic nerve terminals in blood vessels.