Mechanism of action of a novel antivasospasm drug, HA1077.

HA1077, but not the potent calcium entry blocker nicardipine reversed experimental chronic cerebral vasospasm induced in a two-hemorrhage canine model. The i.a. administration of HA1077 produced significant increases in vertebral blood flow in dogs. The effects of HA1077 on the vascular responses were studied in vitro. Spiral strips of rabbit aorta were mounted for isometric tension recording in physiological salt solution. HA1077 produced a competitive inhibition of the Ca++-induced contraction of the depolarized rabbit aorta. The pA2 of HA1077 for the Ca@-induced contraction was 6.71. The inhibitory effect of HA1077 on the KCl-induced contraction was not altered by atropine, propranolol, theophylline or indomethacin. HA1077 (10(-8) to 10(-4) M) inhibited contractile responses to KCl, phenylephrine (PHE) and prostaglandin (PG) F2 alpha similarly, whereas verapamil, diltiazem and nicardipine were much less effective in blocking the contractions induced by PHE or PG. Even in Ca++-free physiological salt solution, both PHE and PG were capable of contracting the aorta. These Ca++-free contractile responses to PHE and PG were antagonized effectively by HA1077. Verapamil failed to inhibit these contractions. We also investigated the effects of HA1077 on guinea pig heart contractility. In contrast to calcium entry blockers (which are known to have a direct negative inotropic effect), HA1077 did not change the developed tension in the left atrium at concentrations up to 3 X 10(-4) M. The present evidence demonstrates that the novel antivasospasm drug HA1077 is a class of calcium antagonists different from the calcium entry blockers.