A post-calcium site of action for HA1004, a novel vasculorelaxant

The novel vasorelaxant HA1004 [N-(2-guanidinoethyl)-5-isoquinolinesulfonamide] was investigated with regard to its effects on transmembrane Ca2+ movement in relation to tension development in the rabbit aortic strips. The contractile responses to KCl (40 mM) and norepinephrine (3 X 10(-7) M) were inhibited by HA1004 (1 and 3 X 10(-5) M) (49-78%), whereas the increases in 45Ca efflux (which reflects increases in cytosolic Ca2+ levels) were not affected. Moreover, HA1004 (1 and 3 X 10(-5) M) did not significantly affect 45Ca influx due to KCl stimulation. While HA1004 at 10(-5) M had no effect on norepinephrine-induced 45Ca influx, the drug at 3 X 10(-5) M showed significant inhibition. Based on this and previously reported work, it is concluded that HA1004 inhibits contraction mainly through uncoupling of the Ca-tension relations in vascular smooth muscle.