Effects of isoquinoline derivatives, HA1077 and H-7, on cytosolic Ca2+ level and contraction in vascular smooth muscle.

The effects of isoquinoline derivatives, HA1077 (1-[5-isoquinolinesulfonyl]-homopiperazine) and H-7 (1-[5-isoquinolinesulfonyl]-2-methylpiperazine), on cytosolic Ca2+ levels ([Ca2+]i) and muscle tension were examined in vascular smooth muscle of rat aorta. High K+ (72.7 mM) and norepinephrine (1 microM) induced a sustained contraction with a sustained increase in [Ca2+]i. HA1077 and H-7 (3-10 microM) inhibited the increase in muscle tension more strongly than the increase in [Ca2+]i. Verapamil (10 microM) completely inhibited the increase in [Ca2+]i and the contraction induced by high K+ whereas it inhibited the increase in [Ca2+]i more strongly than the contraction due to norepinephrine. The verapamil-insensitive portion of the norepinephrine-induced contraction was inhibited by HA1077 or H-7. In Ca(2+)-free solution, 0.1 microM norepinephrine induced a transient increase in [Ca2+]i and muscle tension. The transient contraction was inhibited by 10 microM HA1077 or 10 microM H-7 without inhibiting the increase in [Ca2+]i. 12-Deoxyphorbol 13-isobutyrate (DPB) (1 microM) caused a sustained contraction, and this contraction was inhibited by HA1077 and H-7 at similar concentrations needed to inhibit the contractions induced by high K+ or norepinephrine. In rabbit mesenteric artery permeabilized with Staphylococcus aureus alpha-toxin, 100 microM HA1077 and 100 microM H-7 inhibited the contraction induced by 0.3 microM Ca2+. These results suggest that the inhibitory effects of isoquinoline derivatives, HA1077 and H-7, are due to a decrease in [Ca2+]i and in the Ca2+ sensitivity of contractile elements in vascular smooth muscle.