Effects of isoquinoline derivatives, HA1077 and H-7, on cytosolic Ca 2+ level and contraction in vascular smooth muscle

Abstract

The effects of isoquinoline derivatives, HA1077 (1-[5-isoquinolinesulfonyl]-homopiperazine) and H-7 (1-[5-isoquinoline-sulfonyl]-2-methylpiperazine), on cytosolic Ca 2+ levels ([Ca 2+] i) and muscle tension were examined in vascular smooth muscle of rat aorta. High K + (72.7 mM) and norepinephrine (1 μM) induced a sustained contraction with a sustained increase in [Ca 2+] i. HA1077 and H-7 (3–10 μM) inhibited the increse in muscle tension more strongly than the increase in [Ca 2+] i. Verapamil (10 μM) completely inhibited the increase in [Ca 2+] i and the contraction induced by K + whereas it inhibited the increase in [Ca 2+] 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 μM norepinephrine induced a transient increase in [Ca 2+] i and muscle tension. The transient contraction was inhibited by 10 μM HA1077 or 10 μM H-7 without inhibiting the increase in [Ca 2+] i. 12-Deoxyphorbol 13-isobutyrate (DPB) (1 μM) 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 α-toxin, 100 μM HA1077 and 100 μM H-7 inhibited the contraction induced by 0.3 μM Ca 2+. These results suggest that the inhibitory effects of isoquinoline derivatives, HA1077 and H-7, are due to a decrease in [Ca 2+] i and in the Ca 2+ sensitivity of contractile elemenst in vascular smooth muscle.