Abstract

The effects of forskolin, an activator of adenylate cyclase, on cytoplasmic Ca++ level ([Ca++]cyt) measured simultaneously with muscle tension using fura-2-Ca++ fluorescence were examined in isolated smooth muscle of rat aorta. Forskolin decreased muscle tension and [Ca++]cyt in resting aorta whereas both norepinephrine and high K+ solution produced sustained increase in muscle tension and [Ca++]cyt. Addition of forskolin during the sustained contractions decreased muscle tension more strongly than [Ca++]cyt. Norepinephrine-induced contraction was more sensitive to forskolin than high K+-induced contraction. The inhibitory effect of forskolin was attenuated when the concentration of norepinephrine or K+ was increased. Cumulative addition of norepinephrine or K+ induced a concentration-dependent increase in both [Ca++]cyt and muscle tension and a positive [Ca++]cyt-tension correlation was observed. In the presence of 0.1 microM forskolin, the norepinephrine-induced increments in [Ca++]cyt and muscle tension were inhibited without changing the [Ca++]cyt-tension relationship. In the presence of a higher concentration (1 microM) of forskolin, muscle tension was inhibited more strongly with only a small additional decrease in [Ca++]cyt resulting in a shift of the [Ca++]cyt-tension relationship. Norepinephrine induced transient increments in [Ca++]cyt and muscle tension in Ca++-free solution and forskolin inhibited these changes. These results suggest that forskolin has concentration-dependent inhibitory effects on vascular contractility to decrease [Ca++]cyt at lower concentrations and to decrease the sensitivity of contractile elements to Ca++ at higher concentrations.