Abstract
This study was designed to clarify the mechanism of the inhibitory effect of forskolin on contraction, cytosolic Ca(2+) level ([Ca(2+)](i)), and Ca(2+) sensitivity in guinea pig ileum. Forskolin (0.1 nM~10 microM) inhibited high K(+) (25 mM and 40 mM)- or histamine (3 microM)-evoked contractions in a concentration-dependent manner. Histamine-evoked contractions were more sensitive to forskolin than high K(+)-evoked contractions. Spontaneous changes in [Ca(2+)](i) and contractions were inhibited by forskolin (1 microM) without changing the resting [Ca(2+)](i). Forskoln (10 microM) inhibited muscle tension more strongly than [Ca(2+)](i) stimulated by high K(+), and thus shifted the [Ca(2+)](i)-tension relationship to the lower-right. In histamine-stimulated contractions, forskolin (1 microM) inhibited both [Ca(2+)](i) and muscle tension without changing the [Ca(2+)](i)-tension relationship. In alpha-toxin-permeabilized tissues, forskolin (10 microM) inhibited the 0.3 microM Ca(2+)-evoked contractions in the presence of 0.1 mM GTP, but showed no effect on the Ca(2+)-tension relationship. We conclude that forskolin inhibits smooth muscle contractions by the following two mechanisms: a decrease in Ca(2+) sensitivity of contractile elements in high K(+)-stimulated muscle and a decrease in [Ca(2+)](i) in histamine-stimulated muscle.
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