Forskolin Changes the Relationship between Cytosolic Ca<SUP>2＋</SUP> and Contraction in Guinea Pig Ileum

Forskolin Changes the Relationship between Cytosolic Ca<SUP>2＋</SUP> and Contraction in Guinea Pig Ileum

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&#1356;M) inhibited high K^＋ (25 mM and 40 mM)- or histamine (3&#1356;M)-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&#1356;M) without changing the resting [Ca^2＋]_i. Forskoln (10&#1356;M) 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&#1356;M) inhibited both [Ca^2＋]_i and muscle tension without changing the [Ca^2＋]_i-tension relationship. In &#1345;-toxin-permeabilized tissues, forskolin (10&#1356;M) inhibited the 0.3&#1356;M 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.