Effect of phorbol 12,13-dibutyrate on smooth muscle tone in rat stomach fundus

Abstract

We investigated the effects of phorbol 12,13-dibutyrate (PDBu), a typical protein kinase C (PKC) activator, on smooth muscle tone in the rat stomach fundus. In 5-hydroxytriptamine (5-HT)-precontracted stomach fundus strips, PDBu induced dose-dependent relaxation, but 4α-phorbol 12,13-didecanoate, a phorbol ester that does not activate PKC, did not induce relaxation. A PDBu-induced dose-dependent relaxation was also observed in strips precontracted with platelet-activating factor (PAF), carbachol, or 60 mM K⁺. In stomach fundus strips pretreated with PDBu, the contractile responses to 5-HT and PAF were completely blocked, but those induced by carbachol and endothelin-1 (ET-1) were only partially inhibited. In stomach fundus strips preincubated with carbachol in Ca²⁺-free medium, the Ca²⁺-induced contraction was decreased by preincubation with PDBu. In strips preincubated with 5-HT, PAF, or ET-1 in Ca²⁺-free medium, Ca²⁺-induced contractions were greatly inhibited by pretreatment with PDBu. These results suggest that in rat stomach fundus strips, PDBu-induced relaxation is mediated by activation of PKC. We speculate that a major factor mediating the relaxant action of PDBu in rat stomach fundus smooth muscle is represented by a reduction in Ca²⁺ influx via an inhibition of Ca²⁺ channels.