Action of diltiazem on canine mesenteric artery smooth muscle

We studied the effects of the Ca++ antagonist diltiazem on the contractile response of isolated first order branches of canine superior mesenteric artery. Maximum contraction induced by 60mM KCl was significantly reduced by 10(-9)M diltiazem and the ED50 concentration of KCl was increased by approximately 30% by the antagonist. Increasing concentrations of diltiazem produced dose-dependent reductions in the maximum contraction and increased the ED50 to KCl indicating mixed competitive and noncompetitive inhibition. Norepinephrine-induced contractions reached a maximum with 10(-5)M of the amine. This response was not altered by 10(-9)M diltiazem; however, the ED50 concentration of norepinephrine was nearly doubled when this concentration of antagonist was used, suggestive of competitive inhibition. Higher concentrations of diltiazem altered both the maximum response and the ED50 of norepinephrine, i.e., the mixed inhibition pattern. However, diltiazem did not alter the response to norepinephrine in Ca++-free medium. These data demonstrate that diltiazem causes relaxation of mesenteric arterial smooth muscle by suppressing Ca++ flux at cell membrane sites but is not influencing intracellular mechanisms of Ca++ release.