Inhibition of endothelium-dependent smooth muscle relaxation by calmodulin antagonists.

By using the calmodulin antagonists, calmidazolium and N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7), the hypothesis was investigated as to whether calmodulin is involved in the sequence of events leading to the endothelium-dependent vascular smooth muscle relaxation. Endothelium-dependent relaxations were studied on two different preparations, the rabbit aorta and the pulmonary artery of the guinea pig. Relaxations were produced in the precontracted rings (noradrenaline 3 X 10(-6) mol/l) in response to acetylcholine, 10(-8) to 10(-6) mol/l (aorta), histamine, 3 X 10(-8) to 1 X 10(-6) mol/l (pulmonary artery) or the calcium ionophore A 23187, 1 X 10(-8) to 3 X 10(-7) mol/l (aorta and pulmonary artery). In the presence of calmidazolium and W-7 the endothelium-dependent relaxation was inhibited in a dose dependent manner. This inhibition was seen in a concentration range that coincides with calmodulin inhibition. The half maximal concentrations of calmidazolium for the inhibition of the relaxation of the aorta induced by acetylcholine and A 23187 were 3 X 10(-6) mol/l and 1.4 X 10(-6) mol/l and that of W-7 were 3.1 X 10(-5) and 3.6 X 10(-5) mol/l, respectively. Complete inhibition was obtained both for acetylcholine-and for A 23187-induced relaxations by preincubation with 1 X 10(-5) mol/l calmidazolium or 1 X 10(-4) mol/l W-7. The half maximal concentrations of calmidazolium for the inhibition of the relaxation of the pulmonary artery in response to histamine and A 23187 were 2.7 X 10(-6) mol/l and 3 X 10(-6) mol/l and complete inhibition was achieved at 1 X 10(-5) mol/l.(ABSTRACT TRUNCATED AT 250 WORDS)