Involvement of Calcium in Cyclic Nucleotide Metabolism in Human Vascular Smooth Muscle

Abstract

When cyclic nucleotide phosphodiesterase was purified from isolated smooth muscle layer of human aorta by DEAE-cellulose column chromatography, separated cyclic GMP phosphodiesterase activity was markedly stimulated in the presence of 10–20 µM of Ca²⁺ by a protein modulator which has similar physico-chemical properties to troponin C. Synthetic compound, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, which produced relaxations of arteries contracted by prostaglandin F_2α or KCl was found to inhibit selectively this Ca²⁺-dependent cyclic GMP phosphodiesterase. This compound produced inhibition of superprecipitation of myosin B system obtained form mouse skeletal muscle and also inhibited adenosine triphosphatase activity of myosin B. Our data suggest that calcium is involved through a protein modulator in cyclic nucleotide metabolism of vascular smooth muscle and that the calcium-dependent protein modulator probably participates in the regulation of contractile response of vascular smooth muscle by affecting actomyosin ATPase activity.

Effects of calcium, calcium entry blockers and calmodulin inhibitors on atrioventricular conduction disturbances induced by hypoxia

“…In contrast, W-5, which is a less potent calmodulin inhibitor than W-7 (Hidaka et al, 1981), did not show such a protective effect against hypoxia. The concentrations ofW-7 and Cpz in the present experiment are similar to their dissociation constants for calmodulin and certainly lie within the range of their effective concentrations for inhibiting calmodulin-regulated enzyme reactions in vitro (Hidaka et al, 1979;Weiss & Wallace, 1980;Means et al, 1982).…”

“…Accordingly, an elevation of free Calmodulin, the ubiquitous Ca2+-dependent regulator protein (Cheung, 1980), has attracted a great deal ofattention in recent years, and is now recognized as the major intracellular protein mediating numerous Ca2 -modulated cellular processes, such as cyclic AMP metabolism, glycogen metabolism, cation transport and myosin light chain kinase in the heart (Walsh et al, 1980). The present results showed that hypoxiainduced AH prolongation or AH block was prevented by the pretreatment with W-7 or Cpz, which were reported to be potent calmodulin inhibitors (Levin & Weiss, 1976;Hidaka et al, 1979). In contrast, W-5, which is a less potent calmodulin inhibitor than W-7 (Hidaka et al, 1981), did not show such a protective effect against hypoxia.…”

Calcium‐dependent hydrophobic interaction chromatography of calmodulin, troponin C and their proteolytic fragments

“…Although the original discoveries that antipsychotic drugs [Z] and smooth muscle relaxing agents [3,4] bound to CaM led to the suggestion that specific binding sites for these agents may exist, our studies show that identical results are obtained with phenyl-and CAPP-Sepharose, thus indicating that rather non-specific hydrophobic forces must be involved in the interaction between the drugs and the Ca'+-dependent domains on the surface of CaM. Similar conclusions, based on different types of experiments, have been put forward [9,14,15].…”

1H-NMR Studies of Calmodulin: The Modifying Effect of W-7 (N-(6-Aminohexyl)-5-Chloro-1-Naphthalenesulfonamide) on the Calcium-Induced Conformational Changes of Calmodulin

“…Numerous func tions of calmodulin are known to be in hibited by W-7. It has been shown that calmodulin-induced activation of cyclic GMP phosphodiesterase of human aorta or bovine brain (2,3), Cat+, Mgt+-ATPase of human erythrocytes (4), myosin light chain kinase of chicken gizzard (5), and phospholipase A2 and C of rat renal medulla (6) are selectively inhibited by W-7. Furthermore, we have reported that W-7 antagonizes the pro longation by calcium of ethanol-induced sleeping time in mice (7,8), and the regula tion by central calcium of blood pressure in rats (9).…”