Relaxation of vascular smooth muscle by HA-1004, an inhibitor of cyclic nucleotide-dependent protein kinase

T Ishikawa, M Inagaki, M Watanabe and H Hidaka

A newly synthesized compound, N-(2-guanidinoethyl)-5- isoquinolinesulfonamide (HA-1004), was shown to be a potent inhibitor of two cyclic nucleotide-dependent protein kinases, cyclic GMP- dependent protein kinase and cyclic AMP-dependent protein kinase and the Ki values were 1.4 and 2.3 microM, respectively. HA-1004 relaxed rabbit aortic strips contracted by various agonists and with similar ED50 values. Phenotolamine, propranolol and atropine did not affect this HA-1004-induced relaxation, thereby suggesting that this compound does not act through these membrane receptor associated mechanisms. HA- 1004 shifted the dose-response curve for CaCl2 to the right in a competitive manner in depolarized rabbit renal arterial strips. This compound also relaxed the A-23187 and phenylephrine-induced contractions elicited in Ca++-free solution. These findings suggest that HA-1004 exerts its action at the intracellular or submembranal level. This vasodilator has little effect on actomyosin adenosine triphosphatase and Ca++-calmodulin-dependent myosin light chain kinase. Studies using its derivatives with various lengths of alkyl chain (C0- C6) indicated that the potencies of these compounds, as vasorelaxants, correlated well with their potential to inhibit cyclic nucleotide- dependent protein kinase. HA-1004 should be a useful tool for investigating in smooth muscle, regulatory mechanism(s) by second messengers, cyclic AMP and cyclic GMP.

Volume 235, Issue 2, pp. 495-499, 11/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics