Wy-46,300 and Wy-46,531: vascular smooth muscle relaxant/antihypertensive agents with combined Ca2+ antagonist/myosin phosphorylation inhibitory mechanisms.

1,4,5,6,7,8-hexahydro-2-methyl-5-oxo-4-(pentafluorophenyl)-1,7- naphthyridine-3-carboxylic acid methyl ester hydrochlorides with either a 3-phenoxy-2-hydroxypropyl (Wy-46,300) or 2-hydroxy-4-phenylbutyl (Wy-46,531) substituent at the 7 position are structurally novel vascular relaxant compounds which lower blood pressure by approximately 35 mm Hg at 25 mg/kg p.o. in spontaneously hypertensive rats (SHR) or perinephritic hypertensive beagles. In contrast to standard Ca2+ blockers, both agents also directly inhibit myosin phosphorylation and actin-myosin interactions in Triton-purified arterial actomyosin. The potency of Wy-46,300 (IC50 = 28 microM) in this system is similar to the calmodulin antagonist W-7, whereas Wy-46,531 (IC50 = 18 microM) is more potent. Inhibition of both parameters is attenuated in the presence of maximal Ca2+-calmodulin, consistent with calmodulin antagonism as the mechanism for myosin phosphorylation inhibition. In intact smooth muscle, these agents inhibit K+-depolarized contractions of rabbit aortic strips in a biphasic manner (0.1-10 microM, 30-40% inhibition; 10 microM-100 microM, 90% inhibition). In contrast to comparable inhibition of force by standard Ca2+ blockers, this latter phase of inhibition is not reversible with the Ca2+ agonist Bay K 8644. Moreover, significantly greater inhibition of receptor-mediated contractions (norepinephrine, angiotensin II, histamine) than that observed with nifedipine is apparent with Wy-46,300. In paced rabbit atria, both Wy-46,300 and Wy-46,531 are 10-100 times less potent as negative inotropic agents (IC25 = 3-5 microM) when compared with standard Ca2+ blockers.(ABSTRACT TRUNCATED AT 250 WORDS)