ACTIVATION OF SOLUBLE GUANYLYL CYCLASE BY YC-1 IN AORTIC SMOOTH-MUSCLE BUT NOT IN VENTRICULAR MYOCARDIUM FROM RAT

1 The effects of YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole ), an activator of soluble guanylyl cyclase, on tension, levels of cyc lic GMP and cyclic AMP, and cardiac L-type Ca2+-current (I-Ca(L)) were investigated in aortic smooth muscle and ventricular heart muscle fro m rat. 2 YC-1 (0.1-30 mu M) induced a concentration-dependent relaxati on in aortic rings precontracted with phenylephrine (3 mu M). The rela xant effects of YC-1 were reversed by 1H-[1,2,4]oxadiazolo[4,3-a]quino xalin-1-one (30 mu M; ODQ), potentiated by zaprinast (10 mu M) and ant agonized by Rp-8-Br-cGMPS (100 mu M). 3 In ventricular heart muscle st rips, YC-1 (30 mu M) exhibited no effects on force of contraction (F-c ) in the absence or presence of either zaprinast (10 mu M) or 3-isobut yl-1-methylxanthine (30 mu M). F-c was slightly increased by YC-1 (30 mu M) in the presence of isoprenaline (100 nM), but this effect was no t influenced by ODQ (30 mu M). 4 Cardiac I-Ca(L) was not significantly affected by YC-1 (30 mu M), either in the absence or presence of isop renaline (30 nM). 5 In aortic rings, cyclic GMP levels were increased almost 3 fold by YC-1 (30 mu M); this effect was abolished by ODQ (30 mu M). In isolated ventricular cardiomyocytes, cyclic GMP levels were not affected by YC-1 (30 mu M) but almost doubled by activation of par ticular guanylyl cyclase with atriopeptin II (100 nM). 6 YC-1 (30 mu M ) did not increase cyclic AMP levels either in aortic rings or in vent ricular cardiomyocytes. In contrast, isoprenaline (3 mu M) increased c yclic AMP levels about two fold in both tissues. In cardiomyocytes, th e effect of isoprenaline (3 mu M) was slightly enhanced by YC-1 (30 mu M). 7 It is concluded that relaxation of smooth muscle preparations b y YC-1 is mediated mainly by activation of soluble guanylyl cyclase an d subsequent increase in cyclic GMP levels. The failure of YC-1 to aff ect cardiac F-c, levels of cyclic GMP, and I-Ca(L) suggests that solub le guanylyl cyclase is not influenced by YC-1 in rat heart muscle or o nly barely present in this tissue.