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 cyclic GMP and cyclic AMP, and cardiac L-type Ca2+-current (I[Ca(L)]) were investigated in aortic smooth muscle and ventricular heart muscle from rat. 2. YC-1 (0.1-30 microM) induced a concentration-dependent relaxation in aortic rings precontracted with phenylephrine (3 microM). The relaxant effects of YC-1 were reversed by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (30 microM; ODQ), potentiated by zaprinast (10 microM) and antagonized by Rp-8-Br-cGMPS (100 microM). 3. In ventricular heart muscle strips, YC-1 (30 microM) exhibited no effects on force of contraction (Fc) in the absence or presence of either zaprinast (10 microM) or 3-isobutyl-1-methylxanthine (30 microM). Fc was slightly increased by YC-1 (30 microM) in the presence of isoprenaline (100 nM), but this effect was not influenced by ODQ (30 microM). 4. Cardiac I[Ca(L)] was not significantly affected by YC-1 (30 microM), either in the absence or presence of isoprenaline (30 nM). 5. In aortic rings, cyclic GMP levels were increased almost 3 fold by YC-1 (30 microM); this effect was abolished by ODQ (30 microM). In isolated ventricular cardiomyocytes, cyclic GMP levels were not affected by YC-1 (30 microM) but almost doubled by activation of particular guanylyl cyclase with atriopeptin II (100 nM). 6. YC-1 (30 microM) did not increase cyclic AMP levels either in aortic rings or in ventricular cardiomyocytes. In contrast, isoprenaline (3 microM) increased cyclic AMP levels about two fold in both tissues. In cardiomyocytes, the effect of isoprenaline (3 microM) was slightly enhanced by YC-1 (30 microM). 7. It is concluded that relaxation of smooth muscle preparations by YC-1 is mediated mainly by activation of soluble guanylyl cyclase and subsequent increase in cyclic GMP levels. The failure of YC-1 to affect cardiac Fc, levels of cyclic GMP, and I[Ca(L)] suggests that soluble guanylyl cyclase is not influenced by YC-1 in rat heart muscle or only barely present in this tissue.
Wegener
J W
JW
Pharmakologisches Institut der Universität Mainz, Germany.
Gath
I
I
Förstermann
U
U
Nawrath
H
H
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006162:Guanylate Cyclase / Q000187:drug effects* / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D007191:Indazoles; D010975:Platelet Aggregation Inhibitors; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D000242:Cyclic AMP; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D007545:Isoproterenol; D002118:Calcium