Nifedipine enhances cGMP production through the activation of soluble guanylyl cyclase in rat ventricular papillary muscle

It is known that nifedipine, an L-type calcium channel blocker, increases cGMP production, which partially contributes to the relaxation of vascular smooth muscle. The aim of our investigation was to clarify whether or not nifedipine regulates cGMP production, which has a physiological role in cardiac muscle. To measure contractile responses and tissue cGMP levels, left ventricular papillary muscles prepared from male Wistar rats (350-400 g) were mounted in the isolated organ chamber under isometric conditions and electrically paced by means of platinum punctate electrodes (1 Hz, 1 ms duration). In papillary muscle preparation, the negative inotropic effect induced by nifedipine (30 to 300 nM) was significantly inhibited in the presence of ODQ(1H-[1,2,4]oxidazolo[4,3-a]quinoxaline1-one; 10 microM), a soluble guanylyl cyclase inhibitor. Furthermore, nifedipine (100 nM) strongly increased the tissue cGMP level, which was significantly decreased in the presence of ODQ. On the other hand,N(G)-monomethyl-(L)-arginine (100 microM), a nitric oxide synthase inhibitor, did not inhibit either the negative inotropic effect or cGMP production induced by nifedipine. These results indicate that in rat left ventricular papillary muscle, nifedipine augments its negative inotropic effect at least partly through direct activation of cardiac soluble guanylyl cyclase but not nitric oxide synthase.