No abstract

The cardiac effects of the NO donors sodium nitroprusside (SNP), S‐nitroso‐N‐acetyl‐penicillamine (SNAP) and 3‐morpholino‐sydnonimine (SIN‐1) were studied in frog fibres to evaluate the contribution of cyclic GMP‐dependent mechanisms. SNP and SNAP (0·1‐100 μM) reduced the force of contraction in a concentration‐dependent manner in atrial and ventricular fibres. This effect was associated with a reduction in the time to peak (TTP) and the time for half‐relaxation of contraction (T½). SIN‐1 (100 μM) also reduced the force of contraction in two‐thirds of the atrial fibres. However, it exerted a positive inotropic effect in the remaining atrial fibres, as well as in most ventricular fibres. The guanylyl cyclase inhibitor 1H‐[1,2,4]oxidiazolo[4,3‐a]quinoxaline‐1‐one (ODQ, 10 μM) antagonized the negative inotropic effects of SIN‐1 (50 μM) and SNAP (25 μM) but had no effect on the positive inotropic response to SIN‐1 (100 μM). In the presence of SIN‐1, superoxide dismutase (SOD, 50‐200 U ml−1) either potentiated the negative inotropic effect or turned the positive inotropic effect of the drug into a negative effect. SOD had no effects when applied alone or in the presence of SNAP. 6‐Anilino‐5,8‐quinolinedione (LY 83583, 3‐30 μM), a superoxide anion generator also known as a cyclic GMP‐lowering agent, exerted a positive inotropic effect, which was antagonized by SOD (200‐370 U ml−1) but not by ODQ (10 μM). We conclude that SNP, SNAP and SIN‐1 exert cyclic GMP‐dependent negative inotropic effects, which are attributed to the generation of NO. In addition, SIN‐1 and LY 83583 exert cyclic GMP‐independent positive inotropic effects, which require the generation of superoxide anion.

In the heart, the parasympathetic neurotransmitter acetylcholine (ACh) reduces the force of contraction. Although the effect of ACh can be partly explained by an inhibition of adenylyl cyclase, some of the effects of ACh may also be mediated via stimulation of nitric oxide synthase (NOS) and production of guanosine 3', 5'-cycle monophosphate (cGMP). NOS inhibitors can prevent the negative chronotropic effect of ACh on spontaneously beating cardiomyocytes and suppress the inhibition of the L-type calcium current (ICa) by ACh in sinoatrial myocytes. This pathway may be relevant not only to the chronotropic effect of ACh but also to its inotropic effect, because ACh, NO, and cGMP regulate the force of contraction and ICa in the cardiac ventricle. Here we report the effects of L-arginine (L-Arg), the substrate of NOS, and NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine (L-NNA), two NOS inhibitors, on muscarinic effects in the cardiac ventricle. We found that L-Arg, L-NMMA, and L-NNA have no effect on the muscarinic inhibition of ICa in isolated frog myocytes. In addition, these compounds have no significant effects on basal ICa or beta-adrenergic stimulation of ICa. L-Arg and its analogues did not change the negative inotropic effect of ACh in frog ventricular fibers. Basal active tension and the positive inotropic effect of isoproterenol, a beta-adrenergic agonist, also were unaffected. We conclude that NOS in not involved in muscarinic inhibition of ICa in isolated from ventricular myocytes or the negative inotropic effect of ACh in the frog ventricle.