Positive and negative inotropic effects of NO donors in atrial and ventricular fibres of the frog heart

1. 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. 2. SNP and SNAP (0.1-100 mu M) 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 (T-TP) and the time for half-relaxation of contraction (T-1/2). 3. SIN-1 (100 mu M) 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. 4. The guanylyl cyclase inhibitor 1H-[1,2,4]oxidiazolo[4,3-a]quinoxaline-1-one (ODQ, 10 mu M) antagonized the negative inotropic effects of SIN-1 (50 mu M) and SNAP (25 mu M) but had no effect on the positive inotropic response to SIN-1 (100 mu M). 5. 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. OD had no effects when applied alone or in the presence of SNAP 6. 6-Anilino-5,8-quinolinedione (LY 83583, 3-30 mu M), 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 mu M). 7. 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.