Inhibition of nitric oxide synthase augments the positive inotropic effect of nitric oxide donors in the rat heart

摘要

class="enumerated" style="list-style-type:decimal">In this investigation we studied the effects of nitric oxide on contractility and heart rate in normal saline-perfused rat hearts where shear stress-induced endothelial NO synthesis substantially contributes to total cardiac NO production. In addition, we sought to estimate the concentrations of exogenous NO producing inotropic effects.We investigated the effects of glyceryl trinitrate (GTN), S-nitroso-d,l-penicillamine (SNAP), sodium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolat (DEA/NO), and DEA/NO in the presence of the NO synthase inhibitor N^ω-nitro-l-arginine (L-NA) in constant-flow-perfused spontaneously beating rat Langendorff hearts and in rat working hearts.In Langendorff hearts, GTN (10 nm to 100 μm, n = 32) induced a positive inotropic response that plateaued at 1 μm GTN with a maximal rate of increase of left ventricular pressure during ventricular contraction (+dP/dtmax) of 6.33 ± 2.56 % (n = 11, P < 0.5). Similarly, both spontaneous NO donors (0.1 nm to 1 μm, corresponding to approximately 0.03-0.3 μm NO) induced a positive inotropic response of 10.6 ± 3.1 % (SNAP; n = 15, P < 0.05) and 11.5 ± 2.7 % (DEA/NO, n = 15, P < 0.05).The positive inotropic effect of SNAP and DEA/NO progressively declined from 1 μm to 100 μm of the NO donors (corresponding to approximately 0.3-30 μm NO).In the isolated working rat heart, 0.1 μm DEA/NO induced an increase of +dP/dtmax of 7.5 ± 2.5 % (n = 9, P < 0.05). Inhibition of NO synthase by L-NA produced a 4-fold increase in this effect of DEA/NO.We suggest that physiological NO concentrations support myocardial performance. In normal rat hearts the positive inotropic effect of NO appears to be almost maximally exploited by the endogenous NO production.