The inotropic effect of nitric oxide is dependent on the level of beta 1-adrenergic stimulation in isolated mammalian myocardium

Abstract

We tested the hypothesis that nitric oxide has a positive inotropic effect on mammalian cardiac muscle contractility and that this effect sums with the positive inotropic effect of β1-adrenergic agonists when both are present. Feline right ventricular papillary muscles were stimulated to contract isometrically at 0.2 Hz in Krebs Henseleit bicarbonate buffer (KREBS) gassed with 95% O2 and 5% CO2 (26°C; pH 7.34). The nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine (SNAP, 10 5 M), and the membrane permeable cGMP analog 8-bromoguanosine-3',5'-cyclo phosphate sodium (Br-cGMP, 10 5 M), significantly increased developed force by 13.3 ± 1.5% (n = 11) and 7.8 ± 2.8% (n = 7), respectively. SNAP, at 10-5 M, significantly increased the force developed by papillary muscle treated with 10 11 M or 10 9 M dobutamine hydrochloride (a β1-adrenergic agonist) (n = 25, 11.3 ± 2.9% and 10.0 ± 3.6%, respectively) when compared with the addition of KREBS (n = 27, 2.6 ± 0.9% and 5.5 ± 0.9%), but the increase was less than predicted by the sum of inotropic effects of SNAP and dobutamine. SNAP at 10-5 M did not change developed force in muscles treated with 10 7 M dobutamine but it significantly decreased developed force in muscles challenged with 10 5 M dobutamine (n = 18, 29.3 ± 5.0%) when compared with KREBS (n = 10, 41.5 ± 6.8%). Similarly, 10 4 M 8-bromo-adenosine cyclic 3',5'-hydrogen phosphate monosodium (a membrane permeable cAMP analog) increased developed force 14.9 ± 3.3% and the addition of 10 5 M Br-cGMP to those muscles significantly reduced developed force by 3.5% ± 1.1% (n = 7). Thus, the positive inotropic effect of NO decreased and ultimately became an attenuation as the level of β1-adrenergic stimulation increased due, at least in part, to an interaction between the cAMP and cGMP second messenger pathways.Key words: nitric oxide, β1-adrenergic, cGMP, cAMP, contractility, cardiac muscle.