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

J Physiol. 2000 Jan 15;522 Pt 2(Pt 2):311-20. doi: 10.1111/j.1469-7793.2000.00311.x.

Abstract

1. 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. 2. 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 Nomega-nitro-L-arginine (L-NA) in constant-flow-perfused spontaneously beating rat Langendorff hearts and in rat working hearts. 3. In Langendorff hearts, GTN (10 nM to 100 microM, n = 32) induced a positive inotropic response that plateaued at 1 microM 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 microM, corresponding to approximately 0.03-0.3 microM 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). 4. The positive inotropic effect of SNAP and DEA/NO progressively declined from 1 microM to 100 microM of the NO donors (corresponding to approximately 0.3-30 microM NO). 5. In the isolated working rat heart, 0.1 microM 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. 6. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiotonic Agents / pharmacology*
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Female
  • Heart / drug effects*
  • Hydrazines / pharmacology
  • In Vitro Techniques
  • Male
  • Myocardial Contraction / drug effects
  • Myocardium / enzymology
  • Nitric Oxide Donors / pharmacology*
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitric Oxide Synthase Type III
  • Nitroarginine / pharmacology
  • Nitrogen Oxides
  • Nitroglycerin / pharmacology
  • Penicillamine / analogs & derivatives
  • Penicillamine / pharmacology
  • Rats
  • Rats, Wistar
  • S-Nitroso-N-Acetylpenicillamine
  • Vasodilator Agents / pharmacology

Substances

  • Cardiotonic Agents
  • Enzyme Inhibitors
  • Hydrazines
  • Nitric Oxide Donors
  • Nitrogen Oxides
  • Vasodilator Agents
  • Nitroarginine
  • S-Nitroso-N-Acetylpenicillamine
  • 1,1-diethyl-2-hydroxy-2-nitrosohydrazine
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Nitroglycerin
  • Penicillamine