Nitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation

doi:10.1016/S0008-6363(97)00149-1

Cardiovascular Research 1997 36(2):184-194; doi:10.1016/S0008-6363(97)00149-1
© 1997 by European Society of Cardiology

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Nitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation

Malte Kelm^a^,*, Stefan Schäfer^a, Rüdiger Dahmann^a, Bahar Dolu^c, Stefan Perings^a, Ulrich K.M Decking^b, Jürgen Schrader^b and Bodo E Strauer^a

^aDepartment of Medicine, Division of Cardiology, Pulmonary Diseases, and Angiology, Heinrich Heine University, Moorenstr. 5, 40225 Düsseldorf, Germany
^bDepartment of Physiology, Heinrich Heine University, Moorenstr. 5, 40225 Düsseldorf, Germany
^cDepartment of Pharmacology, Ege University, 53100 Bornova, Izmir, Turkey

^* Corresponding author. Tel.: +49-211-81-18323; fax: +49-211-3179737; email: sschaefe@uni-duesseldorf.de

Objective: It has been suggested that nitric oxide (NO) is involvedin the regulation of myocardial function in a variety of diseasessuch as dilated cardiomyopathy, myocarditis, heart transplantrejection, and septic shock. However, the underlying mechanismof NO mediated reduction of cardiac contractility has not beenclearly established so far. Therefore, we studied the effectsof authentic NO on left ventricular function and myocardialenergy status in the isolated heart. Methods: In 43 isolatedperfused guinea pig hearts quantitative and kinetic changesin coronary flow (CF), left ventricular developed pressure (LVDP),the cardiac release of adenosine, lactate, cyclic GMP, and norepinephrinewere measured during infusion of authentic NO. In parallel,myocardial phosphocreatine (PCr), ATP and the free energy changeof ATP-hydrolysis ( ${Delta}$ G_ATP) were measured using ³¹P nuclear magneticresonance spectroscopy. Results: At low concentrations (0.01to 1.0 µmol/L) NO increased CF only; at higher concentrations(1 to 100 µmol/L) CF remained elevated and LVDP was significantlyreduced. Onset and offset of changes in LVDP occurred alwayswithin 2 to 5 s after start and cessation of NO infusion. Contractiledysfunction was significantly correlated to a pronounced increasein adenosine formation (>70-fold), a significant decreasein myocardial PCr (–78%), ATP (–25%) and a decreasein ${Delta}$ G_ATP from –61.76 kJ/mol to –50.75 kJ/mol. Thiswas paralleled by a significant decrease in myocardial oxygenconsumption (–65%) and a tenfold increase in lactate production.Coronary vasodilation (NO: 0.001 to 1.0 µmol/L) significantlycorrelated with the increase in cGMP release, whereas at negativeinotropic concentrations (NO: 10 to 100 µmol/L) a clearquantitative and kinetic dissociation between NO-induced changesin cGMP and LVDP was observed. Contractile dysfunction was notrelated to cardiac release of norepinephrine. Conclusions: Inthe isolated heart NO can potently depress myocardial energygeneration thus being an effective modulator of cardiac contractility.This effect of NO may be of pathophysiological significancein cardiac muscle disorders in vivo.

KEYWORDS Endothelium-derived factors (nitric oxide); Free radicals; Myocardial contraction; Guinea pig

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