November 1, 1997
View Full PaperNitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation
Key Result
Infusion of nitric oxide in isolated hearts potently depressed myocardial energy generation, decreasing phosphocreatine by 78% and ATP by 25%, and reduced left ventricular developed pressure.
Structured PICO
Does nitric oxide infusion affect left ventricular function and myocardial energy generation in isolated guinea pig hearts?
P
Population
43 isolated perfused guinea pig hearts used to study the effects of nitric oxide on left ventricular function and myocardial energy status.
I
Intervention
Infusion of authentic nitric oxide (NO) at concentrations ranging from 0.01 to 100 mumol/L
O
Outcome
Changes in coronary flow (CF), left ventricular developed pressure (LVDP), and myocardial energy status (phosphocreatine, ATP, and free energy change of ATP-hydrolysis)surrogate
High concentrations of nitric oxide potently depress myocardial energy generation and cardiac contractility in isolated guinea pig hearts, suggesting a mechanism for contractile dysfunction in inflammatory cardiac diseases.
Abstract
OBJECTIVE: It has been suggested that nitric oxide (NO) is involved in the regulation of myocardial function in a variety of diseases such as dilated cardiomyopathy, myocarditis, heart transplant rejection, and septic shock. However, the underlying mechanism of NO mediated reduction of cardiac contractility has not been clearly established so far. Therefore, we studied the effects of authentic NO on left ventricular function and myocardial energy status in the isolated heart. METHODS: In 43 isolated perfused guinea pig hearts quantitative and kinetic changes in coronary flow (CF), left ventricular developed pressure (LVDP), the cardiac release of adenosine, lactate, cyclic GMP, and norepinephrine were measured during infusion of authentic NO. In parallel, myocardial phosphocreatine (PCr), ATP and the free energy change of ATP-hydrolysis (delta GATP) were measured using 31P nuclear magnetic resonance spectroscopy. RESULTS: At low concentrations (0.01 to 1.0 mumol/L) NO increased CF only; at higher concentrations (1 to 100 mumols/L) CF remained elevated and LVDP was significantly reduced. Onset and offset of changes in LVDP occurred always within 2 to 5 s after start and cessation of NO infusion. Contractile dysfunction was significantly correlated to a pronounced increase in adenosine formation (> 70-fold), a significant decrease in myocardial PCr (-78%), ATP (-25%) and a decrease in delta G(ATP) from -61.76 kJ/mol to -50.75 kJ/mol. This was paralleled by a significant decrease in myocardial oxygen consumption (-65%) and a tenfold increase in lactate production. Coronary vasodilation (NO: 0.001 to 1.0 mumol/L) significantly correlated with the increase in cGMP release, whereas at negative inotropic concentrations (NO: 10 to 100 mumols/L) a clear quantitative and kinetic dissociation between NO-induced changes in cGMP and LVDP was observed. Contractile dysfunction was not related to cardiac release of norepinephrine. CONCLUSIONS: In the isolated heart NO can potently depress myocardial energy generation thus being an effective modulator of cardiac contractility. This effect of NO may be of pathophysiological significance in cardiac muscle disorders in vivo.