Inhibition of nitric oxide synthase enhances the myocardial toxicity of phenylpropanolamine.

OBJECTIVE

To investigate the direct and indirect effects of the anorexic agent phenylpropanolamine (PPA) on the heart and to determine whether nitric oxide deficiency exacerbates the myocardial toxicity of PPA.

DESIGN

Dose response effects using sequential drug administration.

SETTING

Animal research laboratory of a large tertiary academic medical center.

SUBJECTS: Isolated hearts (n = 8) from male Sprague-Dawley rats weighing 300-400 g.

INTERVENTIONS: Measurement of heart rate, maximal change in pressure over time (dP/dtmax), -dP/dtmax, and coronary blood flow in isolated hearts perfused on a Langendorff apparatus. PPA was infused through the aortic cannula at 0.05, 0.125, 0.25, 0.5, and 1.25 mmol/L before and after inhibition of nitric oxide synthesis with N-nitro-L-arginine methyl ester (L-NAME).

RESULTS

PPA had little effect on myocardial contractility of normal hearts until the highest dose of PPA (1.25 mmol/L). However, after L-NAME, PPA significantly depressed contractility at a dose of 0.25 mmol/L. PPA had no significant effects on coronary blood flow. PPA failed to induce arrhythmias in normal hearts. However, after L-NAME, PPA induced ventricular fibrillation in 50% of the hearts.

CONCLUSION

PPA causes myocardial contractile depression without altering global coronary artery blood flow. Inhibition of nitric oxide synthesis sensitizes the heart to the myocardial depressant effects of PPA and increases the risk for ventricular fibrillation.