Inhibition of nitric oxide synthase enhances the myocardial toxicity of phenylpropanolamine

Objective: To investigate the direct and indirect effects of the anorexic a gent 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 ce nter. Subjects: Isolated hearts (n = 8) from male Sprague-Dawley rats weighing 30 0-400 g. Interventions: Measurement of heart rate, maximal change in pressure over t ime (dP/dt(max)), -dP/dt(max), and coronary blood flow in isolated hearts p erfused on a Langendorff apparatus. PPA was infused through the aortic cann ula 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 si gnificantly depressed contractility at a dose of 0.25 mmol/L. PPA had no si gnificant effects on coronary blood flow. PPA failed to induce arrhythmias in normal hearts. However, after L-NAME, PPA induced ventricular fibrillati on in 50% of the hearts. Conclusion: PPA causes myocardial contractile depression without altering g lobal coronary artery blood flow, Inhibition of nitric oxide synthesis sens itizes the heart to the myocardial depressant effects of PPA and increases the risk for ventricular fibrillation.