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.


METHODS
Dose response effects using sequential drug administration.


METHODS
Animal research laboratory of a large tertiary academic medical center.


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


METHODS
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.


CONCLUSIONS
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.
Zaloga
G P
GP
Department of Medicine, Washington Hospital Center, DC, USA.
Clark
J D
JD
Roberts
P R
PR
D000818:Animals; D001067:Appetite Depressants / Q000633:toxicity*; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010665:Phenylpropanolamine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000503:physiopathology
D001067:Appetite Depressants; D009569:Nitric Oxide; D010665:Phenylpropanolamine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester