Reduction of Carnitine Content by Inhibition of Its Biosynthesis Results in Protection of Isolated Guinea Pig Hearts Against Hypoxic Damage.

Abstract

BACKGROUND: 3-(2,2,2-trimethylhydrazinium) propionate (THP or mildronate) is an inhibitor of carnitine biosynthesis. This study was carried out to determine whether feeding of guinea pigs with THP results in decreased myocardial-free carnitine content and, as a result, attenuates hypoxic damage in isolated and paced work-performing hearts. METHODS AND RESULTS: Guinea pigs were administered either distilled water of 100 mg THP/kg/day orally for 10 days. The treatment resulted in about a 50% decline in myocardial-free carnitine content, from 11.1 +/- 0.2 (n = 5) to 5.6 +/- 0.2 (n = 5) µM/g dry weight of the heart. The left ventricular contractile function of the hearts was measured during normoxic perfusion (PO(2) = 590 mmHg), hypoxic perfusion (PO(2) = 149 mmHg), and reperfusion (PO(2) = 590 mmHg). In both untreated and THP-treated groups, the rate of development of intraventricular pressure (+dP/dt) under normoxic perfusion was similar; however, +dP/dt declined to about 10% of the initial rate within 20 minutes of hypoxic perfusion. In the THP-treated group of hearts, the initial decline was slower than that of the untreated animal hearts. After 20 minutes of normoxic reperfusion following 60 minutes of hypoxic perfusion, the recovery of +dP/dt and -dP/dt was greater in the THP-treated group than in the untreated group. The elevation of end-diastolic pressure during hypoxia was completely reversed by normoxic reperfusion of the THP-treated group but not in the untreated group. Mitochondria isolated from hearts from the THP-treated group after normoxic reperfusion following hypoxic perfusion exhibited better respiratory function than those from untreated hearts. CONCLUSIONS: The data suggest that feeding guinea pigs with THP results in reduced myocardial-free carnitine content and attenuation of hypoxic and reperfusion injury in isolated hearts.