Cardiovascular Drugs and Therapy 1991; 5: 45-56 0 Kluwer Academic Publishers, Boston. Printed in U.S.A. Short-Term Hemodynamic Effects of Intravenous Propionyl-L-Carnitine in Anesthetized Dogs Antonio Cevese, Federico Schena, Giuliana Cerutti Istituto di Fisiologia Umana, University of Verona, Strada Le Grazie, I-37134, Verona, Italy Summary. The effects of intravenous administration of pro- pionyl-L-carnitine (PLC) were investigated in anesthetized dogs instrumented for the analysis of general hemodynamic and electrocardiographic data, peripheral blood flows, coro- nary blood flow and oxygen consumption, urine flow, and renal function. PLC was administered in bolus (20, 60, and 200 mg/kg) or by infusion (20 mg/kg/min * 15 min or 30 mg/ kg/min * 10 mitt). In some cases also L-carnitine (LC) and L-carnitine + propionate (LC + P) were administered in doses equimolar to those of PLC. PLC elicited dose-dependent, short-lasting enhancements of cardiac output, both in open- and closed-chest conditions. Arterial blood pressure, heart rate, and contractility varied slightly and unpredictably: the substance did not elicit electrocardiographic effects. These responses were not changed by alpha- or beta-adrenergic blockade, nor by the administration of a calcium antagonist, but they were abolished or reversed by the combination of such blocking interventions. Mesenteric and iliac blood flows were increased by both PLC and LC; LC + P increased these, and in addition increased renal blood flow. A strong diuresis obtained with PLC, LC, and LC + P was due to osmotic clear- ance following the administration of hyperosmotic solutions. PLC elicited coronary vasodilation with reduced oxygen ex- traction; this effect lasted longer than the general hemody- namic effects and was not seen with LC. All the cardiovascu- lar actions of PLC can be attributed to its pharmacologic properties, rather than to its role as a metabolic interme- diate. Cardiovasc Drugs Ther 1991; 5:45-56 Key Words. propionyl-L-carnitine, L-carnitine, peripheral vasodilation, coronary flow Carnitine and its acyl derivatives (acetyl and pro- pionyl) are naturally occurring substances that are required for the transport of long-chain acyl groups derived from fatty acids across mitochondrial membranes, a necessary preliminary to fatty acid oxi- dation and hence ATP production [1,2]. For this rea- son it has been proposed that they may protect ische- mic tissues, particularly the myocardium [3,4], by prolonging this oxidative metabolism. Studies on iso- lated myocardial cells and dissected hearts have dem- onstrated that carnitine and acyl carnitines prevent mitochondrial damage [5-81 and decrease the accumu- lation of intracellular long-chain AC-CoA during ische- mia [5,6,9]. An increased rate of recovery of cardiac performance after periods of coronary hypoperfusion has also been reported [lO,ll]. These protective ac- tions are most effective with propionylcarnitine and are less effective with acetylcarnitine; carnitine itself has the least potency [5,11,12]. On this evidence, carnitine derivatives, particu- larly propionyl-L-carnitine (PLC), may be useful as therapeutic agents for the prevention and treatment of myocardial ischemic disease. However, certain es- sential information is at present lacking. In particular, the direct, short-term effects of PLC on the cardiovas- cular system have not yet been studied on in vivo preparations and with doses similar to those used in humans. We now report the results of experiments invest- igating the effects of PLC in anesthetized dogs, fitted with instruments for the analysis of a) general hemo- dynamic parameters and ECG (open and closed chest), b) peripheral blood flows and renal function, and c) the coronary circulation. Materials and Methods Twenty-five dogs of both sexes, ranging in weight from 12 to 28 kg (average 22.6 kg), were used for the study. The animals were anesthetized with sodium pentobarbital(30 mglkg + 3 mgikglh, IV) and placed on a thermostatic operating table, which allowed con- trol of their body temperature. Positive pressure art- ficial respiration was performed through a Harvard model 607 constant-volume respiratory pump. A posi- tive end-expiratory pressure of 5 cm H,O was imposed whenever the chest was opened. The respiratory vol- ume was matched to body weight (12 ml/kg), and the rate was adjusted to keep blood gases in the physio- Address for correspondence and reprint requests: Dr. Antonio Ce- vese, Istituto di Fisiologia Umana, Strada Le Grazie. 1.3’7134, Ve- rona, Italy. 45