Conditioning Effects of Chronic Infusions of Dobutamine COMPARISON WITH EXERCISE TRAINING CHANG-SENG LIANG, RONALD R. TUTTLE, WILLIAM B. HOOD, JR., and HARALAMBOS GAVRAS, Departments of Medicine and Pharmacology, and the Cardiovascular Institute, Boston University School of Medicine, Thorndike Memorial Laboratory, Boston City Hospital, Boston, Massachusetts 02118; The Lilly Research Laboratories, Indianapolis, Indiana 46206 A B S T R A C T We studied the conditioning effects further suggest that sympathetic stimulation during ofchronic infusion ofdobutamine and exercise training exercise plays a role in physical conditioning. in three groups of chronically instrumented dogs. One group was infused with normal saline, a second group INTRODUCTION was infused with dobutamine (40 ,ug/kg per min), and the third group was exercised on a treadmill at 4 mph, Prolonged physical exercise produces a variety of up a 100 incline. Each group was either infused or biochemical and cardiovascular changes in man. These exercised for 2 h a day, 5 d a week for 5 consecutive adaptive changes, known as physical conditioning, wk. Resting heart rate and arterial blood lactate con- include a decrease in resting heart rate (1, 2), and centration, measured at weekly intervals, decreased increases in skeletal muscle mitochondrial enzymes progressively in the dobutamine and exercise groups, (3), maximum exercise oxygen consumption (1-3), but not in the group that received normal saline infu- and myocardial contractility (1, 4). The increase in sion. Cardiovascular responses to submaximal tread- maximum oxygen consumption probably is accounted mill exercise were not changed by 5 wk of normal for by the enhanced capacity of skeletal muscle to saline infusion. However, the increases in heart rate, extract oxygen as well as by the increase in oxygen cardiac output, mean aortic blood pressure, arterial delivery. Lower levels of blood and skeletal muscle blood lactate, plasma renin activity, and norepineph- lactate are also observed in trained subjects, both at rine concentration during exercise were significantly rest and during exercise (3). As a result, a trained in- smaller after 5 wk of conditioning with either dobuta- dividual is able to respond to the same work load with mine or exercise training. After conditioning, the in- less effort and to achieve a higher maximum work creases in arteriovenous oxygen difference during load than a sedentary person. exercise were larger in the latter two groups, but the The hemodynamic and metabolic changes that occur increases in total body oxygen consumption did not during muscular exercise are well-known (5), and many differ before and after conditioning. of them are caused by sympathetic stimulation (5-7). To assess ventricular function, we intravenously It is, however, not known what role sympathetic stim- infused methoxamine both before and after condi- ulation plays in the development ofthe physical condi- tioning. The slope of the line that related systolic tioning response. A preliminary report (8) showed aortic blood pressure and mean left atrial pressure that repetitive stimulation with the sympathomimetic increased in the animals conditioned with either do- drug, dobutamine, caused a conditioning response butamine or exercise, indicating enhanced myocardial in dogs with coronary arterial narrowing such that contractility. Left ventricular blood flow was lower there was a decrease in resting heart rate and an ap- in these two groups ofanimals than it was in the normal parent increase in myocardial contractility. Dobuta- saline group. Left ventricular weight did not differ mine is a new synthetic catecholamine which, when among the three groups. infused intravenously, elicits increases in heart rate, Our results show that chronic infusion ofdobutamine myocardial contractility, arterial blood pressure, and produced cardiovascular and metabolic conditioning coronary and skeletal muscle blood flows that resemble effects like those produced by exercise training, and the effects of exercise. Unlike the naturally occurring J. Clin. Invest. © The American Society for Clinical Inwvestigation, Inc. 0021-9738/79/08/0613/07 $1.00 613 Volume 64 August 1979 613-619 catecholamines (dopamine, norepinephrine, and resting and exercise values in Results. In addition, aortic dobutamine has and pulmonary artery blood samples were taken during the epinephrine), little a-adrenergic resting period and after 15 min of treadmill exercise to meas- action, consequently dobutamine cannot readily in- ure oxygen content by gas chromatography (11). Simulta- duce rises in blood pressure greater than those induced neously, aortic blood samples were obtained to measure by exercise. Yet, unlike isoproterenol, dobutamine pH, Po2, and Pco2 on a Radiometer PHM 71 acid base analyzer does not have so much f3-adrenergic vasodilatory ac- (Rainin Instrument Co. Inc., Wobum, Mass.), and to measure lactate (12), pyruvate (13), plasma renin activity (14), and tivity that it lowers arterial blood pressure. Also, do- norepinephrine (15). Total body oxygen consumption was butamine is less likely to cause arrhythmias or myo- calculated from the equation of cardiac output times the cardial necrosis than are the naturally occurring cate- difference between aortic and pulmonary arterial blood oxy- cholamines or isoproterenol (9, 10, data on file at the gen contents (arteriovenous oxygen difference). Lilly Research Laboratories). 1 h after the treadmill exercise, we placed the animal in a prone position and continuously monitored aortic and left The purpose of this study was to compare the condi- atrial blood pressures as ventricular afterload was elevated tioning effects of chronic dobutamine infusion and with methoxamine hydrochloride (Vasoxyl, Burroughs Well- exercise in normal dogs. Our results show that chronic come Co., Research Triangle Park, North Carolina). The dobutamine infusion produced cardiovascular and peak systolic aortic blood pressures were then plotted against left atrial pressures to construct a left ventricular function metabolic changes like physical conditioning, and curve. Methoxamine is a pure a-adrenergic agonist, which suggest that sympathetic stimulation may play a major produces peripheral vasoconstriction and has no direct effect role in conditioning. on the heart (16). It was diluted in normal saline to a con- centration of 0.33 mg/ml, and infused into a peripheral vein at successively increasing rates of0. 19, 0.38, and 0.78 ml/min, METHODS with a Harvard infusion pump. The infusion was stopped Pure-bred adult beagles that weighed between 8.6 and 15.0 kg when the systolic aortic pressure reached 225 mm Hg or when were used. They were screened for their ability to run on a the aortic blood pressure achieved a plateau at the highest treadmill at 4 mph up a 100 incline; only those dogs that were dose of methoxamine. At the end of methoxamine infusion, free of heart worm infestation and that would run without 5 mg of phentolamine mesylate (Regitine, CIBA-Geigy coercion for more than 20 min were chosen for the study. Corp., Pharmaceuticals Div., Summit, N. J.) was adminis- The animals were housed in individual cages for 1 wk before tered to reverse the effects of methoxamine and the dog was they were anesthetized with pentobarbital sodium (25 mg/kg, returned to the cage. i.v.). A Harvard respirator (Harvard Apparatus Company, The dogs were divided into three groups the day after the Inc., Millis, Mass.) was used to maintain pulmonary ventila- initial treadmill exercise test and methoxamine infusion. tion. A sterile left thoracotomy was done via the fifth inter- Two of the groups remained sedentary and were infused costal space. Heparin-filled Tygon catheters (i.d., 1.02 mm; with normal saline or dobutamine (40 .ug/kg per min; Dobu- Norton Co., Plastics & Synthetics Div., Akron, Ohio) were trex, Eli Lilly & Co., Indianapolis, Indiana) at a rate of 0.38 inserted into the main pulmonary artery, left atrium, and the ml/min with a Harvard infusion pump for 2 h a day, 5 d a descending thoracic aorta. The catheters were then exte- week for 5 consecutive wk. The third group was exercised riorized through the interscapular space and secured at the on the treadmill at 4 mph up a 100 incline for the same inter- back of the dog's neck. After the thoracotomy was closed, vals of time as the two other groups that received infusions. the animal was returned to its cage, and was allowed to re- Resting heart rate, aortic blood pressure, and arterial lactate cover for 2 wks. Veterinary procaine penicillin G (Pfizer concentration were determined at weekly intervals. Chemical Div., New York), 600,000 U/d, was given intra- 24 h after the end of the 5-wk infusion or exercise period, muscularly for 6 d postoperatively, and ferrous sulfate (325 the animal was restudied with treadmill exercise and methoxa- mg/d) was administered orally throughout the study period. mine infusion. In addition to the hemodynamic and metabolic The catheters were checked for patency and refilled with parameters mentioned above, left ventricular blood flow heparin 3 d a week. was measured at rest before treadmill exercise by a modifi- 2 wk after the surgery, the animals were allowed to stand cation (17) ofthe radioactive microsphere method of Rudolph on a standard 1-10 mph mobil treadmill (Warren E. Collins, and Heymann (18). 450,000 microspheres, 15±3 ,um in diam- Inc., Braintree, Mass.). The chronically indwelling catheters eter, and labeled with cerium 141 at a specific activity of were connected to Statham P23Db pressure transducers 10 mCi/g, were injected into the left atrium via the atrial (Statham Instruments, Inc., Oxnard, Calif.) and an 8-channel catheter. This was immediately flushed with 10 ml of normal Brush 480 Recorder (Gould Inc., Instruments Div., Cleve- saline over a 30-s period. Arterial reference blood was with- land, Ohio) to measure blood pressures and heart rate. Cardiac drawn with a Harvard pump at a rate of7.75 ml/min, beginning output was determined by indocyanine green (Cardio-Green, 10 s before the injection of microspheres and continuing for Hynson, Westcott & Dunning, Inc., Baltimore, Md.) injected 80 s thereafter.