View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 1350 JACC Vol. 14, No. 5 November 1, 1989:1350-8 Effects of Methoxamine and Phenylephrine on Left Ventricular Contractility in Rabbits MARVIN W. KRONENBERG, MD, FACC, ROBERT W. McCAIN, MD, ROBERT J. BOUCEK, JR., MD, DAVID W. GRAMBOW, MD, KIICHI SAGAWA, MD, GOTTLIEB C. FRIESINGER, MD, FACC Nashville, Tennessee The end-systolic pressure-volume relation is employed to oxamine. Pretreatment with propranolol blunted the effect evaluate left ventricular contractility. In clinical studies, of phenylephrine on isovolumic pressure (n = 6, p < 0.02). pharmacologic vasoconstriction is used to increase left In protocol 3, cross-circulation experiments allowed ventricular systolic pressure to assess pressure-volume re- study of the effect of these drugs on isovolumic left ventric- lations. However, the effect of vasoconstrictors on the ular pressure in the isolated heart and simultaneously on ventricular contractile state is not well characterized. The the systemic arterial pressure in the intact anesthetized effects of methoxamine and phenylephrine on systemic rabbit (support rabbit). Methoxamine decreased isovolu- arterial pressure and left ventricular contractility in rabbits mic left ventricular pressure at infusion rates that increased were studied with three protocols. mean arterial pressure in the support rabbit. With phenyl- In protocol 1, anesthetized rabbits (n = 10) were ephrine, both the left ventricular isovolumic pressure and injected with incremental doses of methoxamine and phen- the mean arterial pressure increased. ylephrine intravenously. Methoxamine (4 mg) increased the Thus, in the isolated supported heart, phenylephrine mean arterial pressure by 50 -C 12% (mean t SE) (n = 5, increased left ventricular contractility at doses that pro- p = 0.001). Phenylephrine (0.2 mg) increased mean arterial duced peripheral vasoconstriction in the intact rabbit. pressure by 82 -t 14% (n = 5, p = 0.004). In protocol 2, Conversely, methoxamine reduced ventricular contractility isolated blood-perfused hearts were injected with incremen- in the isolated heart at doses that produced peripheral tal doses of these drugs in the ascending aorta in amounts vasoconstriction in the intact rabbit. The isolated hearts approximately equal to the concentrations injected in the had variable susceptibility to the depressant effect of meth- intact rabbits. Methoxamine (2 mg) reduced isovolumic oxamine. These results demonstrated the allowable range peak systolic left ventricular pressure by 43 f 9% (n = 7, for valid results and the limitations of using pharmacologic p = 0.003), whereas phenylephrine (0.1 mg) increased the vasoconstricting agents to manipulate arterial pressure isovolumic pressure by 24 + 9% (n = 7, p < 0.05). These afterload when assessing left ventricular contractility in thii responses indicated an enhanced contractile state with model and possibly in humans. phenylephrine and a reduced contractile state with meth- (.I Am Co11Cardiol1989;14:1350-8) The end-systolic pressure-volume relation is an index of left preload volume and is sensitive to changes in inotropy (1). In ventricular contractility that is relatively independent of the intact animal and in humans, pharmacologic vasocon- striction with methoxamine or phenylephrine is commonly From the Departments of Medicine and Pediatrics, Vanderbilt University employed to increase the ventricular pressure afterload to School of Medicine, Nashville, Tennessee. This study was supported in part by Research Career Development Award 1 K04 HLO0852(Dr. Kronenberg) determine pressure-volume relations (2-4). However, the and a National Research Service Award 5 T32 HL07411from the National direct effects of these drugs on the myocardial contractile Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; Biomedical Research SupportGrant 523713(Dr. Boucek) from the state are understood incompletely. A valid estimate of Division of Research Resources, National Institutes of Health, Bethesda, and ventricular contractility is not possible if these agents modify the Dan May Student Scholarship in Cardiology at Vanderbilt University (Dr. contractility. In animals, phenylephrine increases myocar- Grambow). Manuscript received February 13, 1989;revised manuscript received May dial contractility (5-10). However, the data for methoxamine 9, 1989,accepted May 24, 1989. are more controversial (11); some investigators reported Address for ren_dnts: Marvin W. Kronenberg, MD, Cardiology Division, CC-2218,Vanderbilt University Medical Center North, Nashville, Tennessee minimal effects (12), whereas others found dose-related 37232. myocardial stimulation or depression (13-18). Further, the 01989 by the American College of Cardiology 0735-1097/89/$3.50 JACC Vol. 14, No. 5 KRONENBERG ET AL. 1351 November 1, 1989: 1350-S METHOXAMINE, PHENYLEPHRINE AND CONTRACTILITY effects of methoxamine on pressure-volume relations in an Approximately 100 to 150 ml of blood was withdrawn ejecting heart preparation (19) may be related to the heart or through a femoral artery catheter to prime the isolated heart the arteries, or both (20). perfusion system. Half this volume was replaced with nor- To clarify and quantitate the myocardial and systemic mal saline solution and half with perfluorocarbon (FC-43, efects of methoxamine andphenylephrine, we employed the Alpha Therapeutic Company). The chest was opened by intact rabbit, the isolated isovolumic rabbit heart and a midline sternotomy. The heart was exposed and a cannula cross-circulation experiment in which we assessed contrac- inserted into the aorta. The superior and inferior venae tility in the isolated isovolumic heart and arterial pressure in cavae, the azygos vein and the pulmonary arteries were the intact rabbit simultaneously. ligated. The heart and lungs were excised and suspended by the aortic cannula in a constant temperature chamber that was heated by a water bath to approximately 30°C. Blood Methods drawn from a reservoir with use of a roller pump (Cole- Experimental protocols. New Zealand white rabbits Parmer, model 7562-10) was pumped to the heart at constant weighing 2.5 to 5 kg were anesthetized with intravenous flow through an oxygenation chamber (97% oxygen, 3% pentobarbital (50 mg/kg body weight). Intravascular pres- carbon dioxide), and a 40 p filter (Pall, model SQ4OS), sures were registered by pressure transducers (Gould, series leading to the aortic cannula. The lungs were removed. A P23Db) and recorded on a strip chart recorder (Gould, model polyethylene cannula was placed in the right ventricle from 2400s) running continuously at 1 mm/s. Three types of the pulmonary artery to return the coronary blood flow to protocols were performed: in protocol 1, blood pressure the reservoir. A prestressed balloon attached to a catheter dose-response curves were determined in intact anesthetized was inserted through the mitral valve into the left ventricle rabbits. In protocol 2, left ventricular isovolumic pressure and inflated with a calibrated syringe. A thin polyethylene dose-response curves were evaluated in isolated rabbit cannula was inserted adjacent to the balloon to vent blood hearts. These studies were designed to study the effects of from the Thebesian flow or possible occasional aortic regur- the approximate concentrations found during the protocol 1 gitation. Pressure transducers were connected to the aortic on contractile state. In protocol 3, a cross-circulation study and left ventricular catheters. Small electrodes were clipped was performed with an isolated heart and a support rabbit. to the left atrium for overdrive electrical stimulation at rates This protocol was designed to assess simultaneously the of 90 to 120/min, selected to optimize force development effects of these drugs on arterial pressure in the intact (Grass, model SD9). The preparation was similar to that support rabbit and on left ventricular isovolumic pressure in used previously in this laboratory (21). the isolated heart, with use of the isolated heart as a When the isovolumic systolic pressure was stable, bolus bioassay. injections (0.1 ml each) of serial concentrations of either For the dose-response curves, we used log serial dilutions methoxamine or phenylephrine solution were injected (in in saline solution of methoxamine hydrochloride (20 mg/ml) seven preparations each) into the aortic cannula, starting (Vasoxyl, Burroughs Wellcome) or of phenylephrine hydro- from the most dilute, allowing sufficient time between doses chloride (10 mg/ml) (NeoSynephrine, Winthrop Breon). The to achieve stable isovolumic left ventricular pressure (usu- drugs had similar molecular weights (247.72 versus 203.67 ally 1-5 min). Only one drug was injected into each prepa- g/mole, respectively), but the concentration of methoxamine ration. The arterial pH, PO,, Pco, and bicarbonate concen- per ampule was double that of phenylephrine. tration were measured periodically. The pH was maintained Protocol 1: intact rabbit preparation. After anesthesia, at physiologic levels with injections of sodium bicarbonate catheters were placed in the common carotid artery and the into the venous return of the circuit as necessary. In six internal jugular vein in 10 rabbits. After 210 min of stable phenylephrine studies 0.2 mg of propranolol was injected arterial pressure recording, a series of increasing concentra- after the I mg dose of phenylephrine. Then