View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector JACC Vol. 14. No. 5 1229 November I, 1989: 1229-38 Cardiac and Peripheral Vascular Responses to Adrenoceptor Stimulation and Blockade After Cardiac Transplantation KENNETH M. BOROW, MD, FACC, ALEX NEUMANN, BS, FREDERICK W. ARENSMAN, MD, FACC, MAGDI H. YACOUB, MB, BS, FACC” Chicago, Illinois and Harejield, Middlesex, England A denervated heart coupled to a periphery previously inotropic and chronotropic effects of dobutamine were exposed to high catecholamine levels provides a unique ablated by propranolol. Dobutamine plus propranolol (un- model to study adrenoceptor physiology. Six orthotopic opposed alpha, effect) did not change mean systemic pres- transplant patients (1.3 2 0.8 years postoperative) were age sure in transplant patients while markedly raising mean matched with six atropine-treated normal subjects. Simul- systemic pressures in normal subjects (36 f 18 mm Hg; p < taneous two-dimensionally targeted left ventricular echo- 0.001). In addition, during initial challenge with methox- cardiograms and calibrated carotid pulse tracings were amine, the transplant patients required 60% more alpha, recorded. Left ventricular contractility was assessed with agonist than did the normal subjects (p < 0.001) to obtain use of heart rate- and load-independent end-systolic in- a pressor effect. dexes. Studies were performed at baseline and during In summary, transplant patients who were previously in dobutamine infusion with and without beta-adrenergic severe heart failure have normal left ventricular inotropic blockade with use of propranolol; effects were assessed response to beta, activation and blockade, exaggerated during afterload changes generated by the alpha, agonist chronotropic response to dobutamine and reduced sensitiv- methoxamine. ity to stimulation with alpha,-adrenoceptor agonists. These There were no differences in baseline contractility or findings are consistent with a differential response of reserve between transplant patients and normal subjects. adrenoceptors to long-term stimulation after cardiac trans- The heart rate response to dobutamine was greater for plantation. transplant patients (p < 0.001). In both groups, the positive (J Am Co11Cardiol1989;14:1229-38) Orthotopic cardiac transplantation represents a unique phys- nists in these patients. To explore this issue, load- iologic model for the assessment of adrenoceptor function in independent sensitive indexes of left ventricular contractility humans. In such cases, a denervated “healthy” heart is in conjunction with systemic blood pressure measurements attached to a peripheral vascular bed that has previously and vascular resistance calculations (5-10) were used to been exposed to low cardiac output and markedly elevated establish the myocardial and peripheral effects of adrenocep- plasma catecholamine concentrations (l-5). With transplan- tor stimulation and blockade in transplant patients and tation, normal levels of cardiac output are usually restored. normal subjects. However, little is known about the effects of improved blood Specijically, three agents were used as pharmacologic flow on peripheral vascular responses to adrenoceptor ago- probes: 1) dobutamine, a catecholamine with beta,, beta, and alpha, agonist effects; 2) methoxamine, a catecholamine with only alpha,-agonist actions; and 3) propranolol, a nonspecific beta-adrenoceptor antagonist. From the Cardiology Division, Department of Medicine, The University of Chicago Medical Center, Chicago, Illinois and the *Division of Cardiovas- cular Surgery, Harefield Hospital, Harefield, Middlesex, England. This study was supported in part by a Grant-in-Aid from the American Heart Association Methods of Metropolitan Chicago, Chicago, and by the Louis Block Fund of the University of Chicago, Chicago, Illinois. Study patients. The study group was composed of six Manuscript received December 12, 1988; revised manuscript received men who underwent orthotopic cardiac transplantation at March 22, 1989,accepted May IO, 1989. Harefield Hospital, Harefield, Middlesex, England. Before Address for reurints: Kenneth M. Borow, MD, Director, Cardiac Nonin- vasive Physiology Laboratory, The University of Chicago Medical Center. transplantation, all patients had long-standing congestive 5841South Maryland Avenue, Box 44, Chicago, Illinois 60637. heart failure and were in New York Heart Association 01989 by the American College of Cardiology 073%1097/89/$3.50 1230 BOROW ET AL. JACC Vol. 14, No. 5 ADRENOCEPTORS AFTER CARDIAC TRANSPLANTATION November 1, 1989: 122%38 functional class IV. No one was treated with alpha,- pg/kg per min infusion of dobutamine. This catecholamine adrenergic receptor blocking agents either before or after was chosen because it has beta,-, beta,- and alpha,-agonist operation and all had taken no anti-hypertensive therapy for effects (12-15). After 7 min of infusion, new baseline record- 21 month. At the time of operation, the subjects ranged in ings were performed. The methoxamine challenge was then age from 41 to 53 years (mean ? SD 49 ? 5). The donor repeated during the constant dobutamine infusion. hearts were between 18 and 39 years of age (mean 25 + 7). After the methoxamine infusion was discontinued and The interval from transplant surgery to study was 1.3 ? 0.8 peak systolic pressure had fallen to within 5% of the initial years (range 0.6 to 2.8). During this period, the patients had dobutamine value, the final part of the study was begun. an average of 1.2 ? 1.0 episodes of transplant rejection. No With the dobutamine still infusing, the nonspecific beta- patient had evidence of rejection by endomyocardial biopsy adrenergic blocking agent propranolol was given. The dose performed within 7 days of study nor did any patient have of the propranolol was titrated to return heart rate to the evidence for accelerated atherosclerosis on coronary arteri- pre-dobutamine control value. The total dose of propranolol ography. Immunosuppressive therapy included azathioprine given the transplant patients and normal subjects was not in six cases, 10 to 15 mg/day of prednisone in five cases and significantly different (0.07 +- 0.01 versus 0.09 ? 0.02 mg/kg, cyclosporine in two cases. Portions of the transplant pa- tients’ data on left ventricular contractile reserve have been respectively). The methoxamine infusion was then repeated. reported previously (11). All transplant patients and normal subjects completed this Comparisons of contractility data were performed with portion of the experimental design. data acquired from six normal subjects matched for donor In addition, two ancillary protocols were performed: heart age. Comparisons of peripheral vascular hemodynam- 1) At the end of the study, the transplant patients were its were made using these six normal subjects as well as six challenged with an isoproterenol infusion (26 + 4 ng/kg additional normal subjects matched to the cardiac transplant per min for 5 min) to test for adequacy of beta-adreno- recipients’ ages. The protocol used to study the cardiac ceptor blockade. This dose of isoproterenol was compar- transplant patients met the criteria for human investigation able with the highest dose used by Yusuf et al. (16) in previously established at Harefield Hospital. The protocol their study of adequacy of beta-blockade induced by pro- used for the normal control subjects was approved by the pranolol in patients with an orthotopic cardiac transplant. Committee on Human Protection from Research Risks of The increase in heart rate induced by isoproterenol in our The University of Chicago Medical Center. In all cases, patients was only 4 ? 4 beatslmin, thereby demonstrating a informed consent was obtained. high level of effective beta-blockade. 2) One week after Experimentaldesign. The transplant patients and normal completion of the first study, the same normal subjects subjects were studied with use of similar protocols. Simul- underwent a second study. At this time, the identical dose taneous recordings of two-dimensionally targeted M-mode of propranolol was given before rather than after the initia- echocardiograms of the left ventricle, phonocardiogram, tion of the dobutamine infusion. No methoxamine was electrocardiogram (ECG), indirect carotid pulse tracings and administered. Performance of the second study allowed a blood pressure measurements were performed under base- crossover analysis of the effects of dobutamine plus pro- line conditions. Normal subjects were premeditated with pranolol. In addition, it eliminated the possibility that resid- atropine (0.010 to 0.015 mg/kg body weight). This resulted in ual alpha,-receptor activity secondary to methoxamine pharmacologic depression of vagal tone and allowed baseline would confound the blood pressure response in the normal data to be acquired at heart rates comparable with those subjects. noted in the denervated transplanted hearts. In summary, this protocol allowed assessment of left To assess baseline contractility and the response of the ventricular baseline contractility and contractile reserve as systemic arterial circulation to a hypertensive challenge, recordings were made during infusion of the alpha,-receptor well as the effects of alpha,-, beta,- and beta,-adrenergic agonist methoxamine. This drug has no direct cardiac effect receptor stimulation with and without beta-receptor block- in the doses used in the current study (12). Recordings were ade.