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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 coupled to a periphery previously inotropic and chronotropic effects of dobutamine were exposed to high catecholamine levels provides a unique ablated by . 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- severe 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- . 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 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 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. 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,- 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. This was accomplished in the transplant and normal obtained every 1 to 2 min until peak systolic pressure had subjects over a wide range of afterload conditions. Table 1 increased 30 to 60 mm Hg above baseline at which time the shows the expected adrenoreceptor responses. methoxamine infusion was discontinued. The desired peak Data analysis. Left ventricular end-systolic and end- pressor effect was obtained in all cases and lasted 2 to 5 min. diastolic dimensions (D,,, Ded) as well as wall thicknesses With use of this approach, the effect of afterload changes on (h,,, bed) were measured from two-dimensionally targeted left ventricular performance could be assessed (7-10). When M-mode echocardiographic recordings as described previ- systemic arterial pressure had returned to within 5% of the ously (6-8). Measurements were determined by two of the initial value, the effect of adrenergic stimulation on left principal investigators (K.M.B. and A.N.) as the mean value ventricular contractile reserve was assessed by using a 5 of five cardiac cycles. Left ventricular mass (LVM) was JACC Vol. 14. No. 5 BOROW ET AL. 1231 November I, 1989: 1229-38 ADRENOCEPTORS AFTER CARDIAC TRANSPLANTATION

Table 1. Predicted Receptor Responses

ReceptorType

Alpha, Beta, Beta? Predictive Statement

Methoxamine tt 0 0 Peripheral vasoconstriction Dobutamine t tt t Positive inotropic effect; mixed peripheral vasoconstriction/vasodilation Propranolol 0 _. __ Nonspecific beta-receptor antagonism Dobutamine t t C 0 Blockade of dobutamine’s positive inotropic propranaolol and peripheral effects resulting in unopposed peripheral vasoconstriction

t = partial agonist: t t = full agonist: 0 = no effect: - - = antagonist.

calculated from end-diastolic dimension and wall thickness a,, = (PressureJGeometric Factor,,) by adapting the formula of Devereux et al. (17). Left ventricular end-systolic and end-diastolic volumes were es- = 0.337 (P,,) timated from echocardiographic dimensions by the method of Teichholz et al. (18). This assumes that the visualized portion of the left ventricle is representative of global Statistical analysis. The relation between rate-corrected left ventricular performance, an assumption shown velocity of fiber shortening and end-systolic wall stress was previously to be valid in the absence of significant left assessed for the transplant patients and normal subjects over ventricular asynergy (18,19). Cardiac output was calculated a wide range of left ventricular afterload (i.e., end-systolic in the standard manner from these data. Systemic vascular wall stress) generated by methoxamine. Data were collected resistance was calculated as the systemic mean pressure under baseline, dobutamine and dobutamine plus proprano- (measured by the Dinamap Vital Signs Monitor) (20) times 101 conditions. As previously reported (22), our intraob- the conversion factor (80 dynes.cm-2.mm Hg-‘) divided by server coefficients of variation for rate-corrected velocity of cardiac output. This assumes that the right atria1 mean fiber shortening and end-systolic wall stress are 3.9% and pressure is small and, therefore, has little effect on the 3.8%, whereas interobserver coefficients of variation are calculation of systemic vascular resistance in normal sub- 7.3% and 7.6%, respectively. Under each set of conditions, jects and in transplant patients without congestive heart individual rate-corrected velocity of fiber shortening-end failure. systolic wall stress relation lines were generated from a Left ventricular percent fractional shortening f%ALl) was minimum of four data points by simple linear regression calculated in the usual manner from the echocardiogram (least squares method). Inter- and intrapatient comparisons whereas left ventricular ejection time (ET) was measured were performed by assessing the relative position of the from the carotid pulse tracing. The rate-corrected mean individual rate-corrected velocity of fiber shortening-end velocity of left ventricular fiber shortening (Vcf,) was calcu- systolic wall stress relation lines as well as calculating the lated as (6): rate-corrected velocity of fiber shortening values obtained at equivalent levels of left ventricular afterload (i.e., end- %AD %AD systolic wall stress = 50 g/cm2). This level of end-systolic Vcf, = =- ET, ’ wall stress was chosen as the basis for comparison because it approximates the mean rest end-systolic wall stress for i G i normal subjects (6). An unpaired t test was used for inter- where RR is the interval between adjacent R waves on the group comparisons, whereas a paired t test was used for electrocardiogram and ET, is the heart rate corrected left each patient to assess the effects of drug interventions. All ventricular ejection time. Calibration of the carotid pulse values are expressed as mean values t SD. tracings was performed with assignment of systolic blood pressure to the peak and diastolic pressure to the nadir of the Results tracing (7,20). Linear interpolation to the level of the incisura Baseline cardiovascular hemodynamics (Table 2). There was then performed to estimate end-systolic pressure (P,,) were no differences between the two study groups for heart (6). With these data, the left ventricular end-systolic merid- rate, left ventricular end-systolic wall thickness or wall ional wall stress (a,,) was calculated by an angiographically stress, left ventricular wall mass, peak systemic pressures, validated method (21): cardiac index, overall left ventricular performance or rate- 1232 BOROW ET AL. JACC Vol. 14, No. 5 ADRENOCEPTORS AFTER CARDIAC TRANSPLANTATION November 1, 1989:1229-38

Table 2. Summary of Baseline Cardiovascular Hemodynamics p Value Normal Transplant (normal versus Subjects Patients transplant group) Heart rate (beatslmin) 88 + 4 93 + 5 LV dimensions End-diastolic (cm) 4.70 2 0.29 4.44 + 0.48 co.05 End-systolic (cm) 3.17 2 0.22 2.84 2 0.32 <0.05 LV wall thickness End-diastolic (cm) 1.08 ? 0.05 1.19 2 0.10 co.05 End-systolic (cm) 1.52 + 0.10 1.73 2 0.24 LV wall mass (g) 214 2 29 224 ? 26 Pressures (mm Hg) Peak systolic 133 f 10 138 2 8 Systemic diastolic 70 * 7 92 ? 6

(p < 0.05 versus control for normal subjects; p < 0.001 I I7 TRANSPLANT versus control for transplant patients). However, the in- crease noted for the transplant patients was significantly greater than that experienced by the normal subjects (p < 20 0.001). With the addition of propranolol, heart rate returned ‘P < 0.05 Y. C.TR ?**p

to or slightly below baseline control values for both groups. 10 Myocardial mechanics (Fig. 2 and 3). Figure 2 shows data from a representative transplant patient. Rate-corrected 0 velocity of fiber shortening is plotted on the y axis with left I r ““1 ventricular end-systolic wall stress on the x axis. This L relation, which incorporates afterload in its analysis, has DOBUTAMINE DOBUTAMINE + been shown previously (6,23) to be independent of preload PROPRANOLOL JACC Vol. 14, No. 5 BOROW ET AL. 1233 November 1, 1989: 1229-M ADRENOCEPTORS AFTER CARDIAC TRANSPLANTATION

tractile reserve and the contractile response to beta- blockade for both study groups. There were no differences between the groups for baseline contractile state, contractile reserve or the effects of beta receptor antagonism with propranolol. Of note, comparable total amounts of propran- 0101were given to both study groups. Systemic blood pressures (Fig. 4 to 6). Dobutamine alone significantly increased systemic systolic and diastolic pres- sures relative to baseline control values (p < 0.01) (Fig. 4A). The addition of propranolol to the dobutamine further aug- mented systolic and diastolic pressures (p < 0.001 versus control; p < 0.01 versus dobutamine). Repeat blood pressure data acquired 1 week after initial study indicated that, whereas propranolol alone did not alter aortic pressures, the combination of propranolol plus dobutamine resulted in a 40 60 80 100 marked hypertensive response (p < 0.001 versus control; LV END-SYSTOLIC WALL STRESS (Q/ma) p < 0.001 versus propranolol alone) (Fig. 4B). Whether propranolol was added to dobutamine or dobutamine was Figure 2. Plot of the relation between left ventricular (LV) rate- corrected velocity of fiber shortening (Vcf,) and end-systolic wall added to propranolol, the net response in normal subjects stress for a representative transplant patient. The increase in left was a significant rise in systemic systolic and diastolic ventricular contractility induced by dobutamine (DOB) was ablated pressures. by the addition of propranolol (PROP). The large arrow at the The systemic blood pressure responses to pharmacologic bottom of the figure represents the mean baseline control value (50 interventions differed signijcantly between the study groups g/cm’) for end-systolic wall stress for the normal subjects. (Fig. 5). Dobutamine increased peak systolic pressure by 23 2 10 mm Hg in normal subjects (p < 0.01 versus control) line upward, consistent with a positive inotropic interven- and I1 2 9 mm Hg in transplant patients (p < 0.05 versus tion. The addition of propranolol ablated the positive inotro- control; p < 0.05 normal subjects versus transplant pit effect of dobutamine. By measuring rate-corrected ve- patients). At the same time, systemic diastolic pressure rose locity of fiber shortening values at an end-systolic wall stress by 15 f 12 mm Hg in normal subjects (p < 0.01 versus of 50 g/cm*, which approximates the baseline value for this control) and only I + 6 mm Hg in transplant patients (p = variable, it was possible to assess the left ventricular re- 0.39 versus control; p < 0.01 normal subjects versus trans- sponse to each intervention at a standardized afterload. This plant patients). The addition of propranolol to dobutamine in approach was used to compare baseline contractility, con- the normal subjects significantly raised systemic systolic

TRANSPLANT NORMAL

1.40

N 1.30 E ,” Figure 3. Values for rate-corrected velocity of fiber CD shortening (Vcf,) obtained at a common end-systolic 1.20 wall stress (a,,) of 50 g/cm*. There were no differences between the transplant patients and normal subjects 1.10 for baseline (CTR) contractility and contractile reserve as assessed by dobutamine (DOB) infusion, or the effects of beta-receptor antagonism with propranolol 1 .oo (PROP).

0.90 MEAN 1.05 1.29 1.04 1.02 1.29 1.02

SD 0.08 0.08 0.09 0.03 0.07 0.03 0.80

CTR DO8 DO8 CTR DOB DOB + + PROP PROP 1234 BOROW ET AL. JACC Vol. 14, No. 5 ADRENOCEPTORS AFTER CARDIAC TRANSPLANTATION November 1, 1989: 1229-38

(A) (B) *** ++ *** 000 175 I

Figure 4. Systemicblood pressure responses to pharmacologic interventions in normal sub- SYSTOLIC SYSTOLIC jects. Regardless of the order of dobutamine 1 *** *** (DOB) and propranolol (PROP) administration, ++ 000 the net response was a significant rise in aortic f-4 systolic and diastolic pressures. **p < 0.01 1 versus control (CTR); ***p < 0.001 versus ???? ?? / control; ++p < 0.01 versus dobutamine alone; / P / Ooop < 0.001 versus propranolol alone. A/ /’ 7.5 1 DIASTOLIC / DIASTOLIC

CTR DOB DOB CTR PROP PROP ALONE + ALONE + PROP DOB

(15 ? 9 mm Hg; p < 0.01 versus dobutamine alone) and not alter systemic systolic (1 k 6 mm Hg) or diastolic (1 +- 8) diastolic (20 + 9 mm Hg; p < 0.01 versus dobutamine alone) pressure in the transplant patients. pressures. In contrast, the administration of propranolol did Table 3 summarizes the changes in cardiac output, sys- temic vascular resistance and systemic mean pressure that occurred with each of the pharmacologic interventions. Of Figure 5. Dobutamine (DOB) raised aortic systolic and diastolic note, the response of the transplant patients treated with pressures in the normal (NL) subjects but only systolic pressure cyclosporine was indistinguishable from that found in the in the transplant patients. The addition of propranolol (PROP) other transplant patients. further elevated both systolic and diastolic pressures in the normal To further investigate the sensitivity of the transplant group without altering either pressure in the transplant group. *p < 0.05 normal versus transplant; **p < 0.01 normal versus transplant; ***p < 0.001 normal versus transplant. Figure 6. There was no age-related difference between the two

0 NORMAL groups of normal subjects regarding the total dose of methoxamine required for onset of a pressor effect. The transplant patients ??TRANSPLANT required 60% more alpha,-agonist than did either normal group. SYSTOLIC DIASTOLIC SYSTOLIC DIASTOLIC

s SD +-p<0.001-+ T I ; 40 L i IL 3 cl NORMAL : 30 ??TRANSPLANT ** B II I 20

I ** 0 10

CONTROL CONTROL L Y* “0 AGE: 2526 4825 25 ?:7 (DONOR) DOEIUTAMIiE ALONE DOBr + PROP (yrs) 149 * 5 (RECIPIENT)1 : JACC Vol. 14, No. 5 BOROW ET AL. 1235 November I, 1989: 1229-38 ADRENOCEPTORS AFTER CARDIAC TRANSPLANTATION

Table 3. Change From Baseline Values

p Value Normal Transplant (normal versus Subjects Patients transplant group)

Control versus dobutamine alone Systemic mean pressure (mm Hg) 24 + 9* 8?7

*p < 0.001 versus control; tp < 0.05 versus control. SVR = svstemic vascular resistance.

patients to alpha,-receptor stimulation, the total dose of stores (32). However, unlike the depletion in methoxamine required for onset of pressor effect was eval- the failing ventricle, this depletion is due to interruption of uated. This was defined as the amount of methoxamine postganglionic cardiac sympathetic nerve activity rather required to raise peak systolic pressure by 10 mm Hg above than to factors resulting from intrinsic myocardial damage or baseline control value. In addition to the already mentioned increased sympathetic activity with high plasma norepineph- normal subjects matched for donor heart age, six additional rine concentrations (32). The fact that overall left ventricular normal subjects matched for recipient age were studied. systolic performance is generally well preserved after car- These latter subjects were given atropine followed by 1 mg/ diac transplantation (11,33,34) suggests that normal myocar- min of methoxamine (Fig. 6). There was no age-related dial catecholamine stores are not obligatory for normal left difference between the two groups of normal subjects re- ventricular systolic function. garding the total amount of methoxamine required to elicit a In the current study, load-independent indexes of left pressor effect (50 2 13 mg versus 53 + 4 mg). In contrast, the ventricular contractility were assessed under baseline and transplant patients required 60% more alpha,-agonist than augmented afterload conditions, during challenge with a did either normal group (84 ? 14 mg; p < 0.001 versus catecholamine and during simultaneous administration of a normal). catecholamine and a nonspecific beta receptor antagonist. In all cases, the transplanted heart demonstrated normal ino- tropic responses. Thus, the cardiac beta,-adrenergic recep- Discussion tors are functionally intact long term after cardiac transplan- This clinical pharmacologic study performed after cardiac tation. In contrast to the similar inotropic properties of the transplantation provides evidence for normal left ventricular transplanted and normal hearts, the chronotropic effect of contractile and exaggerated cardiac chronotropic responses dobutamine was greater in the transplant patients. This to beta-adrenoreceptor stimulation in association with de- differential response to a catecholamine’s contractile and creased peripheral vascular sensitivity to drugs with known heart rate effects could be caused by differences in receptor smooth muscle vasoconstrictor action. The following discus- density or number due to chronic cardiac denervation (i.e., sion will integrate our findings with established knowledge of up-regulation) (14,16,25,27,35,36). Specific mechanisms that myocardial and peripheral vascular physiology to construct should be considered (14,16,25,27,37-39) include 1) sub- a framework for the interpretation of our data. specialization of beta-adrenergic receptors in which beta,- Myocardial response to adrenoceptor stimulation and receptors located in the atria are the predominant mediators blockade. The major function of beta,-receptors in the heart of heart rate response, whereas beta,-receptors in the ven- is to mediate positive inotropic responses to an appropriate tricle mediate positive inotropic actions; and 2) the presence agonist (14,24,25). In the decompensated dilated ventricle, of two separate types of beta,-receptors that independently many abnormalities are present, including a decrease in mediate inotropic and chronotropic properties and undergo beta,-receptor density, depletion in myocardial norepineph- differential rates of up-regulation. rine stores and a reduction in isoproterenol-stimulated ade- Peripheral vascular response to adrenoceptor stimulation nylate cyclase activity (14,24-28). These findings correspond and blockade. Patients with dilated cardiomyopathy and well to in vitro and in vivo evidence for decreased overall left symptoms of left ventricular failure have plasma norepineph- ventricular systolic performance (5,8,24,26,29-31). The de- rine levels that are 300% to 500% above normal (l-5). nervated transplanted heart also has a marked reduction in Whereas these high levels initially act as a compensatory 1236 BOROW ET AL. JACC Vol. 14, No. 5 ADRENOCEPTORS AFTER CARDIAC TRANSPLANTATION November 1, 1989: 1229-38

mechanism to support the depressed inotropic state of the trol; p < 0.01 versus normal subjects). Unlike the situation heart, they have the additional effect of increasing systemic with the normal subjects, dobutamine infusion in the trans- vascular resistance (5,8,24). This latter action, which is plant patients resulted in a demonstrable vasodilator (beta,) mediated by the interaction of circulating catecholamines action that overwhelmed any vasoconstrictor (alpha,) effect and the alpha,-adrenergic receptors in the peripheral vascu- of the drug. The addition of propranolol to dobutamine lature, may lead to disadvantageous left ventricular loading returned cardiac output to pre-dobutamine levels while conditions, further deterioration of ventricular performance failing to significantly alter systemic mean pressure. The and worsened congestive heart failure (8,15). It is conceiv- slightly higher than control systemic vascular resistance able that some of the adverse hemodynamic effects of values probably reflected unmasking of a weak, partial peripheral vasoconstriction are blunted by down-regulation alpha, effect. The failure of dobutamine plus propranolol in of alpha,-adrenergic receptors in the systemic vascular re- the transplant patients to produce the marked vasoconstric- sistance vessels. This situation would be analogous to the tor response noted in the normal subjects is strong evidence down-regulation of cardiac beta,-receptors that occurs in for the concept of abnormal peripheral vascular function in patients with heart failure (14,27,28). these patients. Further support of this finding was the need Response to dobutamine alone or combined with pro- for a 60% greater total dose of methoxamine to elicit the pranolol in normal subjects. In the current study, dobu- onset of a pressor effect. This was true regardless of whether tamine, a full beta,-agonist with partial beta,- and alpha,- comparisons were made with donor age-matched or recipi- agonist effects (13,14), was used to pharmacologically probe ent age-matched normal subjects. adrenoceptor physiology. Dobutamine was chosen because Etiologic mechanisms. The etiology of the abnormal pe- its hemodynamic effects are highly dependent on the ade- ripheral vascular response to alpha,-adrenoceptor stimula- quacy of alpha- and beta-receptor function. In the clinical tion may be multifactorial. Levine et al. (4) reported that setting, the drug’s complex hemodynamic behavior is re- mean plasma norepinephrine levels fell dramatically by 6 flected in the interaction among cardiac output, systemic months after cardiac transplantation. However, despite this vascular resistance and systemic mean pressure. Dobu- fall, plasma norepinephrine levels at rest remained greater tamine alone increased systemic mean pressure by 26% in than the mean normal value in 82% of their transplant our normal subject (p < 0.001 versus control). This pressure patients. Although plasma norepinephrine levels were not rise was due to a 23% increase in cardiac output (p < 0.001 measured in our study, it is unlikely that such data would versus control) without a significant change in systemic differ significantly from those of Levine et al. (4). The fact vascular resistance. The latter finding reflects a relative that the peripheral adrenergic receptors are chronically balance between dobutamine’s peripheral vasodilator (i.e., exposed to abnormally high concentrations of alpha,-agonist beta,) and vasoconstrictor (i.e., alpha,) actions. The combi- in patients with heart failure may be an important cause of nation of dobutamine plus propranolol resulted in blockade the blunted peripheral vasoconstrictor response noted in our of dobutamine’s beta, effect leading to a return to pre- transplant patients. This may reflect the presence of a higher dobutamine cardiac output values. In addition, antagonism than normal receptor set point for agonist response, a change of dobutamine’s beta, action left its alpha, effect totally in peripheral vascular alpha receptor number or density or unopposed. As predicted in Table 1, this led to a marked rise underlying structural abnormalities in the vessel wall itself. in systemic mean pressure (p < 0.001 versus control; p < A second possible explanation for our transplant pa- 0.001 versus dobutamine alone). The mechanism of this tients’ abnormal systemic pressure responses is impaired pressure rise was peripheral vasoconstriction with an aver- baroreceptor function. It is known that vascular responses age systemic vascular resistance value 39% above control to postural changes and nitroprusside infusion are abnormal (p < 0.001 versus control; p < 0.001 versus dobutamine in patients with severe heart failure (4,40-42). Interestingly, alone). Thus, dobutamine plus propranolol resulted in hemo- long term after cardiac transplantation, Mohanty et al. (43) dynamics that were very similar to those obtained with the reported that the reflex increases in forearm vascular resist- full alpha,-agonist methoxamine. ance and plasma norepinephrine associated with lower body Response to dobutamine alone or combined with pro- negative pressure were smaller in transplant patients than in pranolol in transplant patients. In contrast to the highly normal subjects. The impaired responses were not due to reproducible effects of dobutamine in normal subjects, the depression of carotid or aortic baroreceptor function be- transplant patients showed only an 8% increase in systemic cause increases in mean arterial pressure during cold pressor mean pressure (p < 0.001 versus normal subjects). This lack test and isometric exercise were not significantly different of a hypertensive response reflected a balance between the between normal and transplant groups (43). Also supporting 31% increase in cardiac output (p < 0.001 versus control; the physiologically intact nature of the peripheral vascular p = 0.32 versus normal subjects) due to dobutamine’s baroreceptors is the fact that long term after transplantation, positive inotropic and chronotropic effects and a significant the hemodynamic responses to nitroprusside infusion are fall in systemic vascular resistance (p < 0.001 versus con- normal (44). The conclusion of Mohanty et al. (43) was that JACC Vol. 14. No. 5 BOROW ET AL. 1237 November 1, 1989: 1229-38 ADRENOCEPTORS AFTER CARDIAC TRANSPLANTATION

their lower body negative pressure data probably reflected to the hemodynamic actions of hydrochloride. Am J Cardiol 1988:62:46C-52C. ventricular deafferentation as the primary etiologic factor. In support of this interpretation are recent findings of Scherrer 6 Colan SD, Borow KM, Neumann A. The left ventricular end-systolic wall stress-velocity of fiber shortening relation: a load independent index of et al. (45) obtained using microelectrode recordings of mus- myocardial contractility. J Am Co11Cardiol 1984;4:715-24. cle sympathetic nerve activity in 12 patients after cardiac 7 Borow KM, Neumann A, Lang RM. vs dobutamine: contribu- transplant. These authors found greatly increased basal tion of afterload reduction and augmented inotropic state to improved left sympathetic nerve discharge in spite of increased mean ventricular performance. Circulation 1986;73(supplIII):III-15341. arterial pressures (108 t 3 mm Hg versus 106 2 5 mm Hg in 8 Borow KM, Lang RM, Neumann A, Carroll JD, Rajfer SI. Physiologic mechanisms governing the hemodynamic responses to positive inotropic our study) and suggested that this may be due to ventricular therapy in dilated cardiomyopathy. Circulation 1988;77:625-37. deafferentation. If these observations are correct, it is pos- 9 Lang RM, Borow KM, Neumann A, Bushinsky DA, Fellner SK. Left sible that increased sympathetic tone in the peripheral vas- ventricular contractility varies directly with blood ionized calcium. Ann culature is, at least in part, the explanation for the decreased Intern Med 1988;108:524-9. alpha,-agonist response noted in our transplant patients. IO Borow KM. Clinical assessment of contractility in the symmetrically Finally, the role of concomitant immunosuppressive therapy contracting left ventricle. Mod Concepts Cardiovasc Dis 1988;57:2%34. in the response to pharmacologic interventions in our study II Borow KM, Neumann A, Arensman FW, Yacoub NH. Left ventricular contractility and contractile reserve after cardiac transplantation. Circu- cannot be specifically addressed. However, regardless of lation 1985;71:86&72. whether or not the patients were taking corticosteroids or 12 Goldberg LI. Bloodwell RD, Braunwald E, Morrow AC. The direct effect cyclosporine, the cardiac as well as peripheral vascular of norepinephrine, epinephrine and methoxamine on myocardial contrac- responses to methoxamine, dobutamine alone and dobu- tile force in man. Circulation 1960:22:1125-31. tamine plus propranolol were the same. 13 Colucci WS, Wright RF, Braunwald E. New positive inotropic agents in the treatment of congestive heart failure. N Engl J Med 1986:314:290-9. Clinical implications. The complex interaction that exists I4 Brodde OE. The functional importance of beta, and beta2 adrenoceptors between the left ventricle and the peripheral vasculature in the human heart. Am J Cardiol 1988;62:24C-9C. long term after orthotopic cardiac transplantation is charac- I5 Rajfer SI. Borow KM, Lang RM, Neumann A. Carroll JD. Effects of terized by 1) normal myocardial beta,-mediated contractility on left ventricular contractile state: relationship to the activa- and contractile reserve, 2) exaggerated myocardial beta,- or tion of beta, adrenoceptors and dopamine receptors. J Am Colt Cardiol 1988:12:43&46. beta,- (or both) mediated positive chronotropic effect, and 3) 16 Yusuf S. Theodoropoulos S, Mathias CJ, et al. Increased sensitivity of the reduced sensitivity to alpha,-receptor stimulation in the denervated transplanted human heart to both before and peripheral vasculature. The clinical model described in this after beta-adrenergic bockade. Circulation 1987:75:696-704. study integrated noninvasive cardiac techniques with phar- I7 Devereux RB. Reichek N. Echocardiographic determination of left ven- macologic probes of alpha,- and beta-receptor physiology to tricular mass in man: anatomic validation of the method. Circulation assess cardiovascular function. This approach may be useful 1977:55:613-8. for assessing the physiologic changes that accompany heart 18 Tiechholz LE. Kreulin T, Herman MV, Gorlin R. Problems in echocar- diographic volume determinations: echocardiographic-angiographic cor- failure as well as other functional alterations in peripheral relations in the presence or absence of asynergy. Am J Cardiol 1976; vascular tone that may occur after cardiac transplantation. 37:7-l I. 19 Kronik G. Slany J, Mosslacher H. Comparative value of eight m-mode echocardiographic formulas for determining left ventricular stroke vol- We thank David P. James and Dorothy J. Douglas for excellent contributions ume. Circulation 1979;60:1308-16. to the preparation of the manuscript, Dianne Altman for organizational skills and Kirk Spencer, MD and Glenn Hallam for assistance with data analysis. 20 Borow KM. Newburger J. Noninvasive estimation of central aortic We also thank Morton Arnsdorf, MD and Sol Rajfer. MD for thoughtful pressure using the oscillometric method for analyzing systemic artery comments. pulsatile blood flow: comparative study of indirect systolic, diastolic, and mean brachial artery pressure with simultaneous direct ascending aortic pressure measurements. Am Heart J 1982:103:879-86. 21 Brodie BR. McLaurin LP, Grossmann W. Combined hemodynamic- References ultrasonic method for studying left ventricular wall stress: comparison with angiography. Am J Cardiol 1976:37:864-70. I. Goldsmith SR, Francis GS, Cohn JN. Norepinephrine infusions in con- 22 Lang KM, Borow KM. Neumann A. Janzen D. Systemic vascular gestive heart failure. 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