Role of Cardiac β2-Receptors in Cardiac Responses to Exercise in Cardiac Transplant Patients
Background In healthy human hearts, β2-receptor–mediated chronotropic and inotropic responses contribute to the cardiac responses to β-agonists. A (patho)physiological relevance for β2-receptor–mediated responses has so far not been demonstrated, in part because β1-receptor–mediated responses to cardiac neuronally released norepinephrine can mask β2-receptor–mediated responses.
Methods and Results In the present study, we evaluated the blood pressure and heart rate responses to bicycle exercise in cardiac transplant patients (n=7) compared with patients with essential hypertension (n=8) on placebo and two doses of the β1-selective β-blocker atenolol (25 and 50 mg/d) and the nonselective β-blocker nadolol (20 and 40 mg/d), each dose for 1 week using a double-blind, randomized, crossover design. Exercise was performed 3 hours after dosing, using a stepwise increase in load until exhaustion. Exercise performance was less in the transplant patients and significantly further (25%) decreased by nadolol. Exercise caused equivalent increases in plasma norepinephrine in the two groups, but more marked increases in plasma epinephrine in the transplant patients despite less exercise. In the essential hypertension patients, systolic blood pressure increased by 80 mm Hg on placebo and 60 mm Hg on either blocker. The increase in heart rate (by about 75 beats per minute) was inhibited by 10% and 20% by the lower and higher doses, respectively, similar for the two blockers. In contrast, in the transplant patients, systolic blood pressure increased by 60 mm Hg on placebo, but this increase was totally blocked by either blocker. The heart rate increase (by 50 beats per minute on placebo) was blunted (dose related) by either blocker but 50% more by nadolol versus atenolol.
Conclusions The present study shows that cardiac β2-receptors contribute to a clear extent to the heart rate responses to endogenous circulating catecholamines in the absence of cardiac neuronally released norepinephrine. Nonselective β-blockade probably is less well tolerated in cardiac transplant patients compared with β1-selective blockade.
Coexistence of β1- and β2-receptor subtypes has been demonstrated in virtually all organs, including the heart.1 In healthy human hearts, the proportion of β2-receptors in ventricular myocardium may range from 15% to 25% and in atrial tissue from 25% to 40%.1 Studies using combinations of nonselective or β1- or β2-selective β-agonists and antagonists have provided evidence for β2-receptor–mediated, chronotropic2 3 4 as well as inotropic5 6 7 responses in humans in vivo. However, such experiments do not establish the (patho)physiological relevance. Ariens and Simonis8 and Bryan et al9 hypothesized that β1-receptors represent “innervated” receptors and β2-receptors are “hormonal” receptors. β1-Receptors would thus be mainly involved in neuronal control of the heart, whereas β2-receptors would respond more to circulating agonists. In support of this concept, exercise-induced tachycardia or hydralazine-induced increases in heart rate and inotropy are equally blunted by nonselective and β1-selective β-blockers.10 11 In contrast, the chronotropic responses to epinephrine or the β2-agonist terbutaline are not affected by β1-selective β-blockade and their inotropic effect only in part.5 6 7 12 It has been postulated that in situations of stress (for example, acute myocardial infarction) and large release of endogenous epinephrine from the adrenal medulla, stimulation of cardiac β2-receptors may contribute to the adverse consequences of cardiac sympathetic stimulation.13 So far, there is no actual evidence in this regard, probably because in most instances, cardiac sympathetic nerve activity also increases and may obscure a β2-receptor–mediated component.
Cardiac transplantation results in sympathetic denervation, which tends to persist for a long time.14 15 Although β-receptor–mediated responsiveness does not appear to be upregulated, adrenergic supersensitivity does occur for agents ordinarily removed by neuronal uptake such as norepinephrine or epinephrine.16 Thus, similar circulating concentrations result in higher effective concentrations around the synaptic cleft after cardiac transplantation versus control hearts. Although denervated, the transplanted heart still responds with increases in heart rate during exercise, largely related to increases in circulating norepinephrine and epinephrine as a result of spillover from other areas as well as release from the adrenal medulla. In this circumstance, “hormonal” cardiac β2-receptors may play a more clear role in the cardiac responses to exercise as compared with innervated hearts. If so, then nonselective β-blockade should be more effective in blunting the increase in heart rate during exercise than β1-selective blockade, in contrast to the similar blockade observed in innervated hearts. For this, we evaluated the blood pressure and heart rate responses to dynamic bicycle exercise in cardiac transplant patients compared with patients with mild essential hypertension on placebo and two doses of the β1-selective blocker atenolol and the nonselective blocker nadolol, using a double-blind, randomized, crossover design.
Eight patients with essential hypertension and seven cardiac transplant recipients consented to participate in the study. Patients with diabetes, autonomic neuropathy, gastrointestinal dysfunction, and abnormal hepatic dysfunction were excluded. Congestive heart failure due to ischemic cardiomyopathy in two patients, idiopathic cardiomyopathy in three patients, valve disease in one patient, and congenital heart disease in one patient were the reasons for transplantation, which had been performed 25±6 months (range, 10 to 57) previously. All transplant patients were stable at entry and during the study, with no histological evidence of rejection, and had a normal coronary angiogram within 1 year of the study. Immunosuppressant therapy (cyclosporine, azathioprine, and prednisone) was continued at constant doses throughout the study. Clinical characteristics of the two groups are shown in Table 1⇓. For both groups, all antihypertensive drug therapy was discontinued at least 2 weeks before the run-in study morning. The study and associated risks were explained to the patients, and written informed consent was obtained. The study protocol was approved by the Research Ethics Committee at the Ottawa Civic Hospital.
The study was performed as a double-blind, randomized, crossover trial. Hemodynamic assessments were performed in a blinded fashion for the type and dose of β-blocker, since the effects of the β-blocker on heart rate precludes true blinding. Over a period of 8 weeks, the patients were treated with the nonselective β-blocker nadolol 40 mg tablet (first week, one-half tablet every morning; second week, 1 tablet every morning), the β1-selective β-blocker atenolol 50 mg tablet (first week, one-half tablet every morning; second week, 1 tablet every morning), or placebo (first week, one-half tablet every morning; second week, 1 tablet every morning). Between treatments, a washout period of 1 week without therapy was placed. Patients were studied at each dose level for a total of 6 study mornings. Compliance was assessed by weekly pill counts.
Each study morning, subjects would take the tablet at about 8:00 am. At about 10:30 am, a small catheter was positioned in an antecubital vein for blood sampling. Exercise would start at about 11:00 am. All exercise tests were performed on a mechanically braked cycle ergometer (Monark 868). Exercise was started at a workload of 15 W (for transplant patients) and 45 W (for hypertensive patients) and every 3 minutes increased in steps of 15 to 30 W, depending on the individual performance. These loads were established during a run-in study preceding the study. Each subject would exercise for 2 to 4 workloads.
Blood pressure (by mercury sphygmomanometer) and heart rate (ECG) were first measured every 2 minutes for 10 minutes of rest while sitting in an easy chair. Subsequently, blood pressure and heart rate were measured at the end of each workload and at maximal workload (defined as the point at which the subject could no longer maintain the pedaling rate of 60 resolutions per minute). Values at rest, at the submaximal workload (the same load for each individual throughout the study), and at maximal workload are presented in “Results.” Blood samples for plasma catecholamines were taken at the end of the rest period and at peak exercise. Plasma catecholamines were measured by a radioenzymatic assay.17
Data are presented as mean±SEM. The results were evaluated by ANOVA for repeated measurements, and significant differences were located with the Duncan test at a level of P< .05. The degree of β-blockade was evaluated by the percent inhibition of the heart rate response at maximal exercise: [(increase on placebo minus increase on β-blocker)/increase on placebo]×100%.
Resting Blood Pressure and Heart Rate
On placebo, both groups of patients showed mild hypertension, somewhat more marked in the cardiac transplant patients (see Table 2⇓). Both β-blockers lowered blood pressure, in the hypertensive patients atenolol more than nadolol; in the transplant patients, the reverse occurred. Resting heart rate was somewhat higher in the transplant patients. Both β-blockers lowered resting heart rate to a similar extent and similarly in the two groups.
Responses to Exercise
Duration of Exercise
As expected, the hypertensive patients exercised significantly longer (and at higher workloads; data not shown) compared with the transplant patients (Table 3⇓). Neither β-blocker affected the duration of exercise in the hypertensive patients. In contrast, in the transplant patients, nadolol decreased the duration by nearly 2 minutes.
On placebo, resting plasma norepinephrine and epinephrine were significantly higher in transplant patients versus hypertensive patients (Table 3⇑). Exercise increased both catecholamines. The extent of this increase was fairly similar for plasma norepinephrine in the two groups, but plasma epinephrine increased significantly more in the transplant patients.
Neither β-blocker affected resting plasma norepinephrine or epinephrine in the two groups of patients. The exercise-induced increase in plasma norepinephrine tended (P<.10) to be blunted by the two β-blockers in the hypertensive patients but not in the transplant patients. The plasma epinephrine response was not affected at all in either group.
Systolic Blood Pressure
On placebo, exercise caused the expected increase in systolic blood pressure, significantly more in hypertensive patients versus transplant patients (Fig 1⇓).
In the hypertensive patients, both β-blockers blunted this increase by about 20 mm Hg, with no significant differences between the two blockers or the two doses. In contrast, in the transplant patients, both blockers nearly completely prevented an increase and only on the lower dose of atenolol a modest increase (P<.05) persisted. Otherwise, the two β-blockers did not differ significantly.
On placebo, exercise increased heart rate to 150 to 160 beats per minute (bpm) in the hypertensive subjects and to 120 to 130 bpm in the transplant patients (P<.01 between the two groups) (Fig 2⇓). In the hypertensive patients, both β-blockers decreased the maximal heart rate by 20 to 30 bpm (P<.01 versus placebo; no difference between the two blockers). In the transplant patients, atenolol decreased the maximal heart rate by 30 to 35 bpm and nadolol by ≈50 bpm.
Taking the effects of the two blockers on resting heart rate into account, in the hypertensive patients, the heart rate response was inhibited by ≈10% by the lower dose and by ≈20% by the higher dose of the two β-blockers, with no significant differences between the two blockers (Fig 3⇓). In contrast, in the transplant patients, the two β-blockers did differ significantly: The lower dose of atenolol inhibited the heart rate response by 34% and the higher dose by 47%, whereas the two doses of nadolol caused inhibition by 61% and 70%, respectively. Nadolol was significantly more effective (Fig 3⇓). Both blockers caused more inhibition in the transplant patients compared with the hypertensive patients (Fig 3⇓).
The present study shows as the major new finding that in cardiac transplant patients the heart rate response to bicycle exercise is significantly more inhibited by nonselective β-blockade as compared with β1-selective blockade. In contrast, in essential hypertensive patients, the two types of β-blockade caused the same inhibition. These results are consistent with cardiac β2-receptors contributing to the chronotropic response to endogenous sympathetic stimulation.
Exercise Responses on Placebo
At rest, sitting on the bicycle, the two groups of subjects showed comparable mild hypertension. The heart rate was only slightly higher in the cardiac transplant patients. In contrast, plasma catecholamines were significantly increased in the transplant patients, norepinephrine by 30% and epinephrine by 50%. The consistency of this difference across all studies (Table 3⇑) suggests that sympathetic nerve activity was increased as a basic abnormality18 rather than secondary to, for example, anticipation of the exercise.
In response to the graded bicycle exercise, both groups of patients showed the expected increases in heart rate and systolic blood pressure. Both responses were less in the transplant patients, but so was the duration and intensity of exercise. Despite this shorter exercise, at peak, both groups showed fairly similar increases in plasma norepinephrine (by ≈600 pg/mL) and in epinephrine (by ≈200 pg/mL), suggesting that the sympathetic response is exaggerated in the transplant patients.19 This increase in plasma catecholamines contributes to a major extent to the chronotropic and inotropic responses of the denervated heart to exercise. In addition, an increase in venous return by the skeletal muscle pump and sympathetic stimulation of the splanchnic bed20 will activate the Frank-Starling mechanism, increasing stroke volume and heart rate.
Effects of β-Blockade
Previous studies in cardiac transplant patients assessed the effects of single (oral or intravenous) doses of propranolol.21 22 23 The present study used more chronic treatment. Resting heart rate was decreased similarly by the two blockers and in the two groups. Resting blood pressure appeared to be decreased more by atenolol in the hypertensive subjects but more by nadolol in the transplant patients. To what extent this represents true differences requires a larger sample size.
Whereas endurance exercise is decreased particularly by nonselective β-blockade in normotensive or hypertensive subjects,24 short-term exercise is usually not affected.25 The present results in hypertensive subjects are in agreement in this regard. In contrast, in the cardiac transplant patients, nadolol significantly decreased the duration of exercise, similarly as previously reported after single doses of propranolol.21 22 23 Atenolol did not show this adverse effect. Since the metabolic effects of β2-blockade are important during endurance but not during short-term exercise,25 these results suggest that β2-receptor blockade inhibited the cardiac output response significantly more than β1-receptor blockade thereby limiting the duration of exercise.
In the hypertensive subjects, both β-blockers caused a dose-related inhibition of the exercise tachycardia (Fig 3⇑) and increase in systolic blood pressure (Fig 1⇑). Higher doses would only cause minor further inhibition (for example, see Reference 10). The two β-blockers were equally effective. These results indicate that β1-blockade was primarily responsible for the blunting of the heart rate and systolic blood pressure responses. The remaining of the responses probably relates to vagal withdrawal and increased venous return not affected by β-blockade. In contrast, in cardiac transplant patients, nadolol completely prevented the exercise-induced increase in systolic blood pressure and most of the increase in heart rate. β1-Blockade by atenolol was significantly less effective than nadolol in blocking the heart rate response and at the lower dose also for systolic blood pressure. Differences in duration of exercise do not explain these different responses to the two β-blockers, since at submaximal exercise (performed in all subjects), similar differences in heart rate and systolic blood pressure were noted. Several conclusions can be drawn from these new observations. First, atrial β2-receptors are being activated by endogenous circulating catecholamines and clearly contribute to the increase in heart rate. Second, the increase in systolic blood pressure during exercise (caused by a larger stroke volume ejected in a shorter time) depends on sympathetic activation in the transplant patients but only to a minor extent in hypertensive patients. Differences in regulation of venous return and/or withdrawal of a negative inotropic effect of the vagus in the hypertensive patients may play a role in this regard. Consistent with our findings on epinephrine,5 ventricular β2-receptors do not appear to play a major role, since the two β-blockers showed only minor differences in blocking the systolic blood pressure response.
Plasma concentrations of nadolol and atenolol were not measured in the present study. Both β-blockers are hydrophilic and depend on renal excretion for elimination. Thus, the decrease in renal function present in several of the transplant patients will have increased plasma concentrations for the two β-blockers to a similar extent. These higher plasma concentrations to some extent explain the larger degree of β-blockade observed in the transplant patients (Fig 3⇑). However, most of this difference relates to the presence/absence of vagal regulation of heart rate.
The present study shows that cardiac β2-receptors to a clear extent contribute to the heart rate responses to endogenous circulating catecholamines but less to inotropic responses. These findings have clinical implications for the management of cardiac transplant patients (for example, exercise tolerance is less affected by β1-selective blockade) as well as other groups of patients (for example, stress-induced angina is blocked better by nonselective β-blockade).
This study was supported by an operating grant from the Heart and Stroke Foundation of Ontario, Canada. Dr Leenen is a Career Investigator of the Heart and Stroke Foundation of Ontario, Canada.
- Received August 11, 1994.
- Accepted September 20, 1994.
- Copyright © 1995 by American Heart Association
Hall JA, Petch MC, Brown MJ. Intracoronary injections of salbutamol demonstrate the presence of functonal β2-adrenoceptors in the human heart. Circ Res. 1989;65:546-553.
Hall JA, Petch MC, Brown MJ. In vivo demonstration of cardiac β2-adrenoceptor sensitization by β1-antagonist treatment. Circ Res. 1991;69:959-964.
Levine MAH, Leenen FHH. Role of β1-receptors and vagal tone in cardiac inotropic and chronotropic responses to a β2-agonist in humans. Circulation. 1989;79:107-115.
Schäfers RF, Adler S, Daul A, Zeitler G, Vogelsang M, Zerkowski HR, Brodde OE. Positive inotropic effects of the β2-adrenoceptor agonist terbutaline in the human heart: effects of long-term β1-adrenoceptor antagonist treatment. J Am Coll Cardiol. 1994; 23:1224-1233.
Ariens EJ, Simonis AM. Receptors and receptor mechanisms. In: Saxena PR, Forsyth RP, eds. Beta Adrenoceptor Blocking Agents. Amsterdam: North Holland Publishing Co; 1976:4-27.
Bryan LJ, Cole JJ, O’Donnell SR, Wanstall JC. A study designed to explore the hypothesis that β1-adrenoceptors are ‘innervated’ receptors and β2-adrenoceptors are ‘hormonal’ receptors. J Pharmacol Exp Ther. 1981;216:395-400.
Pope SE, Stinson EB, Daughters GT II, Schroeder JS, Ingels NB Jr, Alderman EL. Exercise response of the denervated heart in long-term cardiac transplant recipients. Am J Cardiol. 1980; 46:213-218.
Gilbert EM, Eiswirth CC, Mealey PC, Larrabee P, Herrick CM, Bristow MR. β-Adrenergic supersensitivity of the transplanted human heart is presynaptic in origin. Circulation. 1989;79:344-349.
Leenen FHH, Reeves RA. The beta-receptor mediated increase in venous return in humans. Can J Physiol Pharmacol. 1987; 65:1658-1665.
Bexton RS, Milne JR, Cory-Pearce R, English TAH, Camm AJ. Effect of beta blockade on exercise response after cardiac transplantation. Br Heart J. 1983;49:584-588.
Kushwaha SS, Banner NR, Patel N, Cox A, Patton H, Yacoub MH. Effect of β blockade on the neurohumoral and cardiopulmonary response to dynamic exercise in cardiac transplant recipients. Br Heart J. 1994;71:431-436.
Cleroux J, Van Nguyen P, Taylor AW, Leenen FHH. Effects of beta1 versus beta1+2 blockade on exercise endurance and muscle metabolism in man. J Appl Physiol. 1989;60:548-555.