Beta-1 vs. beta-2 adrenergic control of coronary blood flow during isometric handgrip exercise in humans

In this study, we evaluated the role of vascular β1 vs. β2 receptors in coronary exercise hyperemia in a single-blind, randomized, crossover study in healthy men. In response to isometric handgrip exercise, blood flow velocity in the left anterior descending coronary artery was significantly greater with esmolol compared with propranolol. These findings increase our understanding of the individual and combined roles of coronary β1 and β2 adrenergic receptors in humans.

Abstract

During exercise, β-adrenergic receptors are activated throughout the body. In healthy humans, the net effect of β-adrenergic stimulation is an increase in coronary blood flow. However, the role of vascular β1 vs. β2 receptors in coronary exercise hyperemia is not clear. In this study, we simultaneously measured noninvasive indexes of myocardial oxygen supply (i.e., blood velocity in the left anterior descending coronary artery; Doppler echocardiography) and demand [i.e., rate pressure product (RPP) = heart rate × systolic blood pressure) and tested the hypothesis that β1 blockade with esmolol improves coronary exercise hyperemia compared with nonselective β-blockade with propranolol. Eight healthy young men received intravenous infusions of esmolol, propranolol, and saline on three separate days in a single-blind, randomized, crossover design. During each infusion, subjects performed isometric handgrip exercise until fatigue. Blood pressure, heart rate, and coronary blood velocity (CBV) were measured continuously, and RPP was calculated. Changes in parameters from baseline were compared with paired t-tests. Esmolol (Δ = 3296 ± 1204) and propranolol (Δ = 2997 ± 699) caused similar reductions in peak RPP compared with saline (Δ = 5384 ± 1865). In support of our hypothesis, ΔCBV with esmolol was significantly greater than with propranolol (7.3 ± 2.4 vs. 4.5 ± 1.6 cm/s; P = 0.002). This effect was also evident when normalizing ΔCBV to ΔRPP. In summary, not only does selective β1 blockade reduce myocardial oxygen demand during exercise, but it also unveils β2-receptor-mediated coronary exercise hyperemia.

NEW & NOTEWORTHY In this study, we evaluated the role of vascular β1 vs. β2 receptors in coronary exercise hyperemia in a single-blind, randomized, crossover study in healthy men. In response to isometric handgrip exercise, blood flow velocity in the left anterior descending coronary artery was significantly greater with esmolol compared with propranolol. These findings increase our understanding of the individual and combined roles of coronary β1 and β2 adrenergic receptors in humans.

during exercise, sympathetic nervous system activation evokes catecholamine release from sympathetic nerve terminals and the adrenal medulla. As a result, epinephrine and norepinephrine bind to α- and β-adrenergic receptors located in the heart and peripheral blood vessels, thereby raising heart rate (HR) and blood pressure (BP). During exercise, coronary blood flow must increase to enhance oxygen delivery to the myocardium because the myocardium has a limited ability to increase oxygen extraction from the blood (3, 14). In healthy humans and animals, it is well established that coronary vascular resistance is lowered during exercise due to neural, metabolic, and endothelial factors to allow for adequate oxygenation of myocardial tissue (14).

Laboratory experiments performed in dogs and pigs indicate that vascular β1 and β2 adrenergic receptors contribute to coronary vasodilation (13, 17, 19–21, 33, 50, 52–54, 56). This hyperemic response occurs when catecholamines stimulate β1 and β2 receptors in the coronary microcirculation; in dogs and pigs, this process is independent of changes in HR and BP (known to cause metabolic coronary vasodilation). In humans, vascular β1 receptors may influence coronary hyperemia, but this is challenging to prove in vivo. Prior publications from our laboratory demonstrate that metabolic coronary vasodilation is impaired when both β1 and β2 receptors are blocked by the nonselective β-blocker propranolol (40, 46); we also showed that coronary vasoconstrictor responses are enhanced following pre-treatment with propranolol (41). However, it is not clear whether β1 receptors play a role in coronary vasodilation in humans. We recently established the effective dose and infusion parameters of esmolol hydrochloride, a short-acting and selective β1-blocker, to use in human physiology research (37).

The purpose of this study was to noninvasively study the effects of β-adrenergic receptor antagonists on coronary blood flow during isometric handgrip exercise in healthy human subjects. Specifically, we used transthoracic Doppler echocardiography to measure coronary blood velocity (CBV) in the left anterior descending (LAD) coronary artery during infusions of saline, esmolol (β1 selective), and propranolol (β1 and β2 nonselective), while subjects performed isometric handgrip exercise. We hypothesized that esmolol and propranolol would have similar effects on the rate pressure product (RPP; HR × systolic BP) response to fatiguing isometric handgrip exercise but that the change in CBV would be higher under esmolol compared with propranolol.

METHODS

Ethical approval.

All study protocols were approved in advance by the Institutional Review Board of Penn State College of Medicine and conformed to the Declaration of Helsinki. All participants voluntarily provided written and informed consent. They were compensated ($25/h) for their time spent in the laboratory.

Design and subjects.

Experiments were performed using a single-blind, randomized, crossover design. Subjects received infusions of saline, esmolol, and propranolol before and during isometric handgrip exercise, with each drug being administered on a separate day (total of three experimental visits). The primary outcome was the difference in the ratio between ΔCBV and ΔRPP at the end of handgrip exercise between esmolol and propranolol (i.e., peak response minus baseline). After five subjects had completed the experiments, we conducted a power analysis and determined that, if the true difference in the ΔCBV-to-ΔRPP ratio between esmolol and propranolol was 1.0 with a standard deviation of 0.75, then we would need to enroll eight subjects to have 90% power with an α of 0.05. Therefore, a total of eight young healthy Caucasian men (26 ± 2 yr, 1.79 ± 0.09 m, 77.9 ± 14.0 kg, 24.0 ± 2.7 kg/m² body mass index, 14.5 ± 5.6% body fat, 47 ± 8 kg maximal grip strength) participated in this study.

Prior to participating in the infusion studies, all subjects underwent a screening visit, which included a history and physical examination, dual-energy X-ray absorptiometry (DXA) scan, transthoracic echocardiogram at rest, and maximal treadmill exercise test with respiratory gas measurement and 12-lead EKG monitoring. All tests were interpreted by a cardiologist before enrollment. Subjects were excluded if they had a resting heart rate below 45 beats/min or had a history of cardiovascular, pulmonary, renal, or endocrine disease. Using values from the DXA scan, we calculated drug doses based on fat-free mass (FFM), which correlates with blood volume (25). All subjects were asked to fast for 4 h, and to avoid alcohol, caffeine, and exercise for 24 h before the studies.

Imaging protocol and physiological measurements.

All study protocols were conducted in the supine or left lateral position in a clinical research laboratory at 20–22°C. A three-lead EKG (Cardiocap/5; GE Healthcare), a finger BP cuff (Finometer, FMS), a pneumotrace (to monitor respiratory movement), and an intravenous catheter in each arm were placed. Before beginning the infusion, a venous blood sample was obtained for the measurement of hemoglobin, and three resting BPs were obtained by automated oscillometry of the right brachial artery (Philips Sure Signs VS3), which were used to verify the Finometer values as previously described (41). All beat-by-beat variables were collected at 200 Hz by PowerLab (ADInstruments).

CBV of the distal left anterior descending (LAD) coronary artery were obtained from the adjusted apical four-chamber view using a GE Vivid 7 echocardiography system (all images acquired by Z. Gao). The specific procedures for measuring CBV in the LAD have been previously described by our laboratory (35, 46). In brief, CBV was calculated as the peak diastolic velocity (average of three or more cardiac cycles obtained at the end of each minute of exercise) as measured manually by Prosolv 3.0. This approach is consistent with other published reports (1, 32, 47). Studies have shown that percent changes in peak CBV obtained with transthoracic Doppler echocardiography are similar to percent changes in CBV measured by intracoronary Doppler guidewire (34). Other experiments have shown strong correlations between CBV and coronary blood flow in response to vasodilator stimuli (27, 29, 44). Therefore, we believe that CBV measured by Doppler is an appropriate surrogate for coronary blood flow under the conditions of the current study.

Experiments were performed using a single-blind, randomized, crossover design, with each treatment being administered on a separate day and ≥7 days apart. Based on our laboratory's previous publication (37), we chose to administer esmolol hydrochloride (2,500 mg in 250 ml) as 0.5 mg·kg FFM^–1·min^–1 loading dose over 1–3 min; then 0.2–0.25 mg·kg FFM^–1·min^–1 for the remainder of the study. On a separate day, propranolol hydrochloride (50 mg in 245 ml normal saline) was administered as a loading dose of 0.4 mg/kg FFM in 15 min followed by 1.3 µg·kg FFM^–1·min^–1 for the remainder of the study. The saline trial followed the same infusion parameters as the esmolol trial to account for time and volume effects. These drugs were always administered into the left arm by an infusion pump (Alaris PC Model 8015, CareFusion).

After baseline hemodynamic and echocardiography measurements at rest were obtained (i.e., during the maintenance infusion), a second venous blood sample was obtained for the measurement of hemoglobin. All subjects then performed isometric handgrip exercise at 40% of maximal voluntary contraction with their right hand until fatigue was reached. Fatigue was defined as a rating of 19 or 20 on the Borg rating of perceived exertion scale and inability to maintain the target workload (7). The same workload was used for all trials. Isometric handgrip exercise is known to raise RPP and sympathetic nerve activity (30, 38, 39). Handgrip was started 10 min after beginning the maintenance infusion.

Data collection and statistical analysis.

All variables were continuously measured and were analyzed offline using IBM SPSS 23.0. Graphics were produced with Microsoft Excel and Adobe Creative Cloud. Normality of all data was assessed and confirmed by the Kolmogorov-Smirnov test. An average of the last 20 s of each minute and the last 20 s of exercise is presented. RPP was used as an index of myocardial oxygen demand. Both CBV and the ratio of ΔCBV to ΔRPP (i.e., the slope of the relationship between coronary flow and cardiac metabolism at the end of exercise) were used as indexes of myocardial oxygen supply (36, 45). Because coronary velocity waveforms were quantified manually, the person who performed this analysis was blinded to the treatment until all analyses were complete. For all variables, a three treatment (saline, esmolol, propranolol) × four time point (baseline, minute 1, minute 2, fatigue) repeated-measures ANOVA was conducted using the raw physiological parameters. Paired t-tests were used when a significant treatment × time interaction was observed. To account for multiple comparisons, the Holm-Bonferroni step-down adjustment was used. Unadjusted t-tests were also used to compare physiological variables at baseline and the end of exercise (i.e., when it was expected treatment effects would be most prominent). To determine effect sizes for the primary outcomes, Cohen’s d values were calculated as the t-statistic/square root of the sample size. Cohen’s d values of >0.8 were considered to be “strong” effect sizes (12). Data are shown as means ± SD unless otherwise stated, and P values of <0.05 were considered statistically significant.

RESULTS

Infusion of propranolol (28 ± 6 mg over ~25 min; range, 17–33 mg) caused a reduction in HR at rest (before handgrip exercise), but infusion of esmolol (207 ± 72 mg over ~13 min; range, 102–324 mg) did not lower HR at rest (Table 1). Neither esmolol nor propranolol evoked hypotension at rest (Table 1). Handgrip duration was comparable between saline (151 ± 26 s), esmolol (142 ± 16 s), and propranolol (145 ± 13 s). Hemoglobin levels were unchanged by infusion of saline (from 14.2 ± 1.0 to 14.4 ± 1.0 g/dl; P = 0.104), esmolol (from 14.2 ± 0.7 to 14.3 ± 0.7 g/dl; P = 0.072), and propranolol (from 13.9 ± 0.7 to 13.8 ± 0.6 g/dl; P = 0.460). As expected, ratings of perceived exertion in the hand and forearm were reported as 19 or 20 out of 20 in all subjects for all trials, indicating that subjects were indeed fatigued at the end of exercise. No EKG evidence of ischemia was noted during the experiments.

Table 1.

Effect of esmolol and propranolol on hemodynamic responses to handgrip

	Base	1 min	2 min	Fatigue	Delta
Systolic BP, mmHg
Saline	110 ± 4	119 ± 12	140 ± 19	150 ± 18	41 ± 16
Esmolol	109 ± 6	118 ± 9	135 ± 10	139 ± 9	30 ± 6
Propranolol	108 ± 6	119 ± 7	139 ± 11	141 ± 11	33 ± 9
Diastolic BP, mmHg
Saline	67 ± 6	77 ± 10	91 ± 14	98 ± 13	31 ± 9
Esmolol	65 ± 6	74 ± 10	87 ± 10	90 ± 10	25 ± 9
Propranolol	69 ± 4	80 ± 6	95 ± 11	98 ± 11	30 ± 9
Mean BP, mmHg
Saline	80 ± 3	92 ± 8	109 ± 12	117 ± 12	37 ± 10
Esmolol	80 ± 6	91 ± 7	106 ± 7	110 ± 7	30 ± 6
Propranolol	81 ± 4	93 ± 6	110 ± 11	114 ± 11	33 ± 9
Heart rate, beats/min
Saline	56 ± 9	68 ± 11	74 ± 10	77 ± 11	20 ± 7
Esmolol	57 ± 8	62 ± 6	66 ± 6*	68 ± 10*	12 ± 7*
Propranolol	51 ± 5†	56 ± 5*,†	58 ± 5*,†	60 ± 6*,†	9 ± 3*

Values are means ± SD (n = 8). Delta values were calculated as fatigue minus baseline. Base, baseline before exercise; BP, blood pressure. *Significant difference vs. saline trial at same time (P < 0.05). ^†Significant difference vs. esmolol trial at same time (P < 0.05).

As shown in Table 1, isometric handgrip exercise evoked an increase in systolic BP, diastolic BP, mean BP, and HR over time (main effect for time of <0.001 for all variables). However, only HR displayed a main effect for treatment (P < 0.001) and a treatment × time interaction (P < 0.001). During the preexercise baseline, HR was significantly lower with propranolol compared with esmolol (P = 0.026). During the first minute of exercise, HR was significantly lower with propranolol compared with esmolol (P = 0.013) and saline (P = 0.022). During the second minute of exercise, HR was significantly lower with esmolol compared with saline (P = 0.032). At fatigue, HR was lower with esmolol compared with saline (P = 0.010), and HR was also lower with propranolol compared with saline (P = 0.002). However, the change in HR from baseline to fatigue was not different between esmolol and propranolol (P = 0.362).

In Fig. 1, coronary responses for each minute of exercise are displayed with respect to the RPP values measured simultaneously. Both esmolol and propranolol evoked a left-shift compared with saline (i.e., lower RPP), and propranolol also evoked a down-shift (i.e., lower coronary blood velocity). The changes in CBV and RPP from baseline to fatigue are compared statistically in Fig. 2. Specifically, both esmolol (P = 0.032; Cohen’s d = 0.95) and propranolol (P = 0.006; Cohen’s d = 1.4) reduced ΔRPP compared with saline, but there was no difference between esmolol and propranolol (P = 0.535; Fig. 2, top). Consistent with previous studies (39, 40, 46), propranolol blunted the increase in CBV compared with saline (P = 0.029; Cohen’s d = 0.92). However, there was no difference in ΔCBV between saline and esmolol (P = 0.687). In fact, ΔCBV with propranolol was significantly less than with esmolol (P = 0.002; Cohen’s d = 1.6; Fig. 2, bottom).

Fig. 1.

Effect of handgrip exercise on coronary blood velocity (y-axis) and rate pressure product (RPP; x-axis) during saline (open circles), esmolol (shaded circles), and propranolol (filled circles) infusions. From left to right, the data points for each treatment include baseline, 1 min of exercise, 2 min of exercise, and the peak exercise response. The circles represent means, and error bars represent 1 SD. N = 8. Note that esmolol and propranolol evoked a left-shift compared with saline (i.e., lower RPP), and propranolol also evoked a down-shift (i.e., lower coronary blood velocity). Please see text for statistical comparisons.

Fig. 2.

Changes in RPP and coronary blood velocity (CBV) in response to fatiguing isometric handgrip exercise. Data are means ± SD; n = 8. *Significant difference vs. saline trial (P < 0.05). ^†Significant difference vs. esmolol trial (P < 0.05).

As shown in Fig. 3, the effect of esmolol on coronary exercise hyperemia (compared with propranolol) is also evident when the CBV values are normalized to the relative changes in RPP (P = 0.019 for mean data; Cohen’s d = 1.1). In Fig. 3, the comparison between saline and esmolol is not significantly different (P = 0.195 for mean data), and the comparison between saline and propranolol is also not significantly different (P = 0.854 for mean data).

Fig. 3.

Individual ΔCBV-to-ΔRPP ratios in response to fatiguing handgrip exercise for saline, esmolol, and propranolol. Higher values indicate a greater coronary response for a given change in myocardial metabolism. †Significant difference between esmolol and propranolol for the mean data (P < 0.05).

DISCUSSION

The purpose of this study was to evaluate the role of β1 and β2 receptors in regulating hemodynamic and coronary vascular responses to exercise in healthy humans. As hypothesized, beta blockade with esmolol and propranolol reduced myocardial oxygen demand (as measured by RPP) to a similar degree, but the increase in CBV was higher with esmolol compared with propranolol (Figs. 1 and 2). This suggests that, under normal (unblocked) circumstances, the increase in RPP (primarily a β1 effect) and β2 stimulation of the coronary microcirculation by endogenous catecholamines both contribute to coronary exercise hyperemia. Thus, not only does esmolol reduce myocardial oxygen demand during exercise, but it also unveils β2 receptor-mediated coronary exercise hyperemia. To our knowledge, we are the first to demonstrate this finding in humans.

The overwhelming majority of in vivo coronary physiology studies have been performed in healthy dogs and pigs (13, 17, 19–21, 33, 52–54). These studies have described “feedforward coronary vasodilation” in which increased sympathetic nerve activity not only increases HR and contractility but also simultaneously evokes vasodilation of the coronary microcirculation. However, the adrenergic control of coronary blood flow is different between dogs and pigs (14), which makes extrapolation to humans challenging. Several human studies have been performed in the cardiac catheterization laboratory and have demonstrated impaired flow responses in patients with coronary atherosclerosis (3, 5, 9, 24, 28, 31). Patients undergoing cardiac catheterization, by definition, have risk factors for and/or the presence of coronary artery atherosclerosis, which is known to alter coronary regulation (26, 42, 57). Thus we believe that studying healthy humans is necessary to quantify fundamental regulatory processes.

To interpret the current data, one must first consider our rationale for choosing this experimental design and the inherent limitations of the methods we used. We used isometric exercise in the presence and absence of a selective β1-blocker and a nonselective β-blocker, and measured CBV with echocardiography; this imaging method is noninvasive but lacks the ability to quantify absolute coronary blood flow. Moreover, intravenous infusion of medications has systemic effects on multiple organ systems and is less specific than intracoronary infusion. To determine β1 vs. β2 effects in our study, one must assume that esmolol is β1 selective, that esmolol and propranolol have equal efficacy at antagonizing the β1 receptors, and that HR and myocardial contractility are mediated by activation of β1 receptors. Based on our recent publication using identical drug dosages in healthy men and women (37), we believe these assumptions are true. However, based on our experimental design, we are less confident that α-adrenergic and parasympathetic effects on HR and vascular resistance are equal between treatments. In the presence of esmolol and/or propranolol, compensatory changes in coronary vascular resistance may not be detectable by simply measuring coronary velocity, and caution is warranted. Despite these limitations, we believe that our approach is the safest and most cost-effective way to evaluate β1 vs. β2 control of coronary blood flow in humans.

Exercise is a significant stressor to the coronary circulation. Indeed, because myocardial oxygen extraction is near maximal at rest, increasing flow is the predominant way to increase oxygen delivery during times of increased demand (3, 14). Prior studies have shown that handgrip exercise increases HR and BP, resulting in coronary hyperemia (23, 35, 38–40, 45, 46). This hyperemic response to exercise is dependent on coronary endothelial function; in atherosclerosis, blood flow responses are attenuated or absent (5, 57). The current study in young healthy men observed an ~36% increase in CBV in response to fatiguing handgrip exercise during the saline trial, which is consistent with the cited studies above. Other stressors such as the cold pressor test, mental stress, and hypoxia also evoke coronary vasodilation in healthy subjects, largely because of the increased HR and BP that occurs (i.e., metabolic coronary vasodilation) (26, 35, 42, 57). In addition to metabolic and endothelial influences on coronary blood flow, the sympathetic nervous system also plays a role. Both human and animal studies have shown that endogenous catecholamines stimulate α- and β-adrenergic receptors in the coronary microcirculation (3, 14). Coronary blood flow responses during exercise are therefore dependent on the receptors that are blocked or stimulated.

Recent experiments from our laboratory have found that coronary responses to handgrip exercise are attenuated by propranolol in healthy subjects (40, 46). The current study confirms and extends these findings by showing that propranolol, but not esmolol, impairs the coronary hyperemic response to handgrip exercise (Figs. 2 and 3). Gao et al. found that both metoprolol and propranolol impaired the relationship between invasively measured myocardial oxygen supply and demand in response to treadmill exercise in pigs (17). The discrepancy between the present study and the study by Gao et al. (17) may be due to species differences, differences in exercise mode, or pharmacological differences between esmolol and metoprolol. During exercise, the direct vascular effects of adrenergic stimulation are challenging to separate from the effects of increased HR and BP. A strength of the present study is the crossover design and the evaluation of CBV and RPP simultaneously. Esmolol and propranolol had similar effects on the RPP response to handgrip, but coronary responses were greater with esmolol. This suggests that, during exercise (with no blockade), both the increase in RPP and also β2 stimulation of the coronary microcirculation by endogenous catecholamines contribute to coronary exercise hyperemia. We believe our data demonstrate “feedforward coronary vasodilation” for the first time in humans.

Pharmacological stimulation of β2 receptors increases coronary blood flow in healthy humans (55) and in patients with mildly atherosclerotic coronary arteries (5, 43, 51). On the other hand, pharmacological stimulation of β1 receptors has been less studied. When dobutamine (a predominantly β1 agonist) is infused intravenously, there is a large increase in RPP and a resultant increase in coronary blood velocity (1, 32) as well as increased epicardial lumen diameter (4). However, the direct vascular effects of β1 activation (i.e., independent of changes in HR) are less clear. Indeed, prior studies that performed coronary angiography in the setting of β1 blockade also utilized intracoronary vasodilators such as adenosine or dipyridamole, which are known to uncouple the coronary circulation from metabolic and neural control (6, 8, 49). Thus β1 blockade was likely exerting its effects by lowering HR and myocardial contractility and not affecting coronary vascular resistance in these studies. A recent study in patients with coronary artery disease found that esmolol infusion (comparable dose to our study) increased lumen diameter (measured via angiography), reduced central BP, lowered resting HR, and improved diastolic time (10). Because the measurements were obtained at rest and no vasodilator provocation occurred, these data are challenging to compare with the present study.

Clinical implications.

Beta-blockers are standard of care for patients with heart failure, previous myocardial infarction, and stable angina (15, 16, 48). When patients with a mismatch in myocardial oxygen demand and supply are treated, the goal is to optimize myocardial perfusion via coronary arteries while simultaneously reducing the demand for oxygen by the myocardium. Based on our data, we speculate that selective β1-receptor blockade would be more beneficial than nonselective blockade in patients undergoing isometric exercise in their daily lives (e.g., carrying heavy objects, use of power tools, etc.). Future studies should be conducted to determine the effects of β1-receptor blockade on coronary exercise hyperemia in patients with coronary artery disease. Additionally, coronary collaterals are thought to be especially sensitive to β2 stimulation because they do not contain functioning α receptors (3, 22). Thus, in patients who have collateral flow around a stenosis, the use of a nonselective β-blocker could be detrimental.

Limitations

The present study was minimally invasive in nature and enrolled only young, healthy Caucasian men. Therefore, extrapolation to women, older subjects, non-Caucasians, or those with heart disease must be done with caution. For anatomic reasons, we only examined flow in the LAD artery (i.e., the artery most amenable to transthoracic Doppler interrogation), and we cannot comment on myocardial wall motion, a functional marker of ischemia. This study used RPP as a surrogate for myocardial oxygen consumption, and previous studies have shown that there is a correlation between RPP and myocardial oxygen consumption (18). However, the relationship between these two parameters may change as ventricular volume and contractility are altered (2, 11). Unfortunately, it is not possible to measure the LAD artery (at the apex of the heart) and left ventricular dimensions simultaneously with echocardiography. Moreover, the use of the Finometer to estimate peripheral BP may not precisely match aortic diastolic BP (i.e., a component of coronary perfusion pressure). Nevertheless, the crossover design of this study should minimize this issue. Future esmolol studies utilizing parasympathetic blockade along with α-blockade would help to further delineate how β-adrenergic receptors influence coronary blood flow in health and disease.

In conclusion, the present study in healthy young men demonstrates that coronary hyperemia is greater with esmolol compared with propranolol, despite similar changes in RPP. We suggest that the increase in HR and BP due to exercise (primarily a β1-effect) and also β2 stimulation of the coronary microcirculation by endogenous catecholamines separately contribute to coronary exercise hyperemia. These preliminary findings increase our understanding of the individual and combined roles of coronary β1- and β2-adrenergic receptors in humans.

GRANTS

This project was supported by a grant from the Association of Faculty and Friends of the Penn State Milton S. Hershey Medical Center (Dr. Muller). This project was also supported, in part, by NIH Grants UL1 TR-000127 and KL2 TR-000126 from the National Center for Advancing Translational Sciences (NCATS), and also under a grant with the Pennsylvania Department of Health using Tobacco CURE funds (Dr. Muller). The Pennsylvania Department of Health and the NIH specifically disclaim responsibility for any analyses, interpretations, or conclusions.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

S.R.M., A.F.V., and M.D.M. analyzed data; S.R.M., A.F.V., T.A.A., A.J.M., Z.G., U.A.L., D.N.P., and M.D.M. interpreted results of experiments; S.R.M. and M.D.M. prepared figures; S.R.M., A.F.V., A.J.M., and M.D.M. drafted manuscript; S.R.M., A.F.V., T.A.A., A.J.M., Z.G., U.A.L., D.N.P., and M.D.M. edited and revised manuscript; S.R.M., A.F.V., A.J.M., Z.G., U.A.L., D.N.P., and M.D.M. approved final version of manuscript; A.F.V., T.A.A., A.J.M., Z.G., U.A.L., and M.D.M. performed experiments; U.A.L. and M.D.M. conceived and designed research.