Am J Physiol Heart Circ Physiol 292: H3025-H3031, 2007.
First published February 16, 2007; doi:10.1152/ajpheart.01200.2006
0363-6135/07 $8.00
Effects of hypertension on cardiovascular responses to epinephrine in humans
Frans H. H. Leenen,
Anne Fourney,
Elizabeth Coletta, and
Roselyn White
Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
Submitted 1 November 2006
; accepted in final form 12 February 2007
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ABSTRACT
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Cardiac 
-receptor responsiveness is diminished by both aging and hypertension. However, concomitant decreases in the activity of counterregulatory mechanisms, such as the arterial baroreflex and neuronal catecholamine uptake, influence the ultimate cardiac responses to adrenergic agents in vivo. In the present study, we evaluated by echocardiography cardiac responses to intravenous infusion of epinephrine in 14 young and 18 older normotensive men and women and in 10 young and 17 older hypertensive men and women. To assess the relative contribution of intrinsic cardiac and counterregulatory components to the overall response, infusions were repeated combined with a ganglionic blocker in the young groups. Epinephrine-induced increases in heart rate were similar in the four groups. Increases in stroke volume, ejection fraction, and cardiac index were similar in the two hypertensive and two young normotensive groups. In contrast, they were attenuated in the older normotensive group, resulting in higher left ventricular responses in older hypertensive than in normotensive subjects. Heart rate and left ventricular responses to epinephrine in the presence of ganglionic blockade did not differ between the two young groups. Increases in plasma norepinephrine due to epinephrine infusion were larger in hypertensive than in normotensive subjects. One may conclude that compared with young normotensive subjects, in hypertensive subjects mechanisms increasing versus decreasing cardiac responses to epinephrine may remain in balance, and, compared with older normotensive subjects, older hypertensive subjects exhibit enhanced cardiac responses to sympathetic stimulation.
aging; arterial baroflex; neuronal uptake; -receptor responsiveness; heart
HYPERTENSION IS GENERALLY considered to cause a decrease in cardiac -adrenergic responsiveness. Hypertension also leads to blunting of counterregulatory mechanisms such as the arterial baroreflex (5, 16), which also influences cardiac responses to a -agonist in vivo (16). Combined with autonomic blockade, chronotropic responses to the -agonist isoproterenol were not different in young normotensive and hypertensive subjects (7, 18), whereas left ventricular (LV) responses showed blunting in the hypertensive subjects (18). Most studies on this interaction have employed the synthetic agonist isoproterenol. Two major differences between isoproterenol and the endogenous catecholamines preclude extrapolation of findings obtained with isoproterenol to the endogenous agonists. First, both endogenous agonists have substantial 
-receptor agonistic activity, both pre- and postsynaptically, which will influence the final hemodynamic responses. Second, in contrast to isoproterenol, endogenous catecholamines are taken up by the adrenergic nerve terminal (2, 14). A decrease in neuronal uptake leads to higher effective concentrations in the synaptic cleft, particularly in the heart (3) for similar rates of endogenous transmitter release or of exogenous infusion. Such a decrease would not affect the local concentrations of isoproterenol. Both aging (2, 11, 13) and hypertension (14) are associated with a decrease in neuronal uptake of norepinephrine. Aging may also decrease neuronal uptake of epinephrine (11), but the effects of hypertension on uptake of epinephrine have not yet been studied. Little is known regarding the effects of hypertension on the cardiovascular responses to the endogenous neurotransmitters norepinephrine and epinephrine. Bachmann et al. (1) reported modestly enhanced increases in systolic blood pressure (BP) and heart rate and decreases in diastolic BP in response to graded infusion of epinephrine in six hypertensive (mean age, 40 yr) versus six younger normotensive (mean age, 23 yr) men. Kjeldsen et al. (8) reported similar heart rate responses to epinephrine in 40-yr-old hypertensive and normotensive men. Cardiac responses to epinephrine in older hypertensive subjects have not yet been reported. These responses will be determined on the one hand by the decrease in cardiac -receptor responsiveness by both aging and hypertension and on the other hand by concomitant decreases in activity of counterregulatory mechanisms such as the arterial baroreflex and neuronal catecholamine uptake. The present study had, therefore, two objectives: 1) to assess the effects of epinephrine on BP, heart rate, and LV function in young versus older normotensive and hypertensive subjects, and 2) to assess in young subjects the hemodynamic responses to epinephrine in the presence of ganglionic blockade to eliminate differential changes in arterial baroreflex activity.
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METHODS
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Subjects.
Epinephrine without trimetaphan was administered to 14 young normotensive subjects (age: 21–40 yr, mean 30 ± 2 yr; 8 men and 6 women), 18 older normotensive subjects (age: 50–73 yr, mean 60 ± 2; 6 men and 12 women), 10 young hypertensive subjects (age: 30–39 yr, mean 36 ± 1; 4 men and 6 women), and 17 older hypertensive subjects (age: 50–64 yr, mean 59 ± 1; 10 men and 7 women). Of the young subjects, seven young normotensive subjects (4 males and 3 females) and seven young hypertensive subjects (3 males and 4 females) consented to receive epinephrine with concomitant trimetaphan. As previously explained (18), for safety concerns, older hypertensive subjects were not studied with trimetaphan. Cardiovascular responses to epinephrine in normotensive subjects were previously reported using exactly the same study protocol (17). Except for hypertension, all subjects had normal histories, physical examinations, and biochemistry profiles. None had clinical evidence of coronary artery disease or clinically significant LV hypertrophy on echocardiogram. Body weights were within 25% of ideal weight, but average weight was 9–10 kg higher in the hypertensive groups. Only subjects with excellent quality echocardiograms were enrolled in the study.
Hypertensive subjects had mild to moderate hypertension with a known duration of 11 ± 2 yr in the young and 16 ± 3 yr in the older hypertensive subjects. Normotensive BP was defined as 130/85 mmHg or less and hypertensive BP as 140/95 mmHg or more after resting for 5–10 min on two separate occasions. Ambulatory BP monitoring (24 h) was performed in 7 of 10 young and 14 of 17 older hypertensive subjects and confirmed the presence of hypertension (day diastolic BP 
90 mmHg). All antihypertensive drug therapy (mainly short-acting diuretics and -blockers) was discontinued at least 2 wk before the first study morning. Some characteristics of the study populations are presented in Table 1. The study was approved by the Human Research Ethics Committee of the Ottawa Hospital, and written informed consent was obtained from each subject.
Experimental protocol.
A run-in study morning was used to acquaint the subjects with experimental procedures and personnel. On the first study morning, in all subjects epinephrine alone was administered, and on the second study morning, only in young subjects was epinephrine with concomitant trimetaphan administered. Study mornings were at least 4 days apart. On each study morning, following a standardized liquid breakfast, the subjects remained supine until completion of the study. Two indwelling intravenous catheters were inserted, one in each forearm. A BP cuff was applied to the arm that was not used for infusion, and BP was measured automatically with a Roche Arteriosonde (Roche Medical Electronic, Cranbury, NJ). Echocardiogram electrodes were attached to measure heart rate by a Tektronic 414 monitor (Tektronic, Beaverton, OR).
On the first study morning, following a rest period of at least 60 min, epinephrine was started at 20 ng·kg–1·min–1 and increased to 40, 80, 120, or 160 ng·kg–1·min–1 until the heart rate had increased by 20–25 beats/min or the diastolic BP decreased by 15 mmHg. Each dose was infused for 8 min. On the second study morning, young subjects were first titrated with trimetaphan (Arfonad). The latter was started at 20 µg·kg–1·min–1 for 10 min and then increased to 50 µg·kg–1·min–1 again for 10 min and subsequently increased to 100 µg·kg–1·min–1. The rate was not further increased if the systolic BP decreased below 90 mmHg. In the young normotensive subjects, two continued on 50 µg·kg–1·min–1 and five on 100 µg·kg–1·min–1; in the young hypertensive subjects, three continued on 50 µg·kg–1·min–1 and four on 100 µg·kg–1·min–1. After BP had stabilized for 10 min, epinephrine infusion was started as above.
Heart rate and BP were monitored every 2 min for 10-min periods before the start of infusion and twice during the last 2–3 min at each rate of infusion. Mean values were used for statistical analysis. Echocardiograms were obtained at the end of the resting period and at the end of each infusion rate. In a subset of patients, venous samples for plasma concentrations of catecholamines were drawn at baseline and peak infusion rate and measured according to Sole and Hussain (15).
Echocardiography.
Echocardiograms were obtained in the supine position using a Toshiba 2-D sonographer SSH-60A. Tracings were recorded at 50 mm/s paper speed. The measurements were made to the nearest millimeter on at least four cardiac cycles during quiet respiration, and the results were averaged for statistical analysis. The measurements were made by the same observer according to the guidelines of the American Society of Echocardiography. All echocardiograms were obtained by the same research assistant with the subjects in the same position, in the same intercostal area, and in the same LV area, just below the tip of the ventral leaflets. LV end-diastolic and end-systolic dimensions were measured, and end-diastolic and end-systolic volumes were estimated by the cube function formula. The stroke volume index, cardiac index, and LV ejection fraction were calculated accordingly.
Analysis of data.
Baseline (hemodynamic) parameters in the four groups of subjects were compared by ANOVA. The dose-response curves were analyzed by multivariate general linear model. After testing the homogeneity of slopes, we used analysis of covariance to compare the group effect adjusted for the covariate (infusion rate). Variables with nonlinear responses were analyzed by ANOVA with repeated measures. When the F-test was significant, pairwise comparisons of the means were performed by t-test with adjustment for multiple comparisons. A P value of <0.05 was considered statistically significant. Data are expressed as means ± SE.
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RESULTS
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Baseline characteristics.
Resting BPs were similar in the young and older normotensive subjects. The two hypertensive groups had mild hypertension with a higher systolic BP and larger LV mass in the older group (Table 1). LV end-diastolic and end-systolic volumes were significantly larger in the young normotensive group compared with the other three groups (Table 1). Infusion of trimetaphan caused modest decreases in supine BP (to 105 ± 3/74 ± 3 and to 126 ± 5/85 ± 5 mmHg), whereas heart rate increased significantly to 83 ± 4 and 74 ± 2 beats/min in the young normotensives and hypertensives, respectively.
BP and cardiac effects of epinephrine alone.
Infusion of epinephrine caused dose-related increases in systolic BP and decreases in diastolic BP, as well as increases in parameters of cardiac performance such as heart rate, stroke volume, ejection fraction, and cardiac index (Table 2 and Figs. 1–
3). The rate of infusion of epinephrine was increased to 120 ng·kg–1·min–1 in most subjects and increased further to 160 ng·kg–1·min–1 in 23 of 32 normotensive subjects and 13 of 27 hypertensive subjects (Table 2).
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Fig. 1. Changes in heart rate in response to infusion of epinephrine at increasing rates, either alone in young and older normotensive and hypertensive subjects (top) or combined with trimetaphan in young normotensive and hypertensive subjects (bottom). Values represent changes (means ± SE) from baseline.
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Fig. 2. Changes in ejection fraction in response to infusion of epinephrine at increasing rates, either alone in young and older normotensive and hypertensive subjects (top) or combined with trimetaphan in young normotensive and hypertensive subjects (bottom). Values represent changes (means ± SE) from baseline. P < 0.01 older normotensive vs. young normotensive subjects. P < 0.05 older hypertensive vs. older normotensive subjects.
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Fig. 3. Changes in cardiac index in response to infusion of epinephrine at increasing rates, either alone in young and older normotensive and hypertensive subjects (top) or combined with trimetaphan in young normotensive and hypertensive subjects (bottom). Values represent changes (means ± SE) from baseline. P < 0.01 older normotensive vs. young normotensive subjects.
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Increases in systolic BP by epinephrine were somewhat less in both older normotensive and hypertensive subjects. Decreases in diastolic BP were only blunted in older normotensive subjects (Table 2). Increases in heart rate by epinephrine were similar for the four groups (Fig. 1). Epinephrine caused modest increases in LV end-diastolic volume, not different between groups. LV end-systolic volume showed clear decreases that tended to be less in the older subjects (only significant for the normotensive subjects) (Table 2). This pattern of changes in LV volumes resulted in smaller increases in stroke volume (Table 2), ejection fraction (Fig. 2), and cardiac index (Fig. 3) in the older versus young normotensive subjects. In contrast, young and older hypertensive subjects showed similar responses as young normotensive subjects. As a result, older hypertensives showed larger responses than older normotensive subjects for stroke volume and ejection fraction.
Epinephrine caused dose-related decreases in total peripheral resistance index (TPRI), which showed only minor differences between groups: –10 ± 1 and –9 ± 1 units in young and older normotensive subjects versus –12 ± 2 and –10 ± 2 units in young and older hypertensive subjects at the 120-ng·kg–1·min–1 infusion rate.
BP and cardiac effects of epinephrine combined with trimetaphan.
In the presence of ganglionic blockade, epinephrine caused more marked decreases in diastolic BP and TPRI in young hypertensive versus normotensive subjects. Systolic BP increased dose-related in the young normotensive subjects but showed a biphasic response in the hypertensive subjects with a decrease at the lowest rate and increase at the highest rate (Table 3). Increases in heart rate were similar for the two groups (Fig. 1). Other cardiac effects, such as decreases in LV end-systolic volume (Table 3) and increases in stroke volume (Table 3), ejection fraction (Fig. 2), and cardiac index (Fig. 3), were also similar in the young normotensive and hypertensive groups.
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Table 3. Hemodynamic responses to epinephrine combined with trimetaphan in young normotensive versus hypertensive subjects
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Plasma catecholamines.
Baseline values for plasma norepinephrine and epinephrine tended to be higher in the hypertensive subjects compared with their respective control groups (Table 4). Infusion of epinephrine caused marked increases in plasma epinephrine. The extent of these increases was less in both hypertensive groups compared with their normotensive controls. Plasma norepinephrine was also increased by infusion of epinephrine. The extent of these increases was actually larger in the hypertensive subjects. In the presence of ganglionic blockade, infusion of epinephrine again tended to cause larger increases in plasma epinephrine in young normotensive subjects compared with young hypertensive subjects, whereas plasma norepinephrine only increased in the young hypertensive subjects (Table 4).
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DISCUSSION
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When compared with responses in young normotensive subjects, the following new findings are provided in the present study: LV and BP responses to infusion of epinephrine are blunted in older normotensive subjects but not in young and older hypertensive subjects. In contrast, we previously showed that LV responses to the -agonist isoproterenol are diminished in young hypertensive subjects and further blunted in older hypertensive subjects (18).
The cardiovascular responses to infusion of epinephrine in humans have been well documented (4, 6, 10). Both age and hypertension may affect these responses through a variety of mechanisms. Some of these changes may decrease responses; others may enhance responses. For example, "healthy aging" was found to be associated with decreased cardiac responsiveness to epinephrine, but this decrease was balanced by concomitant decreases in the buffering of these responses by less neuronal uptake of (nor)epinephrine and blunting of the arterial baroreflex (11). The present results in young and older hypertensive versus age-matched normotensive subjects should be considered from this "integrative physiology" perspective.
Cardiac responses to isoproterenol alone were similar in young normotensive and hypertensive subjects (18). However, in the presence of ganglionic blockade, LV responses to isoproterenol were decreased in young hypertensive subjects (Fig. 4). We concluded (18) that decreased responsiveness was offset by diminished blunting by the arterial baroreflex in the hypertensive subjects (5, 16). In contrast, in the present study, we show that young normotensive and hypertensive subjects show similar cardiac responses to epinephrine not only when infused alone but also when infused combined with ganglion blocker. With the consideration that decreased cardiac -receptor responsiveness was likely present in young hypertensive subjects (18), it appears that other mechanisms besides the baroreflex also play a compensatory role. Plasma levels of epinephrine at peak infusion rate were lower in the hypertensive subjects, in part reflecting the lower number of hypertensive participants reaching the highest infusion rate and, in part, likely their higher body weight. Despite these lower epinephrine levels, plasma norepinephrine levels actually increased significantly more in the young hypertensive subjects both when epinephrine was infused alone and when combined with ganglionic blockade. This response may suggest enhanced presynaptic responses to epinephrine causing increased norepinephrine release and overflow. However, it appears unlikely that hypertension is associated with enhanced presynaptic -receptor responsiveness and thereby enhanced norepinephrine release. We suggest that these findings reflect a hypertension-induced decrease in neuronal reuptake of norepinephrine, resulting in enhanced overflow into the circulation. A recent study by Schlaich et al. (14) reported a clear decrease in neuronal reuptake of norepinephrine in young hypertensive subjects. Such a decrease in neuronal reuptake can be expected to lead to higher concentrations of norepinephrine in the synaptic cleft and, therefore, larger postsynaptic responses, offsetting a hypertension-associated decrease in -receptor responsiveness. The higher plasma norepinephrine levels may also indicate a decrease in neuronal uptake of epinephrine, leading to higher effective concentrations in the synaptic cleft and thereby enhanced presynaptic -receptor stimulation. Whether neuronal uptake of epinephrine is decreased in hypertensive subjects has not yet been studied. Even if this is the case, this is less likely the primary mechanism for the higher plasma norepinephrine levels, since isoproterenol is not subject to neuronal uptake and also causes larger increases in plasma norepinephrine in young hypertensive versus normotensive subjects (18).
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Fig. 4. Changes in stroke volume, ejection fraction, and cardiac index in response to infusion of isoproterenol in young and older normotensive (nt) and hypertensive (ht) subjects, as previously reported in Ref. 18. Data for only one infusion rate are shown: 20 ng·kg–1·min–1 for isoproterenol alone and 5 ng·kg–1·min–1 for isoproterenol combined with trimetaphan (trim). Statistics refer to whole-dose response curves, as shown in White et al. (Ref. 18). Notations indicate the following: *between young and older hypertensive subjects or between young and older normotensive subjects; abetween hypertensive and normotensive subjects in same age group.
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Epinephrine alone caused similar decreases in diastolic BP and TPRI in the two young groups but, combined with ganglionic blockade, caused larger decreases in the young hypertensive subjects. This difference was not seen with isoproterenol (18). Thus enhanced -receptor-mediated arterial vasodilation in young hypertensive subjects is unlikely. Instead, this finding may reflect an impaired 1-adrenergic vasoconstriction in the young hypertensive subjects, possibly due to downregulation of 1-receptors by high sympathetic tone in this group.
Older subjects showed an unexpected pattern of responses to epinephrine. Older normotensive subjects showed the previously reported blunting of the increases in ejection fraction, stroke volume, and cardiac index in response to epinephrine compared with young normotensive subjects (17). Whereas further blunting was expected, no attenuation at all was apparent in older hypertensive subjects, who exhibited similar responses as young normotensive and hypertensive subjects and significantly larger responses than older normotensive subjects. With the assumption that -receptor responsiveness was indeed decreased in the older hypertensive subjects, it appears that, in older hypertensive subjects, buffering mechanisms change to such an extent that LV responses to epinephrine remain the same as in young subjects. Moreover, the extent of changes in the different mechanisms influencing cardiac responses to epinephrine in either direction appears to be such that older hypertensive subjects exhibit significantly larger LV responses to epinephrine than older normotensive subjects. Both blunting of arterial baroreflex control of LV function and decreased neuronal uptake occur with healthy aging but apparently not to the extent so as to result in the same responses to epinephrine as in young normotensive subjects. Further decreases in baroreflex function and neuronal uptake of norepinephrine by a combination of aging and hypertension may be sufficient to maintain similar cardiac responses to epinephrine in older hypertensive compared with young normotensive subjects. This balanced pattern of cardiac responses to epinephrine contrasts with the cardiac responses to isoproterenol, which are decreased in older hypertensive subjects (Fig. 4 and Ref. 18). One may speculate that isoproterenol has less presynaptic effects since plasma norepinephrine levels increase less (18) with isoproterenol than with epinephrine or that neuronal uptake of both norepinephrine and epinephrine is decreased in hypertensive subjects, leading to larger postsynaptic responses to epinephrine. It is less likely that 1-receptor-mediated inotropic responses (9) to epinephrine are enhanced in hypertensive subjects since arterial responses are suggestive for a decrease.
In conclusion, the present study indicates that in contrast to aging-induced blunting of cardiac responses to epinephrine in normotensive subjects, hypertensive subjects do not show this blunting. A decrease in -receptor responsiveness appears to be offset by sufficient changes in counterregulatory mechanisms such as the arterial baroreflex and neuronal uptake. As a result, at similar levels of sympathetic stimulation, older hypertensive subjects have enhanced cardiac responses that may contribute to progressive cardiac hypertrophy and dysfunction.
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GRANTS
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This study was supported by operating grant T-5340 from the Heart and Stroke Foundation of Ontario, Canada; F. Leenen holds the Pfizer Chair in Hypertension Research, an endowed chair supported by Pfizer Canada, the University of Ottawa Heart Institute Foundation, and the Canadian Institutes of Health Research.
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FOOTNOTES
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Address for reprint requests and other correspondence: F. H. H. Leenen, Hypertension Unit, Univ. of Ottawa Heart Institute, H360, 40 Ruskin St., Ottawa, ON, K1Y 4W7, Canada (e-mail: fleenen{at}ottawaheart.ca)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Copyright © 2007 by the American Physiological Society.
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ABSTRACT
METHODS
