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Hypertension Unit, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
Submitted 4 August 2004 ; accepted in final form 23 December 2004
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ABSTRACT |
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-receptor-mediated responses. To test this concept, nine young (mean 29 ± 2 yr) and eight older (mean 61 ± 2 yr) healthy subjects were infused on three different study mornings with epinephrine at increasing rates either alone or combined with desipramine to eliminate differences in neuronal uptake or with desipramine and trimetaphan to induce ganglionic blockade and thereby also eliminate differences in arterial baroreflex activity. Epinephrine caused the expected rate-related increases in systolic blood pressure, heart rate, stroke volume, ejection fraction, and cardiac index. Except for the systolic blood pressure, the extent of the changes was similar in young and older subjects. After desipramine, cardiac responsiveness to epinephrine was markedly enhanced, although more (P < 0.01) in young vs. older subjects for heart rate and cardiac index (+14 vs. 7 beats/min and +1.6 vs. 1.1 l·min–1·m–2, respectively, at 20 ng·kg–1·min–1). Combined with desipramine and trimetaphan, cardiac responses to epinephrine were further enhanced, again more (P < 0.01) in young subjects, resulting in large differences in heart rate and ejection fraction increases (+29 vs. 17 beats/min and +14 vs. 7%, respectively, at 20 ng·kg–1·min–1). Here, we show that "healthy aging" in humans is associated with decreased cardiac responsiveness to the -agonist epinephrine; however, this decrease can be balanced by concomitant decreases in buffering of these responses by neuronal uptake and the arterial baroreflex.
age; baroreflex; -receptors; desipramine; trimetaphan
-adrenoceptor stimulation. Multiple mechanisms appear to be involved, including downregulation and decreased agonist binding of 1-receptors, uncoupling of 2-receptors, and abnormal G protein-mediated signal transduction (27). However, a concomitant decrease in activity of other control systems may offset this blunted responsiveness. For example, arterial baroreflex control of the heart also decreases with aging (13, 25). Infusion of the -agonist isoproterenol activates the baroreflex, which blunts the cardiac responses to the -agonist (25). The gain of the arterial baroreflex decreases with aging, and the resulting decreased buffering in older subjects may minimize the difference in cardiac responses to a -agonist between young and older subjects. Indeed, in several studies, young and older subjects exhibited fairly similar cardiac responses to infusion of a -agonist on its own, such as isoproterenol (15, 25) or dobutamine (20). In contrast, after ganglionic blockade to eliminate differences in baroreflex control, young subjects clearly showed larger cardiac responses to isoproterenol compared with older subjects (25).
Nearly all studies on the interaction of age and -adrenoceptor-mediated responses have used the synthetic agonist isoproterenol. In the intact organism, several potentially important differences exist between isoproterenol and the endogenous catecholamines, which may lead to different cardiovascular responses. Indeed, our group reported that, with concomitant ganglionic blockade, cardiac responses to isoproterenol (25) but not to epinephrine (26) were decreased in older compared with young subjects. Both endogenous agonists, but not isoproterenol, have substantial pre- and postsynaptic 
-receptor agonistic activity, which may decrease with age (2, 18) and influence the autonomic and hemodynamic responses. In addition, in contrast to isoproterenol, endogenous catecholamines are taken up by the adrenergic nerve terminals (5). This uptake represents one of the major mechanisms for removal of the endogenous agonists from the synaptic cleft, particularly in the heart (6). Decreased uptake leads to higher effective concentrations in the synaptic cleft at similar rates of endogenous release or of exogenous infusion of an endogenous agonist; however, it will not affect the concentrations of isoproterenol. Cardiac transplant patients have no cardiac neuronal uptake and, compared with control patients, show increased cardiac responses to intravenous infusion of epinephrine but not of isoproterenol (10, 17, 23, 24). Animal studies have shown a decrease in cardiac neuronal uptake of norepinephrine with aging (1, 2). In humans, fractional extraction of radiolabeled norepinephrine from plasma by the heart was less in older men (70 vs. 82% in the young subjects), consistent with a decreased uptake of norepinephrine into cardiac sympathetic nerves (8). Transcardiac extraction of epinephrine is less (
50%), and, in a study with a modest sample size (n = 5–6/group), desipramine similarly lowered cardiac extraction of epinephrine in young and older men, suggesting that neuronal uptake of epinephrine in the heart "was not changed materially by aging" (7). Whether functional responses to these two endogenous agonists parallel these kinetic analyses has not yet been studied. Considering the above-described different impacts of aging on cardiac responses to isoproterenol vs. epinephrine, we postulated that a functionally relevant decrease in cardiac epinephrine uptake occurs with aging in humans and that such a decrease in neuronal uptake of epinephrine may balance the decrease in -receptor-mediated responses. To test this hypothesis, we evaluated the effects of age on cardiac responses to intravenous infusion of epinephrine at increasing rates alone, combined with infusion of desipramine to eliminate possible differences in neuronal uptake, or combined with desipramine as well as trimetaphan to induce ganglionic blockade to also eliminate differences in arterial baroreflex activity.
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METHODS |
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Experimental protocol. The study was conducted on four study mornings at least 4 days apart. On the first morning, a run-in study was performed to familiarize the subjects with the experimental procedures and personnel. On each study morning, after a standardized liquid breakfast, the subjects remained supine until completion of the study. Two indwelling intravenous catheters were inserted, one in each forearm. A blood pressure (BP) cuff was applied to the arm not used for infusion of the drugs, and BP was measured automatically with a Criticon Dinamap 8100 (Johnson & Johnson, Tampa, FL). ECG electrodes were attached to measure heart rate by a Tektronic 414 monitor (Tektronic, Beaverton, OR).
On the first regular study morning, after a rest period of at least 60 min, infusion of epinephrine was started at 20 ng·kg–1·min–1, and the rate was increased to 40, 80, and 120 ng·kg–1·min–1 or until the heart rate increased by 20–25 beats/min. Each rate of infusion lasted 8 min. This duration of infusion is sufficient to obtain steady-state responses (19, 22). On the second study morning, after a rest period of at least 30 min, infusion of desipramine was started so that 0.5 mg/kg was administered over 30 min (6, 12). Subsequently, after a 10-min period to obtain new baseline measurements, infusions of epinephrine were performed as above except that the starting rate was lowered to 10 ng·kg–1·min–1. On the third study morning, after the infusion of desipramine, subjects were infused 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 (25, 26). The rate was not increased further if the systolic BP decreased below 90 mmHg. In the young group, one subject continued at 50 µg·kg–1·min–1 and eight at 100 µg·kg–1·min–1; in the older group, two subjects continued at 50 µg·kg–1·min–1 and six at 100 µg·kg–1·min–1. This rate continued until the end of the infusion of epinephrine.
Heart rate and BP were measured every 2 min for 10-min periods before the start of infusion of the agonist 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 each resting period and at the end of each infusion rate. Venous blood samples for plasma concentrations of catecholamines were drawn at each baseline and at the ends of the second and highest infusion rates of epinephrine.
Echocardiography. Echocardiograms were obtained in the supine position with a Toshiba two-dimensional 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 (21). All echocardiograms were obtained by the same sonographer with the subject in the same position, in the same intercostal area, and in the same LV area, just below the tip of the ventral leaflets. The following parameters were measured or calculated: LV end-diastolic and end-systolic dimensions. The end-diastolic and end-systolic volumes were estimated by the cube function formula (3). The stroke volume index, cardiac index, and LV ejection fraction were calculated accordingly.
Assay for plasma catecholamines. Plasma samples were stored at –70°C, and plasma catecholamine concentrations were determined by high-performance liquid chromatography with electrochemical detection. The detection limit was 30 pg/ml for norepinephrine and 10 pg/ml for epinephrine. Recovery for the alumina extraction was the same, 64%, for the two catechols and the internal standard dihydroxybenzylamine. The recovery calculated for spiked samples was 100%. Interassay variation was 6 and 10%, whereas intra-assay variation was 5 and 6% for norepinephrine and epinephrine, respectively.
Analysis of data. Baseline hemodynamic parameters in the two groups of subjects were compared by unpaired t-test. The dose-response curves were analyzed by multivariate general linear model. After we tested the homogeneity of slopes, analysis of covariance was used to compare the group effect adjusted for the covariate (infusion rate). Variables with nonlinear responses were analyzed by ANOVA with repeated measures. 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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Desipramine increased BP and heart rate similarly in the two groups and caused only minor changes in LV function. This pattern of changes was similar for the two study days with desipramine, and the increases in BP persisted throughout the morning on the study day with desipramine alone.
Infusion of trimetaphan after desipramine caused a different pattern of change in young vs. older subjects. In young subjects, trimetaphan significantly lowered total peripheral resistance and markedly increased cardiac index with little change in BP. In the older subjects, trimetaphan caused a smaller decrease in total peripheral resistance, no change in cardiac index, and a clear decrease in (particularly systolic) BP. In the young subjects, the increase in cardiac index was due to a marked increase in heart rate, whereas LV volumes and stroke volume were decreased. In the older subjects, LV volumes and stroke volume decreased similarly, but heart rate showed a less marked increase compared with the young group.
Resting plasma norepinephrine was significantly higher in the older vs. young subjects on all three study days. Infusion of desipramine did not significantly affect resting plasma norepinephrine, whereas subsequent infusion of trimetaphan resulted in significant decreases of plasma norepinephrine in both groups. Resting plasma epinephrine tended to be higher in the older subjects. Infusion of desipramine and trimetaphan did not change plasma epinephrine levels.
Cardiac effects of epinephrine. Epinephrine alone caused the expected dose-related increases in systolic BP, heart rate, stroke volume, and cardiac index (P < 0.01 for all). The increase in stroke volume was related to minor increases in LV end-diastolic volume, a significant decrease in LV end-systolic volume, and therefore an increase in ejection fraction. The extent of the increases in heart rate (Fig. 1), stroke volume (Table 3), ejection fraction (Fig. 2), and cardiac index (Fig. 3) did not differ significantly between the young and older subjects. Only the increase in systolic BP (Table 3) was significantly less in the older vs. young subjects.
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Combined with desipramine and trimetaphan, cardiac responses to epinephrine were further enhanced, again more in young vs. older subjects, resulting in larger differences in the increases in heart rate and now also in ejection fraction. With combined blockade, epinephrine at 20 ng·kg–1·min–1 increased heart rate (Fig. 1) by 29 ± 3 vs. 17 ± 3 beats/min in young vs. older subjects, respectively (P < 0.01), and ejection fraction (Fig. 2) by 14 ± 2 vs. 7 ± 1% (P < 0.01). Both LV end-diastolic and end-systolic volumes now decreased in parallel (Table 3), although significantly (P < 0.01) more in young vs. older subjects (Table 3), whereas cardiac index (Fig. 3) now only tended to increase more in young vs. older subjects (by 1.3 ± 0.5 vs. 0.9 ± 0.3 l·min–1·m–2 at 20 ng·kg–1·min–1).
Epinephrine alone at infusion rates of 40 and 120 ng·kg–1·min–1 caused modest increases in plasma norepinephrine in both groups of subjects (Table 4). When combined with desipramine and trimetaphan, only minor changes were found. Infusion of epinephrine caused the expected dose-related increases in plasma epinephrine (Table 4). Plasma epinephrine concentrations tended to increase more in the older subjects after desipramine and in both groups of subjects when combined with desipramine and trimetaphan. The extent of the increases in plasma epinephrine levels showed only minor differences between young and older subjects.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Cardiac responses to epinephrine.
The cardiovascular effects of epinephrine in humans have been well documented (11, 14). The present study confirms these effects, showing rate-related increases in systolic BP, heart rate, stroke volume, ejection fraction, and cardiac index. These hemodynamic effects by intravenous infusion of epinephrine represent the composite of several mechanisms. We previously demonstrated that 2-receptors play a major role in the increase in heart rate caused by epinephrine, whereas effects on LV function appear to be mediated primarily via 1-receptors (16). Besides direct postsynaptic 1- and 2-receptor stimulation, presynaptic 2-receptor stimulation results in enhanced norepinephrine release and an increase in plasma norepinephrine (9, 19). On the other hand, activation of the arterial baroreflex by an increase in BP blunts the extent of the cardiac responses, particularly of heart rate and to a lesser extent of LV function (26). The extent and duration of these effects are influenced by the effectiveness of neuronal uptake, which, particularly in the heart, controls synaptic cleft concentrations of norepinephrine and, to a less extent, of epinephrine (4, 6–8). The present study provides new insights into the relative role of some of these mechanisms.
Ganglionic blockade by trimetaphan eliminates the arterial baroreflex buffering, which would enhance cardiac responses to epinephrine, whereas the resulting low sympathetic firing rates decrease the extent of presynaptic stimulation by epinephrine, leading to less cardiac and systemic norepinephrine release (9, 26) and thereby lower cardiac responses. On balance, removal of the inhibitory arterial baroreflex effects appears to predominate because, with ganglionic blockade, the cardiac responses to epinephrine become markedly enhanced (26).
Desipramine causes blockade of norepinephrine and epinephrine neuronal (re-)uptake (6); therefore, one may expect increased responses to exogenously administered epinephrine. Indeed, cardiac responses to epinephrine after desipramine were substantially enhanced with clear leftward shifts and higher "maxima" of the dose-response relationships for heart rate, ejection fraction, stroke volume, and cardiac index. On the other hand, desipramine causes inhibition of central sympathetic outflow (6), and the resultant lower sympathetic firing rate makes presynaptic stimulation less effective, likely explaining the absent increase in plasma norepinephrine by epinephrine after desipramine. Addition of trimetaphan to the desipramine effects will further eliminate sympathetic activity and indeed significantly lowered plasma norepinephrine, but it will also remove vagal regulation of cardiac function. In this setting, one may see the postsynaptic effects of epinephrine per se. The results further demonstrate the leftward shifts in the dose-response curves with marked increases, particularly in heart rate at low infusion rates, likely reflecting the absent buffering of vagal tone.
Aging and cardiac responses to epinephrine.
Similar to the findings of our previous study (26), infusion of epinephrine caused fairly similar increases in heart rate, ejection fraction, stroke volume, and cardiac index in the young and older subjects. Only the increase in systolic BP was significantly less in the older group. Desipramine enhanced cardiac responses to epinephrine in both age groups, but this enhancement was significantly more pronounced in the young subjects for heart rate, LV end-diastolic volume, and cardiac index. These differences appeared at similar increases in plasma epinephrine concentrations in the two age groups. With combined desipramine and ganglionic blockade, differences between the two age groups became larger for heart rate and now also became apparent for ejection fraction. Together, these findings therefore suggest that decreases in both neuronal uptake and arterial baroreflex buffering offset the intrinsically decreased cardiac responsiveness to epinephrine in older subjects. At the particular age of the subjects studied (mean age of 61 yr), the impact of the age-induced changes in these mechanisms appears to offset each other. However, the age of onset of these mechanisms may vary, and the extent of the change may be influenced by further aging. The balance may therefore be different in younger (e.g.. 40–60 yr old) or older (e.g., 70–90 yr old) subjects.
Larger cardiac responses to epinephrine in young vs. older subjects emerged after blockade of neuronal uptake by desipramine. One may conclude from this finding that aging decreases neuronal uptake of epinephrine and that therefore at the same infusion rate higher concentrations of epinephrine in the synaptic cleft compensate for an aging-induced decrease in postsynaptic -receptor responsiveness. As such, this would be a different conclusion than the one reached by Esler et al. (7). The present study reflects a functional evaluation of cardiac responses, which particularly for heart rate can be considered very accurate and sensitive. In contrast, the study by Esler et al. (7) was a kinetic study in small groups of subjects and may have missed modest but functionally important differences in neuronal uptake between young and older subjects. Alternatively, this finding may reflect a decrease in aging-induced neuronal uptake of norepinephrine, demonstrated by Esler et al. (8), if norepinephrine release as a result of presynaptic -receptor stimulation by epinephrine plays a major role in the cardiac responses to epinephrine.
Previously, our group (26) showed that ganglionic blockade alone does not result in a differential cardiac response to epinephrine in young vs. older subjects. This and our previous study combined suggest that removal of the different buffering by the arterial baroreflex alone does not reveal significant differences in cardiac responsiveness to epinephrine by age but does so after blockade of neuronal uptake. It is not readily apparent why this may be so.
Limitations of study. Infusions of tritiated epinephrine at tracer doses together with the biologically active doses would have enabled correlations between the effects of aging on functional responses and on actual epinephrine kinetics. However, whole body kinetics do not reflect the heart (4, 7). Repeated invasive approaches would be needed to obtain specific cardiac kinetic data for the three study days, which is ethically difficult to justify. Trimetaphan was infused at rates up to 100 µg·kg–1·min–1. The actual degree of ganglionic blockade was not assessed, but the significant decreases in resting plasma norepinephrine and BP, as well as the increases in heart rate, are consistent with substantial ganglionic blockade.
In conclusion, the present study indicates that "healthy aging" in humans is associated with decreased cardiac responsiveness to the -agonist epinephrine, but this decrease can be offset, even balanced, by concomitant decreases in buffering of these responses by neuronal uptake and the arterial baroreflex. It is tempting to speculate that aging-associated changes in these cardiovascular regulatory mechanisms do not happen to occur as co-phenomena but represent an integrated response to maintain cardiovascular homeostasis, particularly in response to stress.
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GRANTS |
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FOOTNOTES |
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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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REFERENCES |
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-1 vs. nonselective -blockade. Clin Pharmacol Ther 43: 519–528, 1988.[ISI][Medline]
1- versus nonselective -blockade. Clin Pharmacol Ther 64: 522–535, 1998.[CrossRef][ISI][Medline]
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