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Gender differences on the effects of aging on cardiac and peripheral adrenergic stimulation in old conscious monkeys

¹Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07101-1709; ²Simian Conservation Breeding and Research Center, Incorporated, Manila 1231; and ³St. Luke's Medical Center, Quezon City 1102, Philippines

Submitted 2 December 2002 ; accepted in final form 4 April 2003

	ABSTRACT

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We examined the effects of gender and aging on cardiac and peripheral hemodynamic responses to -adrenergic receptor (-AR) stimulation in young (male = 5.9 ± 0.4 yr old and female = 6.5 ± 0.7 yr old) and old (male = 19.8 ± 0.7 yr old and female = 21.2 ± 0.2 yr old) conscious monkeys (Macaca fascicularis), chronically instrumented for measurements of left ventricular (LV) and arterial pressures as well as cardiac output. Baseline LV pressure, the first derivative of LV pressure (LV dP/dt), cardiac index, mean arterial pressure, total peripheral resistance (TPR), and heart rate in conscious monkeys were not different among the four groups. Increases in LV dP/dt in response to 0.1 µg/kg isoproterenol (Iso) were diminished (P < 0.05) in old males (+99 ± 11%) compared with young males (+194 ± 18%). In addition, the inotropic responses to norepinephrine (NE) and forskolin (FSK) were significantly depressed (P < 0.05) in old males. Iso-induced reductions of TPR were less (P < 0.05) in old males (–28 ± 2%) than in young males (–49 ± 2%). The changes of TPR in response to NE and FSK were also significantly attenuated (P < 0.05) in old males. However, the LV dP/dt responses to BAY y 5959 (15 µg · kg^–1 · min^–1), a Ca²⁺ channel promotor independent of -AR signaling, were not significantly different between old and young males. In contrast to results in male monkeys, LV dP/dt and TPR responses to Iso, NE, and FSK in old females were similar to those observed in young females. Thus both cardiac contractile and peripheral vascular dynamic responses to -AR stimulation are preserved in old female but not old male monkeys. This may explain, in part, the reduced cardiovascular risk in the older female population.

sympathetic nerves; nonhuman primates; cardiac function; catecholamine desensitization; vascular function; adenosine 3',5'-cyclic monophosphate

	METHODS

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Animals. Young males (YM; n = 14, aged 5.9 ± 0.4 yr), old males (OM; n = 8, aged 19.8 ± 0.7 yr), young females (YF; n = 7, aged 6.5 ± 0.7 yr), and old females (OF; n = 8, aged 21.2 ± 0.2 yr) monkeys (Macaca fascicularis) were studied. The monkeys were fed with a standard primate diet as previously described (2, 3). All of the young monkeys were born in captivity, thus enabling us to know their exact age. All old monkeys were feral animals captured between the ages of 5 and 7 yr old and had been kept in captivity for 12–15 yr at the Simian Conservation Breeding and Research Center (Manila, Philippines). The age at the time of capture was estimated from eruption of dentition, general appearance, sexual development, and body weight. All monkeys used in the present study had normal fasting blood sugars and were maintained in accordance with guidelines for the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Pub. No. 83-23, Revised 1996).

Implantation of instrumentation. The method of surgically implanting instrumentation has been previously described (2, 3). Briefly, the animals were tranquilized with ketamine hydrochloride (2–3 mg/kg im), anesthetized with thiamylal sodium (5–10 mg/kg iv), and maintained with isoflurane (1.0–2.0 vol/100 ml in oxygen). With the use of sterile surgical techniques, a left thoracotomy was performed at the fourth intercostal space. Tygon catheters were implanted in the descending aorta and left atrium for pressure measurements and administration of pharmacological agents. A miniature solid-state pressure gauge (Konigsberg Instruments; Pasadena, CA) was inserted into the left ventricle (LV) through an apical stab wound for the measurements of LV pressure and the first derivative of LV pressure (LV dP/dt) (n = 8 OM, 8 OF, 14 YM, and 7 YF). A Transonic flow probe (Ithaca, NY) with a diameter of 8–10 mm was placed around the root of the ascending aorta to measure the ascending aortic blood flow, i.e., cardiac output minus coronary blood flow (n = 8 OM, 8 OF, 11 YM, and 7 YF). The incision was closed in layers, and air in the chest was evacuated. All animals were allowed to recover for 10–14 days before experiments were initiated.

Hemodynamic measurements. Hemodynamic measurements were made when the monkeys were fully awake in their individual cages. A special swivel tether system (2, 27) was used to house both the wires and fluid-filled catheters, which were connected to the recording system. There were no signs indicating that the system affected the monkey's daily activities. Throughout the experiment, all animals remained healthy as evidenced by demeanor and normal appetite. Hemodynamic measurements were recorded on a digital multiple-channel recorder (PC216Ax, Sony Precision Technology; Tokyo, Japan) and then analyzed with a computerbased system (Notocord; Croissy, France). The catheters were connected to pressure transducers (Datex Ohmeda; Madison, WI) for measurements of aortic and left atrial pressures, which were calibrated in vitro against a mercury manometer. LV pressure measured by a miniature solid-state pressure gauge was cross-calibrated with aortic and left atrial pressure measurements. LV dP/dt was obtained by electronically differentiating the LV pressure signal. Cardiac output was measured using a volume Transonic flowmeter. Cardiac index (CI) was calculated as cardiac output divided by body surface area (BSA). BSA was calculated as 71.84 · (body weight)^0.425 · (height)^0.725 (7). Total peripheral resistance (TPR) was calculated as the quotient of mean aortic pressure and CI.

Protocol. The following pharmacological agents were administered through the left atrial catheter to investigate the effects of -AR stimulation on LV contractile function and peripheral vascular dynamics: isoproterenol (Iso; 0.02, 0.05, and 0.1 µg/kg), which stimulates both ₁- and ₂-AR; norepinephrine (NE; 0.1, 0.2, and 0.4 µg/kg), which stimulates - and -AR; forskolin (FSK; 25, 50, and 75 nmol/kg), which stimulates the catalytic unit of adenylyl cyclase; and BAY y 5959 (5, 10, and 15 µg · kg^–1 · min^–1), an L-type calcium channel promoter, which acts independently of the -AR signaling pathway. Except for BAY y 5959, all the agents were administered by bolus injection. The responses to Iso, NE, FSK, and BAY y 5959 were allowed to return to baseline values between doses. It was not possible to complete the protocol on all animals. Animals were excluded from data analysis if they did not go through the entire drug dose response. However, the smaller numbers of animals studied in some protocols were always a subset of the overall groups. The specific numbers for each protocol are included in RESULTS.

Blood sampling. Arterial blood samples were obtained for measuring baseline plasma concentrations of NE, epinephrine, and estradiol in the morning before feeding and administration of any agents. NE and epinephrine were measured with electrochemical detection using high pressure liquid chromatography (19). Estradiol was measured by a radioimmunoassay (13).

Histopathology. After completion of the in vivo experiments, the animals were euthanized by an overdose of pentobarbital sodium; the uterus and ovaries were removed from females for histopathological analyses. All samples were fixed with 10% formalin and paraffin. Sections were cut at 6 µm thickness and then stained with hematoxylin and eosin. Histopathology of the aorta was negative for atherosclerosis, as reported previously (2).

Statistics. All data are expressed as means ± SE. A repeated one-way ANOVA (SAS Institute; Cary, NC) was used to determine statistically significant differences among groups, followed by Student-Newman-Keuls test for post hoc comparison of means. The relation between the doses of Iso, NE, FSK, and BAY y 5959 was examined by regression analysis. Comparison of regression lines was performed by determining the significance of differences in the slope of the lines by the F-test. A value of P < 0.05 was taken as the minimal level of statistical significance. The hemodynamic values in Table 1 were averaged for each animal from multiple experiments and then averaged for the group. Therefore, the baseline values in the figures vary slightly, but insignificantly, from the pooled values in Table 1.

	RESULTS

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Baseline values in conscious monkeys. Baseline data including hemodynamic parameters and plasma levels of catecholamines in the YM, OM, YF, and OF groups of conscious monkeys are shown in Table 1. The body weights were lower in the female monkeys than in the male monkeys. Because of gender differences in body weight, cardiac output was indexed to BSA. There were no differences in LV dP/dt, mean arterial pressure, CI, TPR, and heart rate among the four groups. Plasma levels of both NE and epinephrine at rest were significantly elevated (P < 0.05) in the old monkeys compared with the young monkeys. In the OM group, plasma levels of NE were also higher (P < 0.05) than those in the OF group. The plasma estradiol levels were significantly higher (P < 0.05) in the YF group compared with the YM and OF groups.

Cardiac effects of sympathomimetic amines. Administration of Iso, NE, and FSK induced dose-dependent increases in LV dP/dt in all groups (Figs. 1 and 2). However, the increased LV dP/dt induced by Iso, NE, and FSK were attenuated (P < 0.05) in the OM group compared with the YM group. For example, Iso at a dose of 0.1 µg/kg increased LV dP/dt less (P < 0.05) in the OM (+99 ± 11%, n = 8) group than in the YM group (+194 ± 18%, n = 14) group (Fig. 3).

View larger version (47K): [in this window] [in a new window]   Fig. 1. Representative responses of left ventricular (LV) pressure and the first derivative of LV pressure (LV dP/dt) to isoproterenol at a dose of 0.1 µg/kg in a conscious young male monkey (A) and an old male monkey (B). The increase in LV dP/dt was markedly attenuated in the old monkey compared with the young monkey.

View larger version (27K): [in this window] [in a new window]   Fig. 2. Dose-response curves for absolute values of LV dP/dt are shown at baseline (0 dose) and with graded injections of isoproterenol (Iso; A), norepinephrine (NE; B), forskolin (FSK; C), and BAY y 5959 (D) in conscious young male, old male, young female, and old female monkeys. Values are means ± SE. Regression lines were fitted to the data. *P < 0.05 vs. the young group.

View larger version (28K): [in this window] [in a new window]   Fig. 3. Comparison of the percent change in LV dP/dt, mean arterial pressure, and heart rate for young and old male and female monkeys in response to Iso (0.1 µg/kg; A) and NE (0.4 µg/kg; B). The significant differences (*P < 0.05) are for increases in LV dP/dt, which were less in old male monkeys, and increases in heart rate in response to Iso and decreases in heart rate in response to NE, which were diminished in old male monkeys.

The response of LV dP/dt to NE at a dose of 0.4 µg/kg was less (P < 0.05) in the OM (+87 ± 10%, n = 8) group than in the YM (+150 ± 17%, n = 14) group (Fig. 3). The response of LV dP/dt to FSK at a dose of 75 nmol/kg was diminished (P < 0.05) in the OM (+71 ± 16%, n = 8) group compared with the YM (+144 ± 23%, n = 13) group. In contrast to male monkeys, LV dP/dt responses were similar in the OF and YF groups. For example, Iso (0.1 µg/kg), NE (0.4 µg/kg), and FSK (75 nmol/kg) increased LV dP/dt by 129 ± 15% (n = 7), 129 ± 24% (n = 6), and 134 ± 21% (n = 7) in the YF group and 125 ± 16% (n = 8), 114 ± 15% (n = 8), and 101 ± 12% (n = 7) in the OF group, respectively.

BAY y 5959 induced a dose-dependent increase in LV dP/dt in all groups. There were no differences between any of the groups (Fig. 2). For example, BAY y 5959 at an infusion dose of 15 µg · kg^–1 · min^–1 increased LV dP/dt by 86 ± 10%, 63 ± 6%, 70 ± 12%, and 77 ± 9% in the YM (n = 8), OM (n = 6), YF (n = 5), and OF (n = 7) groups, respectively.

The responses of mean arterial pressure and heart rate are compared along with LV dP/dt for Iso (0.1 µg/kg) and NE (0.4 µg/kg) in OM, YM, OF, and YF monkeys in Fig. 3. Mean arterial pressure changes were similar among the groups, but heart rate increased more in YM than in OM monkeys with Iso and decreased more in YM than in OM monkeys with NE.

Peripheral vascular effects of sympathomimetic amines. Administration of Iso and FSK decreased, whereas NE increased, TPR dose dependently in the YM group. However, the responses of TPR to these three agents were significantly attenuated (P < 0.05) in the OM group compared with the YM group. For example, Iso (0.1 µg/kg) decreased TPR significantly less (P < 0.05) in the OM (–28 ± 2%, n = 8) group than in the YM (–49 ± 2%, n = 11) group (Fig. 4). A representative example is shown in Fig. 5. Also, FSK (75 nmol/kg) induced a significantly less (P < 0.05) decrease in TPR in the OM (–10 ± 3%, n = 7) group than in the YM (–45 ± 2%, n = 8) group. NE (0.4 µg/kg)-induced TPR increases were also significantly less (P < 0.05) in the OM (+20 ± 9%, n = 7) group compared with the YM (+67 ± 8%, n = 10) group.

View larger version (22K): [in this window] [in a new window]   Fig. 4. Dose-response curves for absolute values of total peripheral resistance (TPR) are shown at baseline (0 dose) and with graded injections of Iso (A), NE (B), and FSK (C) in conscious young male, old male, young female, and old female monkeys. Values are means ± SE. Regression lines were fitted to the data. *P < 0.05 vs. the young group.

View larger version (22K): [in this window] [in a new window]   Fig. 5. Representative responses of aortic blood flow, mean flow, mean aortic pressure, and TPR to Iso at a dose of 0.1 µg/kg are shown in a conscious young male monkey (A) and an old male monkey (B).

In female monkeys, the responses of TPR to these three agents were similar among all groups. For example, Iso (0.1 µg/kg) and FSK (75 nmol/kg) reduced TPR by –37 ± 3% (n = 7) and –26 ± 4% (n = 7) in the YF group and –36 ± 2% (n = 8) and –34 ± 5% (n = 6) in the OF group, respectively. NE (0.4 µg/kg) increased TPR similarly in the YF (38 ± 10%, n = 7) and OF (25 ± 11%, n = 8) groups.

Histopathology. The YF ovaries were well developed, and multiple large follicles were observed. In addition, the uterus had a well-developed endometrial lining. OF monkeys had an atrophic uterus, a poorly developed endometrium, an increased stroma, and indurated ovaries. Finally, a few atretic secondary follicles and a small number of primary follicles were found in OF monkeys. There was no evidence for atherosclerosis in aortic samples examined histologically.

	DISCUSSION

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Even though there is an important inverse correlation between aging and -adrenergic responsiveness, almost no data are available in determining whether this also occurs in older female subjects or experimental animals. The major finding of the present study was that cardiac contractile and peripheral vascular dynamic responses to Iso, NE, and FSK were not diminished in conscious OF compared with YF monkeys, in contrast to the well-documented -AR desensitization with aging in older male subjects and animals (9, 30), including the data in OM monkeys in the present investigation. On the basis of these findings, we conclude that gender is a key factor involved in -AR desensitization with increased age. In view of NE's peripheral vascular action mediated through -adrenergic receptors, it is likely that -adrenergic responses are also desensitized in OM monkeys, consistent with our prior findings (3). In the present investigation, we also utilized a calcium channel promotor, BAY y 5959, to induce an inotropic effect that is independent of -adrenergic signaling by either the -AR or the catalytic unit of adenylyl cyclase. Clearly, there were no differences in LV dP/dt responses to any doses of the calcium channel promoter among the OM, YM, OF, and YF monkeys, suggesting that the -adrenergic signal transduction pathway is affected primarily. In addition, we also found that NE levels were increased less in the OF monkeys compared with those in the OM monkeys. The increased level of circulating catecholamines, more prominent in OM than OF monkeys, is consistent with chronically enhanced sympathetic tone. Because chronically enhanced -AR stimulation induces desensitization of the -AR (8, 12, 17), these differences in levels of circulating catecholamines can explain, in part, the desensitization in old monkeys and, conversely, the preservation of -AR responsiveness in OF monkeys. However, the cellular mechanisms underlying these differences are not established. Indeed, simple -AR downregulation may not be the answer in view of the divergent results already in the literature with several studies finding no decrease in -AR density, examples of which are cited here (6, 15, 20, 25). More likely, there are several genomic and protein mechanisms involved. In addition, it is possible that the mechanism of desensitization may reside, in part, at the level of the catalytic unit of adenylyl cyclase, based on almost identical degrees of desensitization in response to FSK versus Iso. This concept is further supported by a previous study by O'Connor et al. (23), which suggested that the defect may reside at the level of the adenylyl cyclase catalytic unit.

Relatively little has been done on gender differences in -adrenergic signaling with age. Consistent with our results, a human study (21) has shown that muscle sympathetic nerve activity at rest, both in terms of burst incidence and burst frequency, was lower in older women compared with older men. Furthermore, lower muscle sympathetic nerve activity in younger women compared with younger men was also observed in that study (21). In the present study, although it was not statistically different, the responsiveness to sympathomimetic amines at the highest levels tended to be reduced in YF compared with YM monkeys. A recent study by Turner et al. (29) indicated that responses to Iso were diminished in older female subjects but less than in elderly males and that the responses in younger females were suppressed compared with younger males. A companion study by Spina et al. (28) found that there are gender differences in response to sympathomimetic amines with exercise training.

Parasympathetic regulation is also altered with aging (10, 14, 22). We did not determine whether parasympathetic responses were affected by aging in this study, which could have modulated the sympathetic effects, particularly for heart rate responses. We did observe previously that vascular responses to acetylcholine were blunted in old monkeys, but this was due primarily to depressed vascular endothelial function (2).

Although the mechanism that is responsible for the difference between the OM and OF groups was not determined, it is well known that menopause constitutes a significant cardiovascular landmark in terms of physiology as well as pathology. In the present study, the histopathological findings indicate that the uterus of OF monkeys is in a state of atrophy and the ovaries are indurated. Moreover, only a few atretic secondary and primary follicles were found. Additionally, the blood estradiol level was significantly decreased (Table 1). It is also known that the OF monkeys were infertile for several years. These data, taken together, indicate that these OF monkeys were postmenopausal, consistent with previous reports (18, 24), and despite this -adrenergic desensitization was not observed.

Increased sympathetic tone and circulating catecholamines are inversely related to cardiac function and survival in patients with heart failure (5, 11). Therefore, it is conceivable that in even older animals and in very aged humans, when deterioration in cardiac function occurs independently of primary heart disease, this may occur, in part, as a consequence of chronically enhanced -adrenergic signaling, as it does in transgenic animals with overexpression of -AR, G_s, or protein kinase A (1, 8, 12, 17). However, in older but not senescent humans, myocardial systolic function is not depressed, suggesting the possibility that chronically enhanced sympathetic tone is a compensatory mechanism that plays a role in maintaining cardiac function with aging.

	DISCLOSURES

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This study was supported in part by National Institutes of Health Grants HL-59139, HL-33107, HL-33065, HL-69020, HL-62442, HL-65182, HL-65183, and AG-14121 and by American Heart Association Grant 0030125N.

	FOOTNOTES

 

Address for reprint requests and other correspondence: S. F. Vatner, Chair, Dept. of Cell Biology and Molecular Medicine, Univ. of Medicine and Dentistry of New Jersey, New Jersey Medical School, PO Box 1709, 185 S. Orange Ave., Medical Science Bldg., G609, Newark, NJ 07101-1709 (E-mail: vatnersf{at}umdnj.edu).

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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