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Am J Physiol Heart Circ Physiol 289: H2120-H2125, 2005. First published July 1, 2005; doi:10.1152/ajpheart.01113.2004
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Naloxone does not influence cardiovascular responses to mild mental stress in postmenopausal women

Brigitte Litschauer,1 Georg Schaller,2 and Michael Wolzt2

1Center of Physiology and Pathophysiology, 2Department of Clinical Pharmacology, Medical University Vienna, Vienna, Austria

Submitted 3 November 2004 ; accepted in final form 9 May 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The interaction between central opioid activity, sex hormones, and the cardiovascular reactivity to stress is unknown. Twenty-eight healthy postmenopausal women, 16 without, and 12 with hormone replacement therapy (HRT) participated in this randomized, double-blind, cross-over study. The opioid receptor antagonist naloxone or placebo was administered intravenously on 2 different days and mild mental stress was induced by the Stroop Color-Word Test. Cardiovascular responses were assessed noninvasively by impedance cardiography. Stress significantly increased stroke volume, cardiac output, blood pressure, and heart rate, which was not influenced by opioid receptor blockade. Whereas naloxone increased cortisol plasma concentrations irrespective of HRT status, luteinizing hormone concentrations, which were higher in non-HRT compared with HRT women, were increased by naloxone in women with HRT only. These data suggest that the opioidergic tone of the hypothalamus-pituitary-adrenal axis persists in postmenopausal women, irrespective of HRT use, while the opioidergic tone on the hypothalamus-pituitary-gonadal axis seems to depend on an estrogenic milieu. Naloxone does not alter cardiovascular mental stress reactions in postmenopausal women independent of their hormone substitution status.

hormone replacement therapy; reactivity; luteinizing hormone; cortisol

THE INCIDENCE OF CARDIOVASCULAR diseases (CVD) is lower in premenopausal women compared with men, but this difference is no longer apparent after menopause. While large-scaled randomized trials (37, 42) failed to observe a reduction of cardiovascular events or indicated increased risk for CVD in women on hormone replacement therapy (HRT), several studies suggest a CVD risk reduction (5, 35) and a blood pressure-lowering effect (26, 36) of estrogen or estrogen plus progestin HRT in postmenopausal women. Thus HRT and its impact on the cardiovascular system of women are under debate.

Cardiovascular responses to mental stress are thought to contribute to the risk for hypertension and coronary atherosclerosis (21). Studies suggest that estrogens also modulate cardiovascular functions during stressful encounters, as premenopausal women are less reactive to psychosocial stressors compared with postmenopausal women and men (3, 31, 33) and estrogen treatment blunts pressor and neuroendocrine responses in postmenopausal women (20, 24, 27, 40). Thus an increased reactivity to mental stress may contribute to the risk of cardiovascular morbidity and mortality after menopause.

Endogenous opioids have been implicated in many regulatory functions. Studies have suggested a dampening role of the opioidergic system on cardiovascular stress responses. Activated by mental stress the central opioidergic system is supposed to exert a phasic inhibition on the hypothalamic-pituitary-adrenal (HPA) and the hypothalamo-sympathetic axis, as the nonselective opioid antagonist naloxone enhances catecholamine and cardiovascular responses to mental stress (7, 18, 25, 28). Furthermore, a tonic inhibitory action of central {beta}-endorphin on pituitary proopiomelanocortin (POMC)-related peptides via inhibition of corticotropin-releasing hormone (CRH) release was assumed from increases in plasma adrenocorticotropin (ACTH) and {beta}-endorphin after naloxone infusion (4, 10). Likewise, endogenous opioid peptides, particularily {beta}-endorphin, play a major role in the regulation of the reproductive axis through a tonic inhibitory influence on gonadotropin-releasing hormone (GnRH) secretion (12, 14), as evidenced by a significant increase in circulating luteinizing hormone (LH) in response to naloxone. The reduction in estradiol as a result of both menopause and oophorectomy appears to be associated with a decline of the inhibitory opioid control on LH secretion, as opioid receptor inhibition by naloxone fails to induce an LH response in postmenopausal women (32). This can be restored by HRT (13, 14). Furthermore, cerebrospinal fluid {beta}-endorphin level, supposed to reflect central secretion, is also lower in postmenopausal women compared with premenopausal women (29).

Whereas these studies present compelling evidence for a link between central opioid activity, the hypothalamic-pituitary-gonadal (HPG) axis, and the cardiovascular system, the putative interactions between estradiol, endogenous opioid activity, and cardiovascular regulation are yet unknown. The mechanisms by which estrogen provides protection against the development of CVD in women are not well defined. Besides improvement of microvascular reactivity and endothelial function (22), direct influences on the autonomic nervous system have been reported (9, 26, 36, 39). We tested the hypothesis that estrogen may dampen cardiovascular responses to mental stress via an enhancement of central phasic opioidergic inhibition. To address this question, the effect of the opioid receptor antagonist naloxone on hemodynamic responses to mental stress was assessed in postmenopausal women with or without HRT. Furthermore, LH and cortisol serum concentrations were measured to characterize naloxone effects on the HPG and HPA axis.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study protocol was approved by the Ethics Committee of the Faculty of Medicine, University of Vienna and complies with the Declaration of Helsinki including current revisions and the Good Clinical Practice guidelines.

Subjects. Subjects were recruited by newspaper advertisement. After informed consent was given, 28 healthy postmenopausal women, aged 50 to 63 yr, 16 without (non-HRT), and 12 with stable HRT for at least 6 mo were enrolled in this randomized, double-blind, cross-over study. All women were without additional medications, including "over-the-counter" drugs except for HRT, which consisted of transdermal or oral estradiol (estradiol-hemihydrate, -valeriate) and gestagen combination therapies. Prestudy screening included a medical history and physical examination, blood chemistry, hormone analysis, urinalysis, and urine drug screening. Inclusion criteria were natural menopause for at least 2 yr, absence of major medical condition, no history or signs of arterial hypertension, major disorder in lipid metabolism or other cardiovascular risk factors, a body mass index (BMI) between 18 and 30 kg/m2, and absence of psychiatric illnesses and past or present drug addiction. At prestudy screening, all women had serum follicle-stimulating hormone (FSH) levels >40 IU/l and non-HRT women estradiol levels <75 pmol/l.

Study protocol. Women were randomized to receive intravenous infusions of naloxone (0.1 mg/kg over 10 min, Narcanti, Du Pont Pharma, Bad Homburg, BRD) or PSS as placebo on 2 different days with a wash-out period of 7–14 days. The dosage of naloxone was selected to inhibit hormonal and hemodynamic opioid actions in the absence of side effects (25). Testing was identical on the 2 study days (Fig. 1). Electrodes for impedance cardiography and a blood pressure cuff for monitoring were attached and subjects were seated in a comfortable chair. A needle was inserted into an antecubital vein for drug infusion and blood sampling. After a 20-min resting period (baseline 1), naloxone or placebo was infused over 10 min. After another 10-min resting period (baseline 2), the Stroop Color-Word Test lasting 10 min was started, followed by another 10-min resting period (baseline 3). Venous blood samples for quantification of LH and cortisol were drawn after each baseline and after the Stroop Color-Word Test, respectively.



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  		Fig. 1. Study design. Subjects received naloxone and placebo on 2 different trial days following a randomized cross-over protocol. BP, blood pressure recordings; LH, luteinizing hormone.

 
Mental stress induction. The Stroop Color-Word Test involves the components decision making and time pressure and was chosen because it increases blood pressure and heart rate (HR) at repeated assessments without learning effects or tolerance and is not biased by gender. For the first 5 min, color words in incongruent colors were presented on a computer screen with incremental speed (from 0.6 to 1.0 words/s). Subjects had to name the color of the word. During the following 5 min, a color word appeared with or without a simultaneous sound (constant speed: 0.7 words/s). Subjects had to read the word when it appeared together with the sound or otherwise name the color of the word.

Cardiovascular monitoring. Systolic (SBP) and diastolic blood pressure (DBP) were measured at 2-min intervals using an automatic device (SpaceLabs 90207). HR and stroke volume (SV) were measured using an impedance cardiograph [Ambulatory Monitoring System (AMS): Vrije Universiteit Amsterdam] (41). Cardiac output (CO) was calculated by multiplying HR x SV. Total peripheral resistance (TPR) was calculated as mean arterial pressure/CO x 80 (dyn·s·cm–5).

Laboratory tests. Laboratory tests were carried out according to standard procedures at the Clinical Institute of Medical and Chemical Laboratory Diagnostics, Allgemeines Krankenhaus Wien. LH and cortisol serum concentrations were measured in duplicate using immunoassays (Biosource Europe; Orion Diagnostics).

Data reduction and analyses. Statistical analyses were performed with BMDP statistical software (Cork, Ireland). For all cardiovascular parameters, mean values were calculated for data obtained during the different 10-min observation periods, starting 10 min before drug infusion. Demographic variables were compared by Student’s t-test. Cardiovascular parameters were analyzed by repeated-measures ANOVA using treatment (naloxone vs. saline) and task effects (Stroop vs. baseline 1) as within-subject factors and group (HRT vs. non-HRT) as between-factor grouping variable. LH and cortisol serum concentrations were analyzed by ANOVA using treatment (naloxone vs. saline) and time (baseline 1, baseline 2, Stroop, baseline 3) as within-subject factors and group (HRT vs. non-HRT) as between-factor grouping variable. Where appropriate, simple effect tests were conducted for significant main effects or interaction effect terms. For variables demonstrating significant task effects, reactivity scores were computed by subtracting baseline 1 values from task values and ANOVA computed separately for each reactivity score with factors of treatment (naloxone vs. saline) and group (HRT vs. non-HRT). P < 0.05 was considered statistically significant. Values are expressed as means ± SD unless indicated otherwise.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Naloxone was well tolerated and no adverse reactions were reported during the study.

Sample characteristics. All women had normal laboratory findings, and basal levels of LH, FSH, estradiol, and progesterone were within the normal range of postmenopausal women (Table 1). The two groups were similar regarding age, weight, height, BMI, and time menopausal. As expected, HRT women had significantly higher estradiol- and lower FSH-serum levels compared with non-HRT women. Cardiovascular parameters were comparable between groups (Table 2).


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  		Table 1. Sample characteristics

 

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  		Table 2. Baseline cardiovascular measures

 
LH responses. ANOVA demonstrated a significant group (F = 10.4, P < 0.003) and drug (F = 8.4, P < 0.01) effect on LH (Fig. 2). LH serum concentrations were higher in non-HRT than in HRT women. Post hoc analyses showed that naloxone induced a significant LH increase post Stroop (P < 0.02) and post baseline 3 (P < 0.005) in HRT women, but not in non-HRT women, compared with placebo.



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  		Fig. 2. Means ± SE of LH values in women without hormone replacement therapy (HRT; non-HRT, n = 16) and with HRT (n = 12) during placebo (saline) and naloxone infusion. **t = 3.71, P < 0.005. *t = 2.82, P < 0.02 saline vs. naloxone for HRT women.

 
Cortisol responses. ANOVA on cortisol serum concentrations resulted in a significant drug (F = 12.2, P < 0.002) and time effect (F = 10.1, P < 0.0001) and drug x time interaction (F = 5.6, P < 0.002) but no group effect (Fig. 3). Post hoc analyses showed a decline in cortisol from baseline 1 to baseline 2 on both days, compatible with the well-established circadian rhythm of cortisol release. Following placebo, cortisol levels were unchanged after baseline 2, whereas they increased after naloxone infusion and were significantly higher in HRT and non-HRT women after Stroop (F = 15.2, P < 0.001) and baseline 3 (F = 13.5, P < 0.001) compared with placebo.



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  		Fig. 3. Means ± SE of cortisol values in women without HRT (non-HRT, n = 16) and with HRT (n = 12) during placebo (saline) and naloxone infusion. *t > 3.9, P < 0.001 saline vs. naloxone.

 
Cardiovascular reactivity. Analyses of order effects on baseline 1 values revealed no significant differences when saline was administered during the first vs. the second visit.

Naloxone had no effect on resting cardiovascular parameters in women with or without HRT. Mental stress significantly increased SBP, DBP, HR [all F values (1,26) > 30, P < 0.0001], CO [F value (1,26) = 12.15, P < 0.002], and SV [F values (1,26) = 4.71, P < 0.05], while TPR was unchanged (Fig. 4). This cardiovascular stress reaction was not different between groups and was not affected by naloxone as indicated by similar reactivity scores (Table 3). Furthermore, adjustment of data using physical characteristics or baseline cardiovascular measures as covariates did not influence the statistical analysis.



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  		Fig. 4. Means ± SE of cardiovasular measures in women without HRT (non-HRT, n = 16) and on HRT (n = 12) during placebo (saline) and naloxone infusion. SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; SV, stroke volume; CO, cardiac output; TPR, total peripheral resistance.

 

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  		Table 3. Reactivity measures

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The current study was designed to test the impact of naloxone on stress responses in healthy postmenopausal women and whether they would be influenced by HRT. Although mild mental stress elicited pronounced cardiovascular responses, no differences in cardiovascular responses of women with or without HRT were detectable. Interestingly, naloxone increased cortisol serum levels in both groups, but LH levels only in HRT women, and had no effect on any of the cardiovascular responses.

Although amplitude and duration of stress-induced cardiovascular responses were comparable with previous studies (9, 24, 31, 33), our findings are at variance with previous results where blunted pressor and neuroendocrine responses (20, 24, 36, 39) and decreased vascular resistance (6, 17, 38) were demonstrated after acute or chronic estradiol administration in postmenopausal women. As a result, this investigation does not support the assumption that HRT reduces the hemodynamic reactivity to mental stress in postmenopausal women. However, our study population was heterogenous concerning time menopausal, ranging from 2 to 17 yr, which might influence the endocrine milieu. Furthermore, HRT women under study were on combined estrogen-progestin replacement therapy, and the addition of progestin is assumed to counteract vascular estrogenic effects (34) and may blunt an estrogen-induced reduction in behaviorally induced stress reactivity in postmenopausal women (23). Finally, a recently published study (8) has reported that 6 mo of HRT reduced resting blood pressure and pressure reponses only in women who were less than 5 yr menopausal and concluded that beneficial effects of HRT may be restricted to the early postmenopausal years.

The ability of naloxone to increase LH levels in postmenopausal women with HRT but not in women without HRT is in accordance with previous studies (13, 14). As women on HRT had decreased basal serum LH levels, this difference from non-HRT women suggests that a restraining influence of the opioidergic system on the HPG axis seems to be absent in non-HRT women but can be restored by HRT.

On the other hand, this study demonstrated in both groups a significant increase in serum cortisol concentrations in response to naloxone. This result confirms for postmenopausal women the inhibitory effect of the endogenous opioid system on the HPA axis observed in other studies for younger women and men (10, 15, 25). As these responses were unrelated to HRT use, the opioidergic regulation of the HPA axis seems, in contrast to the HPG axis, not to be dependent on sex steroids. This is supported by studies that did not observe sex differences of opioid antagonism on the HPA axis (1, 10).

However, the cardiovascular findings of this study are in contrast to previous results in men (7, 25, 28) showing enhanced hemodynamic responses to acute stress after opioid blockade. The lack of an influence of naloxone on cardiovascular responses in our study might be attributed to different dosage used. However, similar doses were used in many other studies, irrespective of the study design (10, 13, 14, 16, 25). Therefore, and because of effects on the HPA and HPG axis, it is rather unlikely that dosage might have been too low to detect an effect of naloxone on cardiovascular measures. The pharmacodynamic profile of naloxone with a half-life of ~60 min argues that administration of the antagonist before the Stroop test was appropriate to block opioid activity for the given period. Furthermore, confounding peripheral effects of {beta}-endorphin in response to naloxone were presumably small in our experiments as naloxone would have antagonized opioidergic effects also in peripheral tissue.

Rather, results from this study could be interpreted in several ways. First, compatible with results of Abel and Rance (1) functional differences in opioidergic neuronal networks may exist, some of them being estrogen sensitive. These authors showed a reduction in the number of POMC-expressing neurons in the infundibular nucleus of postmenopausal women compared with premenopausal women but not in the retrochiasmatic region.

Furthermore, it should be considered that most studies addressing opioid system regulation of stress responses have been conducted in young healthy male subjects. Thus our data may also indicate sex differences in the opioidergic regulation of cardiovascular responses. Two studies comparing stress responses between men and women have observed inconsistent results. In one study employing naloxone (16), no sex differences were noted, whereas another experiment (2) demonstrated blunted blood pressure responses to the opioid antagonist naltrexone in women compared with men. Despite these cardiovascular differences, similar responses in ACTH and cortisol were observed in women and men (2). Furthermore, sex differences have been reported for functional opioid mechanisms of pain regulation (19) and also on a structural level for regional µ-opioid receptor density in the brain (43). Experiments in animals have shown sex differences in µ-opioid recepors, with females showing less antinociception to µ-opioid receptor agonists (11, 30).

In summary, our findings indicate functional differences in the endogenous opioid activity depending on the system under study. While the effect of opioid receptor blockade by naloxone on the HPG axis seems to depend on the estrogenic milieu, HPA axis reactivity is not influenced by sex steroids. Naloxone has no effects on resting hemodynamic parameters and does not alter cardiovascular mental stress reactions in postmenopausal women independent of their hormone substitution status.


   ACKNOWLEDGMENTS
 
The authors thank C. Fuchs for study coordination and subject management.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. Wolzt, Medical Univ. Vienna, Dept. of Clinical Pharmacology, AKH-Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria (e-mail: michael.wolzt{at}meduniwien.ac.at)

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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