Comparison of blood pressure response to exogenous epinephrine in hypertensive men and women

SYSTEMIC HYPERTENSION

Comparisonof Blood PressureResponseto ExogenousEpinephrinein HypertensiveMen and Women JACQUES W.M. LENDERS, MD, THEO DE BOO, MS, WIM A.J. LEMMENS, JOEKE REIJENGA, RN, JACQUES J. WILLEMSEN, and THEO THEN, MD

This study investigated posstble dffferences between hypertensive men and hypertens’hre women concerning the hemodynamic effects of incremental doses of exogenous epinephrine. The study population comprised 38 men (37 f 10 years) (standard deviation) and 25 women (33 f 9 years) with mild essential hypertension (mean blood pressure 1471 90 and 147/93 mm Hg, respecthrety). Body mass fndex was sttghtly higher in men (25 f 3 kg/m2) than in women (23 f 2 kg/m2). Both groups received an intravenous infusion with epinephrtne of 15 and 30 ng/kg/mln for 8 minutes each. Despite the similar doses of epinephrine infused in both groups, the increase of venous plasma epinephrine in men was nearly twice that in women (1.04 f 0.09 vs 0.87 f 0.09 nmol/ltter, p
B

y virtue of extensive epidemiologic studies, it has been well established that female hypertensive patients carry a substantially lower cardiovascular risk From the Department of Internal Medicine, Division of General Internal Medicine, and the Departments of Experimental and Chemical Endocrinology, and Statistical Consultation, St. Radboud University Hospital, Nijmegen, the Netherlands. This study was supported in part by grant 52064from the Netherlands Heart Foundation and from the University Research Pool at Nijmegen, the Netherlands. Manuscript received December 14, 1987; revised manuscript received February 29, 1988, and accepted March 1. Address for reprints: J.W.M. Lenders, MD, Department of Internal Medicine, St. Radboud University Hospital, Geert Grooteplein Zuid 8,6525 GA Niimegen, the Netherlands.

larger in men than In women (5.3 f 1.2 vs 1.7 f 1.1 mm tlg, p <0.05). Conversely, the decrease of dfastollc btood pressure wae atso larger in men than in women (-8.8 f 1.0 vs -5.8 * 1.0 mm Hg, p <0.05). The heart rate increased to the same extent in both groups (11.5 f 0.8 and 13.7 f 1.2 beats/mitt). tf the blood preesure responses were corrected for the increase of piasma eptnephrine, the differ~~betwq men and women disappeared: Thus, the greaterbtood pressure responr sivcyss to’exogenous ept@trine In hypertanshre males ts not caused by a higher vascular seqttivlty for epinephrine but is probabty related to a lower clearance of epinephftne from the circutatton. tt Is suggested that this apparent m@abolic dtfference between males and females -ing ephandling contributes to the lower cardiovascutar risk in female compared wtth male hypertensives. (Am J Cardiol 1988;61:1288-1291)

than male hypertensives for any given similar blood pressure (BP] 1evel.rAlthough there is no satisfactory explanation for this clear difference yet, it was recently demonstrated that premenopausal female hypertensive patients have a lower total peripheral resistance and a higher heart rate and cardiac index for any level of BP than male hypertensive subjects2 In addition, a smaller increase of plasma catecholamines during mental stress, head-up tilt and isometric exercise in normo- and hypertensive females as compared with age-matched males has been observed.3It is not clear whether this sex difference is caused by an estrogenmediated difference in sympathetic nerve reactivity (release of neuronal catecholamines) or by a difference in metabolic clearance of catecholamines. Another possible explanation for the hemodynamic sex

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differences might be a lower vascular sensitivity to circulating plasma catecholamines in female hypertensive patients. The purpose of our study was to investigate responsiveness of BP, heart rate, forearm blood flow and plasma catecholamines to exogenous epinephrine in mildly hypertensive men and women.

Methods Patients: Sixty-three patients with essential hypertension (38 men and 25 women) participated in the study on a voluntary basis after informed consent (Table I). Most patients were untreated. Those under treatment were enrolled after withdrawing from antihypertensive therapy for at least 3 months before the study. A diagnosis of mild hypertension was made if the BPSmeasured after 5 minutes of supine rest in 3 outpatient visits yielded a mean BP of >140 mm Hg systolic or 90 mm Hg diastolic or both, but <180/110 mm Hg. Secondary hypertension was excluded according to standard clinical criteria and all patients had normal renal function. Patients with disorders other than hypertension were excluded from the study and no study group patients took medication. All experiments were carried out in the morning, 2 hours after breakfast and with the subjects in the supine position. The subjects were asked to abstain from smoking and caffeine-containing products after midnight before the study. All experiments were carried out by the same investigator. After arrival to a quiet laboratory room with a constant temperature of 21.5 f l.l’C, subjects voided the bladder and their body weight and height were measured. Body mass index was calculated by dividing body weight by height square. Two indwelling catheters (Abbocath 20G) were inserted in the antecubital veins of both arms. The cannula in the left arm was used for taking blood samples to determine plasma catecholamines and the one in the right arm was used for infusion. The intravenous line was kept open with NaCl 0.9%(10 ml/ hr). The BP cuff of a semiautomatic BP monitor (Arteriosonde 1225) and a mercury strain-gauge plethysmograph to register blood flow in the forearm were attached to the subject’s left arm.4 Each given forearm blood flow value represents the mean of 3 measured forearm blood flow curves. Heart rat& was recorded by continuous electrocardiography and calculated from the last 10 RR intervals in a stated minute. Plasma catecholamine analysis: When taking a blood sample, the first 2 ml of blood were discarded and the next 5 ml of blood were collected in a prechilled ttibe on melting ice and immediately centrifuged at +4OC. The plasma was stored at -20OC and all sampleswere analyzed within 6 weeks from collection by a COMT-based (catechol-O-methyltransferase) radioenzymatic method with thin-layer chromatography.5 The interassay coefficient of variation for plasina epinephrine was 9% and for norepitlephrine 7.5%. The lower limit of detection was 0.05 nmol/liter for both catecholamines.

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Clinical Characterlstlcs

Number (n) Age (yrs) Range Body mass index (kg/m? Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beatslmin)

Male (n = 38)

Female (n = 25)

38 37f IO 21-55 25 l 3 147 f IO 90 f 9 74f 10

25 33 f 9 20-46 23 f 2 147 f 8 93zk8 80% 11

All values are mean f standard deviation;

p Value

NS p
NS = not significant.

After a 30-minute equilibration period during which an infusion of NaCl (O-9%,10 ml/hr) was administered, an infusion with a freshly prepared solution of 1 mg epinephrine in 50 ml NaCl 0.9% was administered by means of an infusion pump (Infors). Using different pump speeds, 2 infusion rates of 15 and 30 ng/kg/min of 8 minutes each were used. At the end of the infusion with saline and during the final infusion rate with epinephrine, BP, heart rate and forearm blood flow were measured in triplicate and blood samples for catecholamine determination were drawn. Data analysis: For each hemodynamic variable, the mean of the final 3 values during saline administration and the mean of the final 3 values during epinephrine infusion were calculated. Becausethere was no difference between males and females with regard to the baseline BP, hemodynamic responsesare expressedas the absolute change with respect to values during saline infusion. Comparisons between men and women were made by means of the &sample t test, whereas plasma catecholamines were compared via Wilcoxon’s 2-sample test. Hemodynamic responsiveness in every subject in both groups was corrected for the increase of plasma epinephrine and expressed as the increase of BP and heart rate per 1 nmol/liter increase of plasma epinephrine. Differences were analyzed using Wilcoxon’s &sample test. Unless indicated otherwise, results are given as mean f standard error and considered significant if p <0.(15.

Results The BP at the beginning of the study was similar in men and women but females had a higher heart rate. The body mass index was higher in men (Table I). There was no sex difference concerning the baseline BP during saline infusion, but women had still a higher heart rate than men with 69 f 1 vs 63 f 1 beats/min. The baseline level of plasma epinephrine during saline infusion was slightly higher in males but there was no difference regarding bash1plasma norepinephrine levels (Table II). During epinephrine infusion, the venous plasma epinephrine levels increased significantly in both groups but the mean increase in males was nearly twice as great as that in females (Table II). Venous plasma norepinephrine rose significantly in both

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EPINEPHRINE INFUSION AND SEX IN HYPERTENSION

TABLE II Plasma Catecholamlne Eplnephrlne lniuslons

Levels After Saline and After

Female

Male Plasma epinephrine (nmol/liter) Saline infusion Epinephrine infusion A Plasma epinephrine (nmol/liter) Plasma norepihephrlne (nmol/liter) Saline Infusion Epinephrlne infrislon A Plasrns noreplnephrlne (nmolllker)

0.14*0.01 1.18 f 0.09 1.04 f 0.09

p <0.05 p -5l.05 p
0.11 fO.O1 0.87 f 0.14 0.87 f 0.09

1.52f0.11 2.18 i 0.13 0.86 4 0.08

NS p <0.05 NS

1.32% 0.13 1.73 f 0.15 0.41 f 0.11

All values are mean f standard error of the mean; NS = not significant.

groups but there was no difference between men and women (Table II). The individual values of plasma epinephrine increments are shown in Figure 1. Systolic BP rose maximally from 134 f 3 to 141 f 2 mm Hg in men and from 129 f 3 to 134 f 2 mm Hg in women. Piastolio BP decreased from 90 f 2 to 81 f 2 mm Hg in men and from 89 f 2 to 84 f 2,mm Hg in women. The heart rate increased in both groups, from 63 f 1 to 77 f 2 and from 69 f 2 to 87 f 2 beats/min in men and tvomen, respectively. Concerning the absolute hemodynamic changes (Figure 2, left), men showed a larger increase of systolic BP and a larger decrease of diastolic BP, while the heart rate response was similar in both groups. Once these hemodynamic responses were corrected for the increase in plasma epinephrine, the sex difference disappeared with regard to the BP response, although now women showed a larger heart rate response than men for ihe same increase of plasma epinephrine (Figure 2, right]. The forearm blood flow increased 18 f 6% in men and 37 f 11% in women but this difference reached no statistical significance.

Idg 0 p,lasma epinephrine (nmolll)

3.20 :

Discussion In this study we demonstrated a significantly larger response of both systolic and diastolic BP in male than in female subjects with mild hypertension during an infusion with equal doses of epinephrine. However, despite the same dose, the increase of venous plasma epinephrine level was nearly 2 times larger in men and, if the BP response was corrected for the plasma epinephrine response, the BP response in both sexes was no longer different. Obviously this suggests that vascular sensitivity for an identical increment of plasma epinephrine is simiIar in men and women. How can our results be interpreted? The fact the subjects were not in a fasting state cannot have confused our results because both males and females had a breakfast. Considering that the administered dose was given per kilogram of body weight, the small difference in body mass,index cannot account for the difference in the attained plasma epinephrine levels. Age also cannot have altered our results because both groups were of similar age and, in addition, it has been shown recently that age has no effect on plasma clearance of epinephrine.6 The most obvious explanation for the observed difference in the rise of plasma epinephrine between men and women might be that the clearance rate of the infused epinephrine is lower in men than in women. However, definite conclusions concerning differences in plasma clearance of epinephrine between men and women cannot be drawn from our study. For basal epinephrine kinetics it would be more appropriate to make use of a radiotracer infusion technique with arterial plasma epinephrine sampling because there is a considerable extraction of epinephrine from arterial plasma by peripheral tissue and because A SBP ImmHg)

A DBP ImmHgl

0

0

0

0

ADBP/ lmmtlgi

AEpl nmol/ll

0 i

1.60 i

0.80

A HR (beats/mm)

30

AHR I AEp, lbealslmm / nmol/ll

o.io 0.20 ci

males

females

FIGURE 1. lndlvldual Increments of plasma eplnephrlne (lolog epinephrlne) after eplnephrlne infusion In males and females.

FIGURE 2. reff, mean changesln systolic and diastolic blood pressure (SBP, DBP) and heart rate (HR) after epinephrlne Infusion In males and females. Rlghf, mean changes of systolic and diastolic blood pressure and heart rate per 1 nmol/liter Increase of plasma eplnephrlne after eplnephrlne (Epl) Infusion.

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forearm blood flow alterations by epinephrine may influence venous plasma epinephrine levels.6p7Because the local fractional extraction of epinephrine in the forearm is a considerable 26 to 5170,~it is possible-at least in theory-for the difference in forearm muscle massto play a role. However, since men have a larger muscle massthan women, one would expect the local extraction in the forearm to be higher in men, whereas in reality men had higher increases of plasma epinephrine rather than women. It is tempting to speculate on the role of estrogens concerning catecholamine metabolism. It is known that estrogens inhibit the acetylcholine-induced adrenal secretion of epinephrine from isolated bovine adrenals,8but the effect of estrogenson extraneuronal uptake-2 or subsequent degradation by catechol-O-methyltransferase,or both, has not been studied yet. Finally, having been suggested that epinephrine can regulate its own clearance by p adrenoceptors, one should consider the possibility that females have a higher ,&adrenoceptor density than males. We conclude that the pivotal finding of our study is a larger increase of plasma epinephrine in hypertensive males than in females when a similar dose of epinephrine, related to body weight, is infused, The stronger blood pressure response to epinephrine infusion in men disappears if the blood pressure response is corrected for the larger increase of plasma epinephrine. Therefore, vascular sensitivity to epinephrine seemssimilar in both sexeswhereas females probably have a higher cardiac @-l-adrenoceptor sensitivity for

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epinephrine. The larger increase of plasma epinephrine in males might be caused by a lower clearance of epinephrine from circulation in this sex. It might be possible that a sex difference concerning epinephrine handling contributes to the lower cardiovascular risk in female hypertensives as compared with male hypertensives. Acknowledgment: We thank A. Verweijen for the preparation of this manuscript.

References 1. Kannel WB, Doyle JT. Ostfeld AM, Jenkins CD, Kuller L. Podell RN, Stamler J. Optimal resources for primary prevention of atherosclerotic diseases: Atherosclerosis Study Group. Circulation 1984;70:155A-205A. 2. Messerli FH, Garavaglia GE, Schmieder RE, Sundgaard-Riise K. Nunez BD, Amodeo C. Disparate cardiovascular findings in men and women with essential hypertension. Ann Intern Med 1987:107:158-161. 3. Lenders JWM. Willemsen JJ,de Boo Th, Lemmens WAJ, Thien Th. A Iower increase of plasma catecholamines in both normo- and hypertensive women as compared to men after adrenergic stimulation. J Hypertension 1967; 5(suppI5):S337-s339. 4. Brakkee AJM. Vendrik AJH. Strain gauge plethysmography, theoretical and practical notes on a new design. J AppI Physiol 1986;21:701-704. 5. Hoffmann JJML, Willemsen JJ.Lenders JWM. Benraad ThJ. Reduced imprecision of the radioenzymatic assay of plasma catecholamines by improving the stability of the internal stondards. CIin Chim Acta 1986:156:221226.

8. Morrow LA, Linares OA, Hill TJ, Sanfield JA, Supiano MA, Rosen SG, Halter JB. Age differences in the plasma clearance mechanisms for epinephrine and norepinephrine in humans. J Clin Endocrinol Metab 1987;65:508511.

7. Best JD. Halter JB. Release and clearance rates of epinephrine in man: importance of arterial measurements. J Clin Endocrinol Metab 1982;55:263268.

8. Wiechman BE, Borowitz JL. Effect of steroid hormones and diethylstilbestrol on adrenomedullary catecholomine secretion. Pharmacology 1979;18: 195-201.