(Hypertension. 1995;25:517-523.)
© 1995 American Heart Association, Inc.
Articles |
Gender Difference in Endothelial Dysfunction in the Aorta of Spontaneously Hypertensive Rats
From Berlex Biosciences, Cardiovascular Department, Richmond, Calif.
Correspondence to Gabor M. Rubanyi, MD, PhD, Berlex Biosciences, Cardiovascular Department, 15049 San Pablo Ave, Richmond, CA 94804-0099.
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Abstract |
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Abstract We investigated endothelium-dependent responses of thoracic aorta isolated from age-matched male and female spontaneously hypertensive rats (SHR) to explore gender differences in endothelial dysfunction that may contribute to the sexual dimorphism observed in the development of hypertension in this strain. Endothelium-dependent relaxation in response to acetylcholine (10-9 to 10-4 mol/L) was significantly greater in female rats than in male rats, although impaired responses were seen in both sexes compared with normotensive controls. Inhibition of cyclooxygenase by indomethacin (10-5 mol/L) improved endothelium-dependent relaxation, but it did not abolish the gender difference. Relaxations in response to sodium nitroprusside were identical in denuded aortic rings from male and female SHR. Acetylcholine at higher concentrations (10-6 to 10-4 mol/L) induced endothelium-dependent contraction in intact, quiescent aortic rings from male SHR but not in those from female SHR. After incubation with NG-nitro-L-arginine (10-4 mol/L), contraction in response to acetylcholine became apparent in rings from female SHR, but it was still significantly less pronounced than in similarly treated rings from male SHR. Endothelium-dependent contraction was prevented by indomethacin in both sexes, suggesting that a cyclooxygenase product such as endoperoxide may be mediating this effect. Because responses evoked by the thromboxane/endoperoxide receptor agonist U46619 (10-10 to 10-6 mol/L) were not greater in rings from male SHR than those from female SHR, increased smooth muscle responsiveness or higher thromboxane/endoperoxide receptor density in the males could not account for the differences in endothelium-dependent contraction. These results suggest that sex steroid hormones may control endothelium-dependent vascular reactivity. The less severe endothelial dysfunction in the female SHR can contribute to the gender differences observed in the extent and rate of progression of hypertension in the SHR.
Key Words: acetylcholine • rats, inbred SHR • nitric oxide • endothelium-derived relaxing factor • endothelins • prostaglandins • sex hormones
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Introduction |
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Epidemiological studies demonstrate that the incidence of cardiovascular diseases related to hypertension or atherosclerosis is significantly lower in premenopausal women than in men of similar age.1 Sexual dimorphism in the degree of high blood pressure has been observed in several forms of hypertension in both humans and animals. The prevalence of essential hypertension is lower in premenopausal women than in age-matched men.2 Hypertension develops more rapidly and becomes more severe in male than in female animals in several models of the disease, such as the spontaneously hypertensive rat (SHR),3 the deoxycorticosterone acetate–salt rat,4 and the Dahl salt-sensitive rat.5
Diminished endothelium-dependent relaxation has been demonstrated in all of these animal models.6 7 8 Similar impairment of endothelial function has been observed in vivo in the forearm circulation of human patients with essential hypertension.9
Endothelial dysfunction—characterized as attenuated production and release of endothelium-derived relaxing substances (EDRFs)10 such as nitric oxide (NO),11 enhanced synthesis of endothelium-derived vasoconstrictor substances (EDCFs),12 or both—has been extensively studied in association with spontaneous hypertension. The nature of EDCFs in the thoracic aorta of the adult SHR is most likely analogous to that of the cyclooxygenase product prostaglandin H2 (PGH2).13 PGH2 exerts its vasoconstrictor effect by stimulating thromboxane A2/PGH2 (TXA2/PGH2) receptors on vascular smooth muscle cells.14 It has also been suggested that the concomitant release of EDRF/NO can inhibit endothelium-dependent contraction, probably by chemically inactivating the EDCF.15
Although a causative relationship between endothelial dysfunction and hypertension has not been clearly established, the following experimental evidence suggests that decreased EDRF/NO production, augmented EDCF release, or both could contribute to the development of the disease: (1) alteration in endothelium-mediated responses in young SHR precedes the onset of hypertension,16 and (2) treatment of SHR with angiotensin-converting enzyme inhibitors (including captopril, enalapril, and cilazapril), which can prevent the development of spontaneous hypertension,17 augments endothelium-dependent relaxation in parallel with lowering of blood pressure.18 19
Despite the well-documented gender difference in the development and severity of hypertension in animal models and in humans, as well as the increasing evidence supporting the role of endothelial dysfunction in the pathogenesis of hypertension, no data are available on gender differences in endothelial dysfunction associated with hypertension. The aim of the present study was to examine whether differences exist in endothelial dysfunction between age-matched male and female SHR, in which blood pressure elevation exhibits sexual dimorphism.
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Methods |
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Experimental Animals and Conditions
Male (n=10) and female (n=8) SHR were purchased at the age of 16 weeks from Mollegard Breeding Center, Ejby, Denmark, and Taconic Farms, Germantown, NY. Male (n=10) and female (n=10) normotensive Wistar rats of the same age were obtained from Schering AG, Berlin, Germany. All animals were housed in accordance with institutional guidelines (constant temperature; 12-hour dark/light cycle; standard rat chow and water ad libitum). The phase of the estrus cycle of each female rat was determined by microscopic evaluation of the vaginal smear taken by a cotton swab before the animal was killed. The animals were randomly selected for the experiment at different days in their estrus cycles.
Systolic pressure was measured in conscious, restrained rats by the tail-cuff method using plethysmography (Hugo Sachs). The average of three successive measurements, which were made after a 3-day training period, was taken as the mean systolic pressure value. These data, and data on the body weight of the rats at the time they were killed, are presented in the Table. There was no difference between the blood pressures of the SHR from different breeders. The unusually high values of the systolic pressure in both the normotensive and hypertensive animals are due to the use of the tail-cuff method.
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The animals were killed by CO2 inhalation, and the thoracic aortas were dissected. Experiments were performed on rings of thoracic aorta, with (E+) or without (E-) endothelium, isolated from hypertensive and normotensive male and female rats. In de-endothelialized rings, the endothelium was removed by gentle mechanical rubbing of the intimal surface.
The rings were mounted in Schuler organ chambers (Hugo Sachs) containing 10 mL aerated (95% O2 and 5% CO2) temperature- and pH-controlled physiological saline solution (37°C, pH 7.40 to 7.45) with the following composition (mmol/L): Na+ 141, Cl- 125, Ca2+ 2.5, K+ 4.7, Mg2+ 0.76, H2PO4- 1.7, HCO3- 25, EDTA 0.026, glucose 11, HEPES 5. Changes of isometric tension were measured by force transducers (Grass FT03) and recorded on a four-channel recorder (Graphtec Linearcorder WR 3310, Hugo Sachs). Some of the experiments were performed in the presence of indomethacin (10-5 mol/L) to block the synthesis of prostanoids, and some were performed in the presence of NG-nitro-L-arginine (L-NNA, 10-4 mol/L) to inhibit NO production.
Experimental Protocol
Eight rings from the same aorta were suspended in individual
organ chambers and studied in parallel, each given different treatment.
The rings were allowed to equilibrate for 60 minutes, and the optimal
resting tension (2 g) was reached by stepwise stretching of the aortic
rings. Each ring was then contracted twice by KCl (60 mmol/L) and once
with phenylephrine (10-6 mol/L), evoking about 80% of the
maximal contraction achieved by 60 mmol/L KCl. When a plateau of the
contraction was reached, the presence or absence of functional
endothelium was tested by acetylcholine (10-6 mol/L).
Endothelium-dependent relaxations were investigated by measuring acetylcholine-induced changes in tension of phenylephrine-contracted E+ (phenylephrine, 10-6 mol/L) and E- (phenylephrine, 3x10-7 mol/L) thoracic aortic rings isolated from male and female rats (acetylcholine, 10-9 to 10-4 mol/L). Endothelium-dependent acetylcholine-induced constriction was studied in quiescent E+ and E- rings isolated from male and female SHR (acetylcholine, 10-8 to 10-4 mol/L). The acetylcholine dose-response measurements were repeated in the presence of indomethacin (10-5 mol/L), L-NNA (10-4 mol/L), or both after 30 minutes of incubation with the inhibitors.
The effect of the TXA2/PGH2 receptor agonist U46619 (10-10 to 10-6 mol/L) was examined in the presence of indomethacin (10-5 mol/L) by calculation of cumulative dose-response curves for E+ and E- rings of male and female SHR. Sodium nitroprusside (10-10 to 10-6 mol/L) was tested in vessels without endothelium contracted by phenylephrine (3x10-7 mol/L).
Drugs
All drugs were purchased from Sigma Chemical Co. Stock solutions
of the drugs were prepared daily and kept on ice until used. The drugs
were dissolved in distilled water, except for indomethacin, which was
dissolved in Na2CO3 (0.2 mol/L) and distilled
water (1:9). Drug concentrations are expressed as final molar (moles
per liter) concentration in the organ chamber.
Calculations and Statistics
Vasorelaxation evoked by acetylcholine and sodium nitroprusside
is expressed as percent inhibition of the contraction evoked by
phenylephrine. Contractions of the quiescent rings in response to
acetylcholine and U46619 are expressed in grams per milligram of wet
weight of the aortic rings (the wet weight was determined at the end of
the experiments). Results are shown as mean±SEM for the number of rats
used in each experiment. Statistical evaluation of the data was carried
out by one-way ANOVA or by Student's t test for paired and
unpaired observations. The difference was considered significantly
different at a value of P<.05.
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Results |
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Blood Pressure and Body Weights
The body weight and blood pressure values of the four groups are summarized in the Table. The systolic pressure of SHR was significantly higher than that of age-matched normotensive rats in both sexes (P<.05). There was no significant difference between systolic pressures of male and female normotensive rats, but the mean blood pressure of male SHR was significantly higher than that of female SHR (P<.05). Body weights of male and female normotensive rats were not different, whereas the mean body weight of female SHR was significantly lower than that of male SHR (P<.05).
Endothelium-Dependent Relaxation in Response to
Acetylcholine
Acetylcholine (10-8 to 10-4 mol/L)
evoked dose-dependent relaxation in phenylephrine-contracted E+
thoracic aortic rings isolated from normotensive rats and
SHR (Fig 1A and 1B). The relaxations were significantly
impaired in aortic rings isolated from the SHR, irrespective of gender
(P<.05). Acetylcholine-induced,
endothelium-mediated relaxation was significantly
greater in tissues isolated from female animals in both the
normotensive and hypertensive groups (P<.05) (Fig 1A and 1B).
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Indomethacin (10-5 mol/L) significantly augmented the responses to acetylcholine in rings isolated from SHR (P<.05), but it had no effect on the relaxation in rings from normotensive rat aorta (Fig 2A and 2B). The difference between the relaxation of the aortic rings from male and female rats was not abolished by cyclooxygenase inhibition. Endothelium-dependent relaxation curves for acetylcholine in aortic rings isolated from normotensive rats and SHR became superimposable after indomethacin incubation (Fig 2A and 2B).
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Endothelium-Dependent Contraction in Response to Acetylcholine
Acethylcholine evoked dose-dependent contraction of
quiescent thoracic aortic rings from male SHR; this contraction was
endothelium dependent at concentrations lower than 10-4
mol/L (Fig 3). At 10-4 mol/L, acetylcholine
caused contraction of the denuded rings as well because of the direct
effect of acetylcholine on vascular smooth muscle. In contrast,
acetylcholine caused no significant contraction in quiescent aortic
rings of female SHR (Fig 3). Inhibition of NO synthesis by L-NNA
(10-4 mol/L) did not significantly affect
acetylcholine-induced contractions in rings from male SHR (Fig 4A). However, in the presence of L-NNA, acetylcholine
caused endothelium-dependent contraction in vessels
from female SHR (Fig 4B). Indomethacin (10-5 mol/L)
abolished the contractile responses of the quiescent rings to
acetylcholine in both sexes (Fig 4A and 4B).
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Smooth Muscle Responsiveness to U46619 and Sodium Nitroprusside
In the presence of indomethacin (10-5 mol/L), U46619
(10-10 to 10-6 mol/L) evoked dose-dependent
contraction in E+ aortic rings isolated from male and female SHR (Fig 5). Removal of the endothelium significantly
potentiated the contractile responses to U46619. There was no
gender difference in the calculated EC50 (male E+,
9.5[±0.2]x10-8 mol/L; female E+,
1.2[±0.2]x10-7 mol/L; male E-,
2.1[±0.4]x10-8 mol/L; and female E-,
1.3[±0.2]x10-8 mol/L) or in the maximal responses of
E+ and E- rings at 10-6 mol/L U46619 (male E+, 0.6±0.1
g/mg wet wt; female E+, 0.6±0.2 g/mg wet wt; male E-, 1.2±0.1 g/mg
wet wt; female E+, 1.1±0.1 g/mg wet wt).
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Endothelium-independent vasorelaxation induced by sodium nitroprusside (10-10 to 10-6 mol/L) was not different in E- rings isolated from male and female SHR (Fig 6).
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Discussion |
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The present study demonstrates for the first time that significant gender differences exist in endothelial dysfunction of thoracic aorta isolated from SHR. Our results show that acetylcholine-induced endothelium-dependent relaxation is more pronounced in female SHR aorta and that acetylcholine evokes endothelium-dependent contraction in quiescent thoracic aortic rings from male but not from female SHR.
Endothelial dysfunction in hypertension has been characterized as being a result of reduced synthesis and release of EDRF/NO, increased production of EDCF, or both.12 Therefore, the significantly less pronounced endothelial dysfunction (as assessed by acetylcholine-induced endothelium-dependent relaxation and contraction) in aortic rings of female SHR can be explained by the following possibilities: (1) the endothelium of the female rat aorta produces more EDRF/NO; (2) similar amounts of EDRF/NO are synthesized in both sexes, but the smooth muscle of the female aorta is more sensitive to NO; (3) the endothelium of the female SHR aorta produces less EDCF; (4) the same amount of EDCF is produced by the endothelia of both sexes, but smooth muscle sensitivity to the cyclooxygenase product EDCF (PGH2) is greater in males; or (5) the difference between the endothelial dysfunction in male and female SHR aorta is the result of a combination of the above. The present experimental data allow us to distinguish between these equally possible explanations.
Differences in EDRF/NO Production and Reactivity
Acetylcholine-induced endothelium-dependent
vasorelaxation was significantly greater in isolated rings from female
SHR. The relaxation in the female rat aorta remained significantly
greater after indomethacin treatment. Responses to the exogenous NO
donor sodium nitroprusside were identical in denuded aortic rings from
male and female SHR, ruling out gender differences in smooth muscle
reactivity to NO. Thus, the greater acetylcholine-induced relaxation in
female SHR is probably due to increased production of EDRF/NO by the
endothelium.
Previous experiments in our laboratory in which a superfusion bioassay was used showed a greater release of EDRF/NO from isolated thoracic aortic segments of normotensive female rats than from those of male rats.20 This finding is in agreement with earlier data, reported by other investigators, illustrating greater endothelium-dependent suppression of vasoconstrictor responses in female rabbits compared with males.21 The present data extend these observations to the aorta of SHR.
Differences in EDCF Production and Reactivity
Endothelium-dependent contraction has been demonstrated in
isolated thoracic aorta,6 22 mesenteric resistance
arteries,23 24 and cerebral arterioles25 of
male SHR in response to acetylcholine,6 26
serotonin,27 28 and ADP.25 29 Inhibitors of
cyclooxygenase (but not thromboxane synthase)14 and
TXA2/PGH2 receptor antagonists, such as
SQ 2954814 or ONO-3708,30 are similarly
effective in preventing or inhibiting acetylcholine-induced
endothelium-dependent contraction in aorta of male SHR.
It has been suggested that the most likely candidate for EDCF is
PGH2.30 31 The acetylcholine-induced
contraction of the quiescent thoracic aorta of the SHR in our
experiments was also endothelium dependent, and it was inhibited by
indomethacin, suggesting that, as indicated by previous observations,
it is probably mediated by the cyclooxygenase metabolite
PGH2.
It has been suggested that NO may inactivate EDCF in the rat aorta.15 If the neutralizing effect of the larger amount of NO produced by the female SHR endothelium accounts for the gender difference, one would expect similar contraction in response to EDCF in the presence of an NO synthase inhibitor such as L-NNA. However, endothelium-dependent contraction in response to acetylcholine, in the presence of the L-arginine analogue, was significantly less in aortic rings from female SHR than in those from male SHR. These observations suggest that differences in EDRF/NO production alone cannot account for the gender difference in endothelial dysfunction.
These experimental results also rule out the possibility that EDCF production is totally absent in vessels of the female SHR. The less pronounced endothelium-dependent contraction in female SHR aorta than in male SHR aorta after NO synthase inhibition can be due to reduced production of EDCF/PGH2, decreased reactivity of the female aortic smooth muscle to EDCF/PGH2, or both. Indeed, it has been shown that male rat aorta is more sensitive to U46619 than is female rat aorta, and that the maximal response is greater in males than in females.32 Studies on cultured rat aortic smooth muscle cells demonstrated that testosterone increases TXA2 receptor density.33 To investigate whether differences in TXA2/PGH2 receptor density or sensitivity could contribute to the observed differences between endothelium-dependent contraction in male and female SHR, the effect of U46619, a TXA2/PGH2 mimetic, on isolated thoracic aortic rings was studied. The experiments were performed in the presence of indomethacin to exclude possible effects of other prostanoids, such as prostacyclin or thromboxane, released by the TXA2/PGH2 mimetic.34 35 There was no difference between the U46619 dose-response curves of male and female SHR, indicating that variations in vascular TXA2/PGH2 receptors and responsiveness cannot account for the differences in endothelium-dependent contraction. Thus, the most likely explanation for the observed gender difference is that acetylcholine stimulates the synthesis and release of more EDCF/PGH2 in the endothelium of male SHR.
Role of Sex Steroid Hormones
Gender differences in vascular contractility have been reported by
several investigators.21 32 36 37 38 39 Experimental data also
indicate that sex hormones can alter sensitivity of blood vessels for
different agonists after both short- and long-term
treatment.40 41 42 43 44 Treatment of ovariectomized rabbits for 4
days with 17ß-estradiol enhanced
endothelium-dependent relaxation in response to
acetylcholine in isolated femoral arteries.42 This effect
of estrogen could involve changes in different
endothelium-derived factors; however, the enhanced
relaxation in response to acetylcholine was not affected by
indomethacin, suggesting that the effect was most likely caused by
increased NO production.42
Earlier reports clearly indicate the role of sex steroids in the development of hypertension in SHR.45 46 Studies conducted in gonadectomized animals given male and female sex steroid hormones demonstrated that estrogens can significantly decrease blood pressure,3 47 whereas more recent studies indicate that testosterone is responsible for the development and maintenance of hypertension in SHR.48 49 50 The mechanism of the effect of sex steroid hormones is not known. It has been suggested that in some rat strains the chromosomes may contain loci that have a direct effect on blood pressure.51 52 Specifically, a blood pressure–elevating effect has been linked to the Y chromosome,53 but contradictory findings have been reported as well.54 55
The effect of sex hormones on endothelial function in the SHR has not been extensively investigated. Only one study reported that treatment with 17ß-estradiol significantly enhanced endothelium-dependent relaxation in female SHR.56 Pregnancy was shown to significantly lower high blood pressure in female SHR, and endothelium-dependent responses in blood vessels isolated from pregnant SHR were restored compared with nonpregnant controls.57 This finding suggests that female sex steroid hormones (estrogen and progesterone) may influence endothelial function in a beneficial way, which could contribute to the slower progression and lower incidence of hypertension in female animals and humans.
In summary, we have demonstrated significant gender differences in endothelial dysfunction of SHR. Intact blood vessels from female SHR seem to produce or release more EDRF/NO and less EDCF. Because endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases, it is possible that gender-dependent differences in endothelial function could contribute to the difference in cardiovascular morbidity observed between men and women.
Received July 14, 1994; first decision August 30, 1994; accepted November 29, 1994.
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