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Department of Pharmacology, College of Medicine, University of California, Irvine, California 92697-4625
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Gender is known to influence the incidence and severity of cerebrovascular disease. In the present study, luminal diameter was measured in vitro in pressurized middle cerebral artery segments from male rats that were either untreated, orchiectomized (ORX), ORX with testosterone treatment (ORX+TEST), or ORX with estrogen treatment (ORX+EST). The maximal passive diameters (0 Ca2+ + 3 mM EDTA) of arteries from all four groups were similar. In endothelium-intact arteries, myogenic tone was significantly greater in arteries from untreated and ORX+TEST compared with arteries from either ORX or ORX+EST. During exposure to NG-nitro-L-arginine-methyl ester (L-NAME), an NO synthase (NOS) inhibitor, myogenic tone significantly increased in all groups. The effect of L-NAME was significantly greater in arteries from untreated and ORX+EST compared with arteries from ORX and ORX+TEST rats. Differences in myogenic tone between ORX and ORX+TEST persisted after inhibition of NOS. After endothelium removal or inhibition of the cyclooxygenase pathway combined with K+ channel blockers, myogenic tone differences between ORX and ORX+TEST were abolished. Wall thickness and forced dilation were not significantly different between arteries from ORX and ORX+TEST. Our data show that gonadal hormones affect myogenic tone in male rat cerebral arteries through NOS- and/or endothelium-dependent mechanisms.
testosterone; estrogen; nitric oxide
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MEN HAVE HIGHER RISK OF CEREBROVASCULAR morbidity and mortality than do women of the same age (51). Both epidemiological and experimental evidence suggests that a part of these gender-related differences are due to the sex hormones estrogen and testosterone (30, 51). For example, the cerebrovascular protective effects of estrogen are most evident following menopause where the lower plasma concentration of estradiol coincides with the increasing incidence of female cerebrovascular disease (51). Similarly, alterations in normal concentrations of serum androgens unfavorably affect risk factors (lipid profile, mean arterial blood pressure, and vascular smooth muscle growth) normally associated with cerebrovascular disease (2, 33, 34).
The mechanisms by which estrogen affects the female cardiovascular system have been the focus of intense investigation (3, 4, 25). In contrast, only a handful of studies have determined the effects of estrogen on the reactivity of male blood vessels. In animal studies, chronic estrogen treatment elevates endothelial nitric oxide (NO) synthase (NOS) protein expression in cerebral microvessels from orchiectomized rat (32). Estrogen also decreases blood pressure and inhibits the synthesis of vascular connective tissue (17). In human studies, agonist-mediated dilations through NOS-dependent mechanisms were improved in males taking high doses of estrogen (38). Similarly, NO-dependent dilation in response to a flow stimulus was impaired in an adult male with estrogen deficiency (43). These observations suggest that estrogen may offer some degree of protection against cardiovascular disease in males, as in females.
In contrast to the apparent role of estrogen on vascular reactivity of males, reported effects of androgens on the cardiovascular system are conflicting. Testosterone is known to be associated with higher risk of cardiovascular disease in men (51). These effects of testosterone may be mediated through changes to blood pressure and/or vascular smooth muscle cell growth (12, 17, 44). Alternatively, natural androgens have been shown to inhibit male atherosclerosis (1). Testosterone may also mediate beneficial cardiovascular effects through direct stimulation of endothelium-derived NO (11) or vascular smooth muscle K+ channels (52).
Cerebral blood flow is maintained relatively constant during changes in systemic blood pressure through multiple mechanisms of autoregulation unique to the cerebral circulation (15, 16). Myogenic reactivity, one form of cerebral autoregulation, regulates the diameter of small cerebral arteries and arterioles in response to changes in transmural pressure. In most vascular beds, the vascular smooth muscle cells are solely responsible for myogenic reactivity (13), although endothelium-derived substances are active modulators of the myogenic response (13).
Because gonadal steroids appear to affect blood vessel physiology, we investigated the effects of chronic treatment with testosterone or estrogen on the myogenic reactivity of cerebral vessels from male rats. The primary hypothesis of the present study was that myogenic tone increases with testosterone and decreases with estrogen treatment. Additionally, we hypothesized that the effects of gonadal hormones would be mediated by alterations in NOS.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Animal procedures were approved by the Animal Care and Use Committee of University of California, Irvine. Male 3-mo-old Fisher 344 rats were purchased from Harlan Sprague Dawley (Indianapolis, IN) and housed under a 12 h:12 h light-dark cycle with food and water available ad libitum. Four groups of rats were used in the present study: untreated males (n = 6), orchiectomized males (ORX; n = 18), ORX with testosterone replacement (ORX+TEST; n = 18), and ORX with estrogen treatment (ORX+EST; n = 6). ORX, ORX+TEST, and ORX+EST were performed with the rats under anesthesia (ketamine, 90 mg/kg and xylazine, 10 mg/kg). At the time of ORX, either a 10-mm (estrogen) or 15-mm (testosterone) silicone elastomer capsule was inserted subcutaneously (10). Lengths of capsules were selected to achieve plasma levels of steroids in the physiological range. Capsules were made from Silastic medical grade tubing (1.57 mm ID × 3.18 mm OD, Dow Corning) and sealed with silicone elastomer adhesive type A (Dow Corning). Animals were euthanized 1 mo after surgery.
Tissue preparation.
At 4 mo of age, rats were euthanized by either decapitation or
CO2. Trunk bleed (decapitation) or cardiac puncture
(CO2) were performed to collect blood for determination of
17
-estradiol and testosterone by radioimmunoassay. Brains
were rapidly removed from the cranial cavity and placed in a dissecting
dish with cold oxygenated physiological salt solution (PSS) containing
(in mM) 118 NaCl, 4.8 KCl, 1.6 CaCl2, 1.2 KH2PO4, 25 NaHCO3, 1.2 MgSO4, 0.3 ascorbic acid, and 11.5 glucose. A 1- to 2-mm
segment of the middle cerebral artery, taken about 1 mm from the circle
of Willis, was carefully dissected and mounted in an arteriograph
(Living Systems, Burlington, VT). Micropipettes were inserted into each end of the artery and secured in place with nylon ties. The proximal cannula was connected through a pressure transducer and windkessel to a
reservoir of PSS equilibrated with 95% O2-5%
CO2. The distal cannula was connected to a Luer-Lok that
was open during the initial equilibration to gently flush the luminal
contents. After the equilibration period, the Luer-Lok remained closed
so all experiments were conducted under no-flow conditions. A
constant-flow peristaltic pump continuously superfused (30 ml/min) the
artery with PSS. During a 60-min equilibration period, a pressure
servo-system maintained transmural pressure at 40 mmHg. The artery was
viewed with an inverted microscope equipped with a video camera and
monitor. A video-electronic dimension analyzer was used to measure
luminal diameter. Changes in transmural pressure and lumen diameter
were digitized by a MacLab analog-to-digital converter and recorded on
a Macintosh computer. Endothelium removal was performed by perfusing 1 ml of air through the artery lumen. Successful removal of the
endothelium was determined by complete inhibition of dilation to ADP
(10 µM). All drugs, individually or in combination, were added to the
superfusate in their final concentration.
Experimental protocols. In all protocols the changes in artery diameter in response to increased transmural pressure (no flow) were measured. Only those vessels that developed spontaneous tone were used. After the 60-min equilibration period, pressure was reduced to 20 mmHg. Pressure was then increased to 80 mmHg with a single 60-mmHg pressure step, maintained for 10 min, and then returned to 20 mmHg. Three such cycles were performed on each vessel to remove mechanical hysteresis. Another 20-min rest period followed the three initial cycling periods, which was then followed by one of the following four protocols. Protocol 1 consisted of three separate series of pressure steps (each from 20 to 80 mmHg in 10-mmHg steps). The first series of pressure steps was in PSS, the second in the presence of NG-nitro-L-arginine methyl ester (L-NAME; 10 µM), and the third in 0 Ca2+-EDTA (3 mM). Protocol 2 included three separate series of pressure steps (each from 20 to 80 mmHg in 20-mmHg steps). The first series of pressure steps was in the presence of indomethacin (10 µM) plus a cocktail of K+ channel blockers (KCB), the second in the presence of indomethacin with KCB plus L-NAME, and the third in 0 Ca2+-EDTA (3 mM). L-NAME, indomethacin, and a "cocktail" of KCB [apamin (small conductance Ca2+-dependent K+ channels) (53), tetraethylammonium (large conductance Ca2+-dependent K+ channels) (36), and Ba2+ (inward rectifier K+ channel) (27)] were combined to inhibit known endothelium-derived vasodilatory substances and block hyperpolarization of the vascular smooth muscle cells (40, 53). Protocol 3 was performed in the presence of either indomethacin, KCB plus L-NAME, or 0 Ca2+-EDTA alone (3 mM) and in increasing pressure steps from 80 to 180 mmHg in 20-mmHg steps. In protocol 4, four separate series of pressure steps (each from 20 to 80 mmHg in 20-mmHg steps) were performed. The first series of pressure steps was with the endothelium-intact artery in PSS, the second series of pressure steps were performed after endothelium removal, the third was with endothelium-damaged arteries in the presence of KCB, and the fourth was with endothelium-denuded arteries in 0 Ca2+-EDTA (3 mM). All drugs were perfused for 20 min before the first pressure step, and each pressure step was maintained for 5-10 min to allow the vessel to reach a stable condition before diameter was measured. Control arteries showed consistent responses to four series of pressure steps.
Myogenic tone was determined by subtracting the steady-state diameter at any given pressure in PSS from the passive diameter (0 Ca2+ + 3 mM EDTA) at that same pressure. Constriction to L-NAME was determined by subtracting steady-state diameter at any given pressure in the presence of L-NAME from the steady-state diameter in PSS at that same pressure.Radioimmunoassay for serum levels of testosterone or estradiol.
Immediately after euthanization was performed, blood was collected by
either trunk bleed or cardiac puncture, placed in plain tubes, and
centrifuged at 1,000 rpm for 5 min. The supernatant was decanted and
frozen at 
70°C. Serum testosterone and 17-estradiol levels were determined by radioimmunoassay with commercially available kits (Diagnostic Products, Los Angeles, CA). Assay sensitivities were
0.4 ng/ml and 8 pg/ml for testosterone and estradiol, respectively.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of orchiectomy and hormone treatment on serum hormone
concentrations, body weight, and artery wall thickness.
Serum testosterone was undetectable in ORX male rats and ORX+EST.
Testosterone replacement (ORX+TEST) resulted in significant plasma
levels of testosterone; however, the concentrations were significantly
lower than testosterone concentrations in untreated male rats. Serum
concentrations of estradiol in ORX+EST were not significantly different
from estradiol concentrations of untreated male rats. Serum estradiol
concentrations in both untreated and ORX+EST rats were significantly
higher than estradiol concentrations in either ORX or ORX+TEST rats
(Table 1; P < 0.05).
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Effect of orchiectomy and hormone treatment on myogenic responses.
Middle cerebral arteries from untreated, ORX, ORX+TEST, or ORX+EST male
rats responded passively to each step increase in pressure in the
absence of extracellular Ca2+ plus EDTA (3 mM) (Fig.
1). Maximal passive artery diameters (80 mmHg) were not significantly different among untreated (294 ± 2 µm), ORX (290 ± 4 µm), ORX+TEST (289 ± 7 µm), and
ORX+EST (300 ± 15 µm) rats. As shown in Fig. 1, in PSS,
diameters of male and ORX+TEST arteries were smaller at 20 mmHg than
arteries from ORX or ORX+EST (P < 0.05). These
diameter differences among treatment groups persisted throughout each
step change in pressure. After each pressure step, the steady-state
myogenic tone (difference between passive diameter and diameter in PSS)
was significantly greater in arteries from males and ORX+TEST compared
with ORX and ORX+EST (Fig. 2;
P < 0.05).
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Effect of NOS inhibition.
To determine whether artery diameter was modulated by NO, arteries were
treated with the NOS inhibitor L-NAME (10 µM). As shown
in Fig. 1, in the presence of L-NAME, artery diameters from all groups were significantly smaller at each pressure step compared with PSS alone. Although NOS inhibition had significant contractile effects in all groups, L-NAME constriction was
significantly greater in arteries from untreated males and ORX+EST rats
compared with arteries from ORX or ORX+TEST (Figs. 1 and
3). The greater effect of
L-NAME in arteries from untreated males and ORX+EST
correlates with higher serum estradiol concentrations (Table 1).
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Effect of endothelium removal.
Although our studies of NOS inhibition suggest a relationship between
serum estradiol levels and NO function, the mechanism of action of
circulating testosterone on artery diameter is not as clear. Therefore,
we investigated whether the endothelium was a target of testosterone.
In the next series of experiments, endothelium-intact and -denuded
arteries from ORX and ORX+TEST were exposed to multiple pressure steps.
As shown previously, maximal passive artery diameters (80 mmHg) were
not significantly different between ORX (300 ± 3 µm) and
ORX+TEST (295 ± 3 µm). At lower pressures (20 and 40 mmHg) in
these groups of arteries, passive diameters from ORX+TEST were
slightly, but significantly, smaller than passive artery diameters from
ORX. Confirming the data in PSS presented in Fig. 1, diameters of
endothelium-intact arteries from ORX+TEST were smaller through all the
pressure steps compared with endothelium-intact arteries from ORX (Fig.
4).
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Effect of inhibition of cyclooxygenase,
K+ channels, and NOS.
Because diameter differences between ORX and ORX+TEST were abolished
after endothelium removal, experiments were carried out to determine
whether endothelium-derived substances, independent of NOS, could be
responsible for the effects of testosterone. Indomethacin was combined
with KCB [tetraethylammonium, 1 mM (large conductance
Ca2+-activated K+); barium, 50 µM (inward
rectifier K+ channel); and apamin, 10 nM (small conductance
Ca2+-activated K+)] to effectively inhibit
metabolites of the cyclooxygenase pathway and abolish the
K+ equilibrium potential (Fig.
6). As before, maximal passive artery diameters (80 mmHg) were not significantly different between ORX (291 ± 5 µm) and ORX+TEST (292 ± 5 µm). In the presence
of indomethacin and KCB, diameters of arteries from ORX and ORX+TEST
rats were smaller at each pressure step compared with either the
passive response (EDTA) (Fig. 6) or with the PSS response at 60 mmHg
(Fig. 5; P < 0.05). But more importantly, in the
presence of indomethacin and KCB, diameter differences between arteries
from ORX and ORX+TEST were eliminated (P > 0.05; Fig.
6).
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Effect of testosterone on artery structure.
Testosterone is known to stimulate myointimal hyperplasia
(9, 20). Therefore, in the next series of
experiments we determined whether testosterone treatment affected
structural characteristics (thickening or remodeling) of the vascular
smooth muscle. Arteries were subjected to excessive pressures
(80-180 mmHg) in the presence of indomethacin, KCB, and
L-NAME. As shown in Fig. 7,
maximal passive artery diameters (180 mmHg) were not significantly
different between ORX (315 ± 5 µm) and ORX+TEST (320 ± 7 µm). In the presence of indomethacin, KCB, and L-NAME,
artery diameters at 80 mmHg from ORX and ORX+TEST were not
significantly different (Fig. 7). Artery diameters from ORX and
ORX+TEST were not altered by increasing transmural pressure to 180 mmHg. Interestingly, at intraluminal pressures as high as 180 mmHg,
forced dilation or autoregulatory breakthrough did not occur in either
ORX or ORX+TEST arteries.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study has shown that the gonadal hormones, estrogen and testosterone, influence myogenic tone of male rat cerebral arteries through either NOS- and/or endothelium-dependent mechanisms. In endothelium-intact arteries, myogenic tone was significantly greater in arteries from untreated and ORX+TEST rats compared with arteries from either ORX or ORX+EST rats. These data suggest that myogenic tone correlates with circulating testosterone concentration. Interestingly, the effect of inhibiting NOS was significantly greater in arteries from untreated and ORX+EST rats compared with arteries from ORX and ORX+TEST rats. In this case, the magnitude of the effect of NOS inhibition correlated with circulating estrogen levels, suggesting that estrogen modulates the function of NOS. After removal of either the endothelium or combining inhibition of cyclooxygenase and K+ channels, myogenic tone differences between ORX and ORX+TEST were abolished. These data suggest that testosterone affects myogenic tone through modulation of endothelium-derived factors independent of NOS. Therefore, our data suggest that testosterone increases, whereas estrogen decreases, myogenic tone in rat cerebral arteries. Both NO-dependent and independent mechanisms are involved, and the effects of testosterone are endothelium dependent.
Estrogen and NO. Numerous previous studies have shown that endothelium-derived NO modulates myogenic reactivity of cerebral (13, 16, 19) and peripheral arteries (26, 49). In the present study, inhibition of NOS with L-NAME significantly increased myogenic tone in all treatment groups. However, the constriction to L-NAME was significantly greater in arteries from animals exposed to high plasma levels of estrogen, including untreated males. The present data corresponds with our previous findings that levels of endothelial NOS protein are significantly greater in cerebral microvessels from ORX+EST rats. However, our current functional data with intact male rats do not correspond with NOS protein levels in these same animals (32). Although these findings are difficult to interpret, one obvious possibility is that estrogen also affects NOS activity. In fact, in female human endothelial cells, NOS activity has been shown to be affected by exposure to estrogen (9, 26). Whatever the mechanism, our current data suggest that high serum estrogen affects NOS-dependent modulation of myogenic tone.
The relationship between NOS activity and serum estrogen concentrations in our intact (33 ± 10 pg/ml) and ORX+EST (41 ± 8 pg/ml) male rats could have resulted from serum estrogen concentrations above the normal physiological range. For example, phytoestrogen-rich diets are known to artificially elevate serum estradiol concentrations that could have artificially increased NOS activity in the present study (14, 21). If that were the case, then our serum estradiol concentrations should be significantly higher than estradiol concentrations reported in the literature. However, in normal male rats, reported physiological concentrations of serum estrogen range from ~8 to 40 pg/ml (6, 22, 32, 42, 44, 45, 49, 50). These reported values are well within the serum estradiol concentrations determined in the present study. In comparison, reported serum estrogen concentrations in normal cycling (ovary-intact) female rats range between 20 and 500 pg/ml, with peak concentrations occurring in proestrus (8, 28). Combined, these observations suggest that serum estradiol levels in our study were not artificially elevated. More importantly, however, our work demonstrates that physiological concentrations of estrogen in male rats appear to affect NOS-sensitive mechanisms in a manner similar to the effect of estrogen on NOS function seen in arteries from female rats (19, 49). Together with the study by McNeill et al. (32), the present study is one of the first to show that estrogen augments NO function in male cerebral arteries. However, three recent studies in humans support our findings. In genetic males taking high doses of estrogens, reactive hyperemia caused endothelium-dependent dilation of peripheral arteries that was significantly greater than in untreated males (31, 38). Furthermore, in a male subject with estrogen resistance due to a disruptive mutation in the estrogen receptor gene, flow-dependent and NO-mediated dilation were impaired, and coronary artery disease occurred prematurely (43). Therefore, estrogen exposure may also provide cardiovascular protective properties in males. A substantial portion of the effects of estrogen appear to be NO dependent, presumably via an action on endothelial NOS activity.Testosterone and myogenic tone. In the present study, arteries from untreated male rats increased myogenic tone in response to elevation of transmural pressure. These findings support our previous work with rat cerebral arteries (19) as well as studies of myogenic tone in the rat coronary vascular bed (49). After ORX, the myogenic tone of cerebral arteries was significantly lower compared with myogenic tone in arteries from untreated rats. Treatment of ORX animals with testosterone reestablished myogenic tone in cerebral arteries to a level similar to that seen in untreated males. These results support the hypothesis that vascular reactivity and myogenic tone are modified by circulating testosterone.
Testosterone treatment significantly increased myogenic tone to levels very similar to those of arteries from untreated males. However, in the present study, plasma testosterone levels from ORX+TEST animals were significantly lower than levels found in untreated males as well as previously reported values for control male rats (10). These data suggest that testosterone replacement in our ORX+TEST was sufficient to affect myogenic responses similar to the intact male. Another possible interpretation from our myogenic tone and testosterone data in arteries from ORX and ORX+TEST rats is that the ratio of serum testosterone to estrogen impacts the level of myogenic tone. Testosterone may influence myogenic tone through modulation of connective tissue content and the ratio of collagen to elastin in the vascular wall. For example, testosterone has been shown to increase the collagen-to-elastin ratio in aorta of intact male rats (12), which could increase resistance to stretch (17). However, in the present study, differences in passive diameters and wall thickness were not detected between groups, suggesting that gonadal hormones enhanced myogenic tone through mechanisms independent of passive elements of the vessel wall. Whether higher plasma levels of testosterone or a period of exposure longer than 1 mo would have caused significant changes in the passive properties of the vessel wall is a subject for further study. Testosterone could directly alter pressure-sensitive contractile mechanisms or modulatory mechanisms specific to the vascular smooth muscle. There is some evidence that testosterone influences vascular smooth muscle contractility in response to agonist stimulation (20, 24). We are currently unaware of any data suggesting that testosterone, acting solely on vascular smooth muscle, alters myogenic reactivity. Furthermore, our data with endothelium-damaged arteries showed that the vascular smooth muscle response to pressure was not altered by testosterone treatment.Testosterone and the endothelium. Findings of the current study suggest that testosterone increases myogenic tone though endothelium-dependent mechanisms sensitive to cyclooxygenase and/or K+ channel inhibition but independent of NOS. For example, myogenic tone was higher in arteries from animals with elevated plasma testosterone and low plasma estrogen (ORX+TEST) compared with arteries from ORX animals with chronically low gonadal hormone exposure. These myogenic tone differences remained despite similar constrictor effects with NOS inhibition. But more importantly, during combined inhibition of K+ channels and the cyclooxygenase pathway, myogenic tone differences between ORX and ORX+TEST were abolished.
The mechanism whereby male gonadal hormones might affect normal endothelial cyclooxygenase or K+ channel function is presently unknown. A previous study has shown that a physiological concentration of testosterone suppresses prostacyclin production in arterial smooth muscle cells (35). Alternatively, our data in endothelium-intact arteries also suggest that sex hormones might interfere with the function of endothelial cell K+ channels. Blocking endothelial K+ channels would lower cytosolic Ca2+ (26) and blunt synthesis of endothelium-derived vasoactive substances (29). However, we are only aware of reports of an effect of testosterone on vascular smooth muscle cell K+ channels (48, 52). Testosterone might enhance myogenic reactivity through other endothelium-dependent mechanisms. For example, plasma testosterone concentrations correlate well with circulating endothelin levels in adult human males (39). Furthermore, when female-to-male transsexuals are treated with testosterone, plasma endothelin levels increase (39). Because endothelin is a powerful vasoconstrictor that could potentiate myogenic reactivity through changes in intracellular Ca2+ and second messenger mechanisms (46), an interesting area of future research would be to determine whether endothelin receptor antagonists modify the myogenic reactivity of cerebral blood vessels after testosterone treatment. Alternatively, plasma cholesterol or triglycerides are also modified by androgens, which could influence the course of atherosclerosis and normal endothelial function (5). Although our data conclusively show that testosterone affects endothelial function, the mechanism by which testosterone might affect cyclooxygenase or K+ channel function requires additional study.Gonadal hormones and cardiovascular risk. Evidence for the effect of testosterone on cardiovascular risk is conflicting. Epidemiological evidence demonstrates that the risk of stroke and cerebrovascular disease is greater in males compared with females of the same age (51). This evidence is supported by the experimental finding that in rats testosterone stimulates vascular smooth muscle growth and elevates systemic blood pressure (10, 17, 18, 41). Incidence of cerebrovascular disease also parallels plasma testosterone levels in abusers of androgenic steroids (2, 33, 34). On the other hand, it has been suggested that testosterone has cardiovascular protective effects (1, 7, 23). For example, in men with coronary artery disease and low plasma testosterone, administration of testosterone delayed the onset of acute exercise-induced myocardial ischemia (47). It is obvious from our present study and results of previous studies that testosterone can affect vascular reactivity. What continues to be unclear are the physiological parameters that dictate beneficial or deleterious effects of testosterone.
In summary, the present study has shown that myogenic tone is correlated with the presence of testosterone. NOS inhibition significantly increased myogenic tone, and our studies support the idea that the activity of endothelial NOS may be regulated by estrogen, even in males. Effects of testosterone were abolished by removal of the endothelium or after combined inhibition of the cyclooxygenase pathway and K+ channels. Wall thickness, passive artery diameters, and forced dilation were not significantly affected by testosterone treatment. Therefore, our data suggest that treatment with testosterone increases, whereas estrogen decreases myogenic tone in rat cerebral arteries. These effects of gonadal hormones appear to be mediated by NO-dependent and independent mechanisms.| |
ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant RO1 HL-50775.
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. G. Geary, Dept. of Pharmacology, College of Medicine, Univ. of California, Irvine, Irvine, CA 92697-4625 (E-mail:gggeary{at}uci.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. §1734 solely to indicate this fact.
Received 22 November 1999; accepted in final form 8 February 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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