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Vol. 296, Issue 3, 782-788, March 2001
Center for Cardiovascular Sciences, Albany Medical College, Albany, New York
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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The objective of this study was to examine the effects of gender and age on electrical field stimulation (EFS)-induced vasoconstriction. Fisher 344 rats were studied: young females (YF, n = 38), young males (YM, n = 29), old females (OF, n = 33), and old males (OM, n = 30). Isolated mesenteric resistance arteries (endothelium-intact or denuded) were pressurized, and outer diameter was monitored. Dose-response curves were performed to KCl and phenylephrine (PE). EFS (0.1-16 Hz) responses were expressed as percentage of constriction from baseline. Area under the curve (AUC) was calculated and comparisons were made using analysis of variance and t tests. Females became less responsive to EFS-induced constriction with age, whereas constrictor responses among males were unaffected (AUC: YF = 454 ± 15, OF = 284 ± 22, p < 0.001; YM = 391 ± 35, OM = 357 ± 31, p = 0.22). Endothelial denudation produced a significant increase in EFS-induced constriction in OF and OM. Endothelium removal in OF increased the EFS constrictor response to the level seen in arteries from YF. BQ 123 (ETA receptor antagonist) significantly decreased EFS-induced constriction in YM and OM. In YM, SQ 29,548 [thromboxane A2 (TXA2)/PGH2 receptor antagonist] and indomethacin depressed constrictor responses. There were no differences among groups in the sensitivity to KCl, but YF were the most sensitive to PE. In conclusion, EFS-induced vasoconstriction declined with age among females but not males. The decrease in EFS constrictor responses in OF may be due to a selective decrease in vascular smooth muscle sensitivity to adrenergic agonists and an increase in the production of an endothelium-derived vasodilator. Among males there is also an endothelin-1 and TXA2/PGH2 component to EFS-induced constriction that is absent among females.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Cardiovascular
function is altered with age in men and women. It is well established
that advancing age is a risk factor for the development of
cardiovascular disease. With advancing age there are a number of
structural alterations in the vasculature, which occur in otherwise
healthy individuals as part of the normal aging process. With advancing
age vascular function and reactivity are impaired, resulting in
increased stiffness, decreased distensibility and compliance, wall
thickening (Folkow and Svanborg, 1993
; Marin, 1995), and impaired
endothelial function (Egashira et al., 1993; Taddei et al., 1995;
Gerhard et al., 1996).
Epidemiological evidence suggests that aging affects the cardiovascular
system of men and women differently. Women have been reported to lag
behind men in coronary heart disease morbidity, as well as mortality
rates, by approximately a decade (Castelli, 1988; Celermajer et al.,
1994). Castelli (1988) reported that men and women differ in the
development of atherosclerotic lesions, with lesion onset occurring a
decade earlier in men. Celermajer et al. (1994) reported that
endothelial dysfunction occurs a decade earlier in men than in women as
assessed by flow-mediated dilation in response to reactive hyperemia.
In this study, we examined the effect of age on vascular adrenergic
function in male and female rats. Animal studies examining electrical
field stimulation (EFS) of adrenergic nerves in isolated tail arteries
have reported that arteries from male rats are more responsive to
EFS-induced vasoconstriction compared with those from females (Li and
Duckles, 1994; Garcia-Villalon et al., 1996; Li et al., 1997). Li and
Duckles (1994) reported that the observed gender difference in
EFS-induced vasoconstriction was abolished by ovariectomy of females,
but unaffected by orchidectomy in males. An effect of gender on
vascular smooth muscle sensitivity to adrenergic agonists has also been
examined. Sensitivity and maximum response to the 
-adrenergic
receptor agonist norepinephrine has been reported to be unaffected by
gender in the rat tail artery, although following orchidectomy in
males, maximum response is decreased (Li and Duckles, 1994). In the rat
aorta sensitivity to norepinephrine is unaffected by gender, however
the maximum response is enhanced in males (Stallone et al., 1991).
These findings suggest that male sex hormones increase vascular smooth
muscle sensitivity to adrenergic vasoconstriction. In regard to age,
EFS-induced vasoconstriction has been reported to decrease with age in
isolated tail arteries from male Ivanos (Fouda and Atkinson, 1986),
Wistar, and Fisher 344 rats (Thorin et al., 1994). In contrast,
EFS-induced vasoconstriction has been reported to be unaffected by
advancing age in both femoral and renal arteries isolated from male
rats (Duckles et al., 1985; Duckles, 1987). In experiments examining
the effect of age on adrenergic receptor sensitivity, the majority has
revealed that advancing age does not alter vascular smooth muscle
sensitivity to adrenergic agonists (Duckles et al., 1985; Docherty and
Hyland, 1986; Duckles, 1987; Elliott, 1988; Tsai et al., 1993).
However, in the rat tail artery (Fouda and Atkinson, 1986) and aorta
(Docherty, 1988), advancing age has been reported to decrease
vasoconstrictor sensitivity to -adrenergic receptor agonists.
Although studies have been done examining the effects of age or gender on the functional response of arteries to adrenergic nerve-induced vasoconstriction, no studies have examined the interaction of age and gender. A majority of the work that has been done to examine the effect of gender on EFS-induced vasoconstriction has focused on responses in young animals. Studies that have been performed to examine the effects of aging on EFS-induced constrictor responses have exclusively used male animals. Since cardiovascular function is known to be altered with advancing age, our study was designed to examine the effects of age on EFS-induced vasoconstriction in both male and female animals. We hypothesized that the effect of aging on EFS-induced vasoconstriction would differ in males and females.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Animals
Male and female Fisher 344 rats of two different ages were used in this study: 3-month-old (young rats) and 26-month-old (senescent) rats. The rats were obtained from the colonies at the National Institute on Aging and were barrier-raised. The rats were housed in individual Thoren cages (laminar airflow, autoclaved food, water, and bedding) in temperature- and humidity-controlled, light-cycled (6:00 AM-6:00 PM) quarters with ad libitum access to standard rat chow and water. Rats were fasted overnight before sacrifice. All procedures involving the use of animals were approved by the Institutional Animal Care and Use Committee and conform to federal, state, and institutional guidelines.
Preparation of Vascular Tissue
The rats were weighed and then euthanized using an overdose of sodium pentobarbital (120 mg/kg i.p.) followed by thoracotomy. A portion of the small intestine was removed and placed in cold physiological salt solution of the following composition: 130 mmol/l NaCl, 4.7 mmol/l KCl, 1.17 mmol/l MgSO4·7H2O, 1.18 mmol/l KH2PO4, 14.9 mmol/l NaHCO3, 5.5 mmol/l dextrose, 0.03 mmol/l NaCa2EDTA, and 1.6 mmol/l CaCl2·2H2O. Using a dissecting microscope, a mesenteric resistance artery was isolated, cleared of fat and connective tissue, and placed in a chamber of a dual-chambered arteriograph (Living Systems Instrumentation, Burlington, VT). One end of the vessel was cannulated with a glass microcannula and the vessel lumen was rinsed with physiological salt solution to remove the blood. The distal end of the artery was then secured to another glass microcannula. The artery was secured to the cannulae using nylon ties. The vessel was pressurized to 60 mm Hg and the pressure was maintained using an automatic servo device (Living Systems Instrumentation).
The artery was bathed by warmed (37°C), gassed (95% O2, 5% CO2) physiological salt solution, at a flow rate of 20 ml/min. The arteriograph was placed on the stage of an inverted microscope and the outer diameter of the vessel was monitored using computerized image analysis consisting of a Framegrabber card (PCVision Plus) and appropriate software (Microsciences Incorporated, Seattle, WA). The vessel was allowed to equilibrate for 45 min. At this point the viability of the vessel was determined by contracting the vessel with 1 µM phenylephrine (PE) followed by 10 µM acetylcholine to relax the vessel.
Electrical Field Stimulation-Induced Vasoconstriction
Electrical field stimulation was performed by securing two parallel platinum electrodes (Living Systems Instrumentation) on either side of the isolated artery in the arteriograph. The electrical current was driven by a Grass S48 stimulator set to the following parameters: 0.3-ms delay, 0.5-ms duration, 10 V, and 60 mA. Between the stimulator and the electrodes was placed a Stimu-Splitter II (Med-Lab Instruments, Loveland, CO), a device that serves to modulate wave form distortion and allows for measurement of current at the electrodes.
The arteries were stimulated at each frequency (0.1, 0.5, 1, 2, 4, 8, and 16 Hz) until a steady-state response was obtained and allowed to
rest between stimulations (approximately 5 min) until the artery
returned to the resting diameter. Following a frequency-response curve
the artery was allowed to reequilibrate for 30 min and then a second
curve was performed in the presence of a pharmacological inhibitor.
Preliminary studies confirmed that multiple frequency-response curves
could be performed reliably. To verify that adrenergic nerves mediated
the response, frequency-response curves were performed in the absence
and presence of the neurotoxin tetrodotoxin (300 nM; Kawasaki et al.,
1990) and the adrenergic nerve inhibitor guanethidine (5 µM; Li and
Duckles, 1992).
Role of the Endothelium
To examine the role of the endothelium, frequency-response
curves were performed in endothelium-denuded arteries. Endothelium denudation was accomplished by first rubbing the vessel lumen with a
human hair and then passing air bubbles through the lumen (Osol et al.,
1989; Case and Davison, 1999). Denudation was verified by the absence
of a vasodilator response to acetylcholine in a vessel preconstricted
with PE. The role of endothelium-derived vasoactive factors was
determined by performing frequency-response curves in the absence and
presence of pharmacological inhibitors. Frequency-response curves were
performed following a 10-min incubation with the inhibitor.
Endothelial-derived constricting factors were examined using the
selective ETA receptor antagonist BQ 123 (10 µM; Awane-Igata et al., 1997) and the
TXA2/PGH2 receptor
antagonist SQ 29,548 (1 µM; Ward et al., 1990). The
ETA receptor has been demonstrated to mediate
ET-1-induced vasoconstriction, whereas the
TXA2/PGH2 receptor mediates
the contractile responses of endogenous eicosanoids (Ward et al., 1990;
Awane-Igata et al., 1997; Ergul et al., 1998). Endothelial-derived
nitric oxide was examined using the nitric-oxide synthase inhibitor
N
-nitro-L-arginine
(LNA; 100 µM; Case and Davison, 1999). The role of
endothelial-derived cyclooxygenase products was examined using the
cyclooxygenase inhibitor indomethacin (10 µM; Case and Davison, 1999).
Vasoconstrictor Studies
Cumulative concentration-response curves were performed in
endothelium-intact arteries to 1) the -adrenergic receptor agonist PE (1 nM-10 µM) and 2) KCl [4.7-100 mM, in the presence of
phentolamine (1 µM)]. Each concentration of agonist was added only
after the vessel had reached a plateau from the previous dose. The
vessel was then rinsed with fresh physiological salt solution
and allowed to reequilibrate for 30 min.
Drugs
Acetylcholine, PE, LNA, indomethacin, tetrodotoxin, guanethidine, BQ 123, and phentolamine were all purchased from Sigma Chemical Co. (St. Louis, MO). Buffer reagents, including KCl, were purchased from Fisher Scientific (Pittsburgh, PA). SQ 29,548 was purchased from Cayman Chemicals (Ann Arbor, MI). Stock solutions of acetylcholine (100 mM), phenylephrine (10 mM), LNA (10 mM), tetrodotoxin (1 mM), guanethidine (5 mM), and KCl (3 M) were all made in distilled water. Stock solutions for indomethacin (10 mM) and SQ 29,548 (1 mM) were made in 95% ethanol. All further dilutions were made in water. The maximum ethanol concentration in the bath did not exceed 0.1%.
Statistical Analysis
Electrical Field Stimulation. All data are expressed as mean ± S.E.M. Frequency-response curves are expressed as percentage of constriction from baseline diameter. Curves were analyzed by calculating the area under the curve (AUC; GraphPad Prism 2.01; GraphPad, San Diego, CA). All statistical analyses were performed using STATISTICA for Windows 4.0 (StatSoft, Inc., Tulsa, OK). Control responses between the four rat groups were compared using a two-way ANOVA (factor 1, age; factor 2, gender). Individual comparisons were then performed using a Student-Newman-Keuls test. To analyze the effects of pharmacological inhibitors on the AUC, within-group comparisons were made using a t test for dependent samples. Between-group comparisons were made using repeated-measures ANOVA followed by t tests for independent samples.
Dose-Response Curves. KCl and PE concentration-response curves are expressed as percentage of the maximum response. KCl and PE concentration-response curves were analyzed with nonlinear regression of sigmoidal dose-response curves (GraphPad Prism), which was used to calculate the EC50 (concentration of agonist that elicited 50% of the maximum response), maximum response, and slope. The negative log EC50 values (pD2) for KCl were compared using a two-way ANOVA. Since there were significant differences in the slope of the PE curves between groups, PE sensitivity was analyzed by calculating percentage of constriction at a threshold concentration of PE (0.16 µM). The percentage of constrictions was compared using a two-way ANOVA. Individual comparisons for both KCl and PE were then performed using a Student-Newman-Keuls test. For all comparisons, p < 0.05 was considered significant.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Effect of Age on EFS-Induced Adrenergic Vasoconstriction in Female
and Male Rats.
Frequency-response curves for arteries from females
and males are shown in Fig. 1, A and B,
respectively. Shown in Fig. 2 are the
integrated AUC values for the four rat groups. Baseline diameters (in
µm) of the arteries at the beginning of the experiment were as
follows: young females (YF), 252 ± 5, and old females (OF),
280 ± 6; young males (YM), 261 ± 7, and old males (OM), 276 ± 8. Arteries from YF were slightly but significantly smaller than arteries isolated from OF and OM (YF versus OF, p = 0.0083; YF versus OM, p = 0.023). EFS produced a
frequency-dependent vasoconstriction in all rat groups (Fig. 1). Among
the females there was a significant decrease in EFS-induced adrenergic
vasoconstriction with age (Figs. 1A and 2). Advancing age had no effect
on adrenergic vasoconstriction among the males (Figs. 1B and 2). YF
were significantly more responsive to EFS-induced constriction compared
with the other rat groups, as indicated by a significantly greater AUC
(Fig. 2). OF were significantly less responsive, indicated by a
significantly lower AUC compared with the other three rat groups (Fig.
2, AUC values, and Fig. 2, legend for p values). The
adrenergic nature of the response was verified by complete blockade
with either tetrodotoxin or guanethidine in all four rat groups (data
not shown).
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Effect of the Vascular Endothelium on EFS-Induced Adrenergic
Vasoconstriction.
Endothelial denudation significantly increased
EFS-induced vasoconstriction in OF and OM, whereas constrictor
responses in YF and YM were unaltered (Fig.
3, AUC values). Removal of the endothelium in OF increased the EFS constrictor responses to the level
seen in denuded arteries from YF (N.S., p = 0.56).
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Effect of Gender and Age on Agonist-Induced Vasoconstriction.
Cumulative concentration-response curves to PE in young and old, male
and female rats are shown in Fig. 5.
Baseline diameters (in µm) of the arteries at the beginning of the
experiment were as follows: YF, 265 ± 17; OF, 317 ± 16; YM,
259 ± 17; and OM, 315 ± 13. Arteries from OM were slightly
but significantly larger than arteries isolated from YF and YM (OM
versus YF, p = 0.029; OM versus YM, p = 0.036). Since we found the slope of the PE curve increased
significantly with age (data not shown), data were analyzed by
calculating the constrictor response to PE at a threshold concentration (1.6 × 10
7 M). Arteries isolated
from YF were significantly more sensitive to PE compared with arteries
from the other three rat groups (Fig. 5, see legend for % constriction
values). There were no differences in absolute maximum responses to PE
(% constriction from baseline: YF, 50 ± 2; OF, 53 ± 2; YM,
51 ± 2; and OM, 55 ± 2) (N.S., p = 0.62 for
the effect of gender and p = 0.084 for the effect of age).
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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In this study we found that in isolated mesenteric resistance arteries, there is a gender difference in EFS-induced adrenergic vasoconstriction. Arteries isolated from young females were more responsive to constriction relative to arteries isolated from young males. With advancing age, there was a decline in EFS-induced constriction among females; however, advancing age has no effect on constrictor responses among males. These data suggest that advancing age effects vascular reactivity differently in males and females. In addition, there were gender- and age-dependent alterations in the role of the vascular endothelium to modulate EFS-induced vasoconstriction.
A selective enhancement in vascular smooth muscle sensitivity to
-adrenergic receptor agonists among YF appears to account for the
observed gender difference to EFS-induce vasoconstriction, as there
were no differences in KCl sensitivity. There are a number of possible
mechanisms that may mediate the enhanced sensitivity among YF.
Adrenergic vasoconstriction is mediated primarily by the binding of
norepinephrine to 1-adrenergic receptors
located on vascular smooth muscle cells. Arteries from young females
may possess more 1-adrenergic receptors than
arteries from males, resulting in a greater amplification of the signal
and enhanced vasoconstriction. Norepinephrine-mediated vasoconstriction
is dependent upon increasing intracellular levels in
Ca2+. Knot et al. (1999) reported that
[Ca2+]i is greater in
endothelial cells of coronary arteries isolated from female rats
compared with males. Therefore, it is possible that vascular smooth
muscle cells from females also have higher [Ca2+]i, which would
result in enhanced vasoconstriction. In addition, although in this
study we only examined the overall constrictor response to EFS and
postjunctional adrenergic receptor sensitivity, our data do not rule
out the possibility of prejunctional neuronal changes with advancing age.
In contrast to our findings, other investigators have reported a gender
difference to EFS-induced vasoconstriction with tail arteries from
young females being less responsive relative to arteries from males (Li
and Duckles, 1994; Garcia-Villalon et al., 1996; Li et al., 1997). Li
et al. (1997) reported that ovariectomy, but not orchidectomy,
abolished this gender difference. Garcia-Villalon et al. (1996)
reported no effect of gonadectomy on EFS-induced vasoconstriction,
although incubation of arteries with estradiol significantly decreased
constrictor responses in males and females. These studies suggest that
ovarian hormones depress adrenergic vasoconstriction. In reference to
adrenergic agonists, in the rat tail artery, sensitivity, as well as
fractional norepinephrine release (Garcia-Villalon et al., 1996;
Garcia-Villalon et al., 1997), have been reported to be unaffected by
gender (Li and Duckles, 1994; Li et al., 1997). In the rat mesentery,
PE sensitivity has been reported to decrease following estrogen
replacement in ovariectomized rats (Meyer et al., 1997; Zhang and
Davidge, 1999).
Published experiments examining EFS-induced adrenergic vasoconstriction have primarily been performed using isolated rat tail arteries. Tail arteries are typically used in these studies due to the fact that they are richly innervated by adrenergic nerves. Mesenteric arteries, however, are innervated by both adrenergic nerves as well as sensory nerves. In addition, tail and mesenteric arteries serve very different functions in the body. The rat tail is a thermoregulatory organ. The tail artery allows the animal to modulate its body temperature by adjusting the amount of blood in the tail via arterial constriction/dilation. Mesenteric arteries on the other hand have been demonstrated to be important in the control of blood flow and regulation of systemic vascular resistance. For these reasons, responses found in the tail artery would not necessarily be expected to be reproduced in resistance arteries.
With advancing age, we found a decrease in EFS-responsiveness and PE
sensitivity among females but not males. In contrast to our results,
published studies report that in other vascular beds, EFS-induced
vasoconstriction either declines or is unaffected by advancing age.
EFS-induced vasoconstriction in isolated tail arteries has been
reported to decrease with age in male Ivanos, Wistar, and Fisher 344 rats (Fouda and Atkinson, 1986; Thorin et al., 1994) as well as
subcutaneous resistance arteries from humans (Nielsen et al., 1992). In
femoral and renal arteries isolated from male Fisher 344 rats,
EFS-induced vasoconstriction has been reported to be independent of age
(Duckles et al., 1985; Duckles, 1987). In experiments examining
vascular smooth muscle sensitivity to adrenergic agonists,
investigators have reported either no effect (Duckles et al., 1985;
Docherty and Hyland, 1986; Duckles, 1987; Elliott, 1988; Tsai et al.,
1993) or a decrease in sensitivity with age (Fouda and Atkinson, 1986;
Docherty, 1988).
Although the basis for these discrepancies between our results and
those of others is not obvious, possibilities include differences in
vascular beds and rat strains. Within Fisher 344 rats EFS-induced vasoconstriction has been reported to decrease with age in tail arteries, whereas constrictor responses in femoral and renal arteries are maintained. These results support the proposal that the vascular bed influences arterial reactivity. Our results however, do support the
postulate that advancing age affects the vasculature of males and
females differently. More specifically, age-related alterations in the
vasculature enhance vasoconstriction in males relative to females. The
selective decline in adrenergic vasoconstriction among females with
advancing age is mediated, at least in part, by a decrease in vascular
smooth muscle sensitivity to adrenergic agonists. The mechanism
mediating this decline may involve
1-adrenergic receptors, the signal
transduction pathway or alterations in
[Ca2+]i.
We examined the role of the vascular endothelium in adrenergic nerve-induced vasoconstriction. Among YF the endothelium does not have a role to modulate constrictor responses. In YM, removal of the endothelium has no net effect on EFS-induced vasoconstriction. Among YM, however, the use of pharmacological inhibitors suggests that ET-1, constrictor cyclooxygenase products, and TXA2 are released from the endothelium and enhance EFS-induced vasoconstriction. Since the magnitudes of the indomethacin and SQ 29,548 effects are similar, it is possible that the constrictor cyclooxygenase product is TXA2. Therefore there is a gender difference in the role of the endothelium to modulate EFS-induced vasoconstriction, among males the endothelium liberates vasoconstrictors that enhance EFS-induced constriction.
This finding suggests that the ET-1 and
TXA2/PGH2 pathways of
vasoconstriction are controlled differently in males and females. Although this study did not assess the functionality of the ET-1 and
TXA2/PGH2 pathways or
receptors, the evidence suggests that perhaps ETA
and TXA2/PGH2 receptors in
arteries from males are more sensitive to stimulation in response to
EFS than in arteries from females. Ergul et al. (1998) have
demonstrated that in human saphenous veins men have a greater density
of ETA receptors compared with women and a 2-fold
greater contractile response to exogenous ET-1. In addition,
testosterone has been reported to increase TXA2/PGH2 receptor density
and sensitivity (Halushka et al., 1995). These studies suggest that the
male gender has a greater contractile response to ET-1 and
TXA2/PGH2, which may
account for the gender difference observed in our study in the effects
of BQ 123 and SQ 29,548 on EFS-induced vasoconstriction.
The fact that endothelial denudation has no net effect on EFS-induced vasoconstriction among YM, combined with evidence supporting a role for endothelium-derived constrictors, suggests that endothelium-derived vasodilators are also being released, which counteract the effect of the constrictors. Cyclooxygenase inhibition decreased constriction, and inhibition of nitric-oxide synthase did not significantly alter constriction, indicating that neither prostaglandin I2 or NO are modulating constriction. Therefore, it is likely that EDHF is being liberated and is acting to dampen the constrictor response.
In contrast to our findings, there is evidence in the literature that
the vascular endothelium functions, in part, to suppress adrenergic
nerve-induced vasoconstriction. In the rat tail artery (Bucher et al.,
1992; Li and Duckles, 1992), rat mesenteric artery (Nase and Boegehold,
1997), mesenteric arteries from monkeys (Tsuchiya et al., 1994), and
cerebral arteries from humans (Aldasoro et al., 1996) it has been
reported that removal of the endothelium, or incubation with
nitric-oxide synthase inhibitors, enhances EFS-induced
vasoconstriction. The enhanced EFS-induced vasoconstriction in rat tail
arteries (Vo et al., 1991; Li and Duckles, 1992), caudal arteries (Vo
et al., 1992), and mesenteric arteries (Nase and Boegehold, 1997)
following incubation with nitric-oxide synthase inhibitors was lost in
arteries denuded of their endothelium. Additionally, Boric et al.
(1999) have recently demonstrated a direct correlation between
EFS-induced norepinephrine release and increases in NO release and cGMP
levels in the perfused rat mesentery. These studies suggest that
endothelial-derived NO depresses constrictor responses.
Our study does not support a large role for endothelial modulation of adrenergic responses in young animals. However, a majority of the studies described above were performed using only male rats. Those studies that did include female rats did not differentiate their findings between the genders. In addition, endothelial NO has primarily been examined. Although our results do not support a role for NO modulation of EFS-induced vasoconstriction, the endothelium-dependent vasodilator EDHF does appear to modulate constrictor responses among YM. The ability of endothelium-derived vasoconstrictors and EDHF to modulate EFS-induced constriction has been largely unexplored before this study and is a novel finding of this study.
Endothelial denudation abolished the observed age effect among females and uncovered an age effect among males. The enhanced constrictor response among old males and females following denudation suggests that with advanced age there is an increase in the production of an endothelium-derived vasodilator that normally acts to oppose constriction. Pharmacological inhibitors of nitric-oxide synthase and cyclooxygenase failed to enhance EFS-induced adrenergic vasoconstriction, suggesting that with advanced age there is an increase in the production of EDHF, which acts to antagonize vasoconstriction. Among old males there also appears to be a loss of endothelium-derived TXA2. The mechanism of this effect, either via a direct alteration in the function of the receptor or through a change in the signaling pathway, was not investigated in this study. Although there does still appear to be an ET-1 component to EFS-induced constriction with age in males, the overall effect of the endothelium is to depress, and not enhance, constriction. Therefore, taken together, the contribution of ET-1 to EFS-induced constriction may be negligible. These results do however support the postulate that endothelial function is altered differently in males and females with advancing age.
We conclude that there is a gender difference in EFS-induced adrenergic
vasoconstriction, with YF being more sensitive to constriction relative
to YM. Advancing age affects adrenergic vasoconstriction
differently in males and females. Among females there is a decline in
EFS-induced constriction with age, whereas advancing age has no effect
on constrictor responses among males. The decreased response among
females is likely mediated by a decrease in vascular smooth muscle
sensitivity to -adrenergic receptor agonists as well as an increase
in the production of an EDHF from the vascular endothelium. In
addition, there is a gender difference in the role of the endothelium
to modulate EFS-induced vasoconstriction. Among YM, the endothelium
liberates both vasodilators as well as vasoconstrictors, whereas the
endothelium has no role in EFS-mediated constrictor responses among YF.
Furthermore, in both males and females, with advancing age the
complement of factors released from the endothelium is altered.
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Acknowledgment |
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We acknowledge the excellent technical assistance of Carlos O. Rivera.
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Footnotes |
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Accepted for publication November 3, 2000.
Received for publication July 28, 2000.
This work was supported by grants (to C.A.D.) from the National Institutes of Health (AG15658), the American Heart Association (9950341N), and (to J.C.S) Pharmaceutical Research and Manufacturers of America Foundation.
This work is a part of the doctoral thesis of Jennifer C. Sullivan.
A portion of this work was previously presented in abstract form at Experimental Biology 2000 [Sullivan JC and Davison CA (2000) Effect of age and gender on electrical field stimulation (EFS)-induced vasoconstriction. FASEB J 14:A482.12].
Send reprint requests to: Dr. Jennifer C. Sullivan, Center for Cardiovascular Sciences, Albany Medical College, 47 New Scotland Ave., Albany, NY 12208. E-mail: jsullivan{at}mcg.edu
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Abbreviations |
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EFS, electrical field stimulation;
PE, phenylephrine;
ET, endothelin;
TXA2, thromboxane
A2;
PGH2, prostaglandin endoperoxide 2;
LNA, N-nitro-L-arginine;
AUC, area
under the curve;
ANOVA, analysis of variance;
YF, young female;
OF, old
female;
YM, young male;
OM, old male;
NO, nitric oxide;
EDHF, endothelium-derived hyperpolarizing factor.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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) and denuded (
). Denudation
significantly increased EFS-induced vasoconstriction in OF
(p = 0.0051) and OM (p = 0.047). Constrictor responses among YF (N.S., p = 0.47) and YM (N.S., p = 0.33) were not
significantly altered. *Indicates significant difference from control.
**Indicates significant difference between groups.
n = 13 for YF and YM, n = 10 for OF and OM. Values represent means ± S.E.M.
1.3 ± 0.04, OF =