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HIGHLIGHTED TOPICS
Skeletal and Cardiac Muscle Blood Flow
Department of Exercise Science, University of Iowa, Iowa City, Iowa 52242
Submitted 2 February 2004 ; accepted in final form 7 April 2004
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ABSTRACT |
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-estradiol on TAQ, MAP, and VC. The analysis revealed that female sex did not influence TAQ but reduced MAP and increased VC at rest and during exercise conditions. Plasma 17-estradiol (measured by immunoassay) significantly decreased MAP and increased TAQ and VC, irrespective of sex. Cyclooxygenase inhibition eliminated the significant association between MAP and estrogen, suggesting that estrogenic modulation occurred through PG-dependent processes. In contrast, the significant influence of estrogen on TAQ and VC was eliminated after NO synthase inhibition. On the basis of the overall findings of this study, estrogen influenced the vascular responses to dynamic exercise through PG- and NO-dependent pathways, but this occurred independent of sex. active hyperemia; dynamic exercise; limb blood flow; arterial pressure
Inhibition of NO synthase, the class of enzymes catalyzing the formation of NO, is characterized by a significant decrease in resting blood flow and vascular conductance (VC), although the magnitude of the rise in blood flow and VC in response to exercise is not affected (14, 18, 21). Similarly, cyclooxygenase inhibition, which attenuates prostaglandin (PG) production (including endothelially derived prostacyclin), decreases the absolute level of blood flow and VC achieved during exercise (12). One common limitation to studies examining the contributions of endothelium-induced vasodilation to exercise hyperemia is that the production of only one endothelial vasodilator is inhibited. It is possible that, in the event of NO synthase inhibition, a greater stimulus for endothelial PG production exists and sustains the "normal" hyperemic response to exercise and vice versa. Furthermore, it has been found in isolated skeletal muscle arterioles that sex alters the specific endothelial mediators that elicit flow-induced vasodilation (3, 27). It is unknown whether sex differences in the relative contributions of NO and PG production or overall vascular tone are present during exercise conditions or whether estrogen modulates vascular responses to dynamic exercise.
Therefore, the purpose of this study was to determine whether estrogen influenced the contributions of NO and PG to the hyperemic response to treadmill locomotion. To test this, we used four groups of rats: males, females, ovariectomized females, and ovariectomized females with chronic estrogen supplementation. Each rat completed an exercise protocol consisting of treadmill locomotion at several speeds (5, 7.5, 10, and 15 m/min). All data were collected after efferent autonomic function was inhibited by hexamethonium. This was done to eliminate potential sex differences in sympathetic function, thereby allowing us to focus on the influence of sex on peripheral vascular factors. Exercise bouts were imposed under control (hexamethonium) conditions, during the time that both autonomic function and cyclooxygenase were inhibited, and during the time that autonomic function, cyclooxygenase, and NO synthase were inhibited. All animals performed exercise under all of these conditions. Although we created four distinct animal groups with the intent of creating varying levels of plasma estradiol (E2) concentrations, neither our hypotheses nor our analysis explicitly focused on comparisons among the individual groups of animals. Rather, we focused on determining the importance of specific factors that are known to vary within each group of animals (e.g., plasma E2 concentrations) as well as across the groups of animals (e.g., being female, ovary removal). For example, although plasma E2 concentrations were certainly expected to be high in the 17-estradiol-supplemented treatment group and could potentially exert an important influence on vascular function, E2 concentrations were also expected to vary within the sham-operated female group (and indeed among the male treatment group as well), and our analysis sought to take these factors into account. Our hypotheses are as follows: 1) VC will be positively associated with estrogen status and 2) to the extent that hypothesis 1 is correct, cyclooxygenase inhibition and NO synthase inhibition will decrease VC in proportion to the contribution that each of these vasodilator pathways makes to any estrogen-mediated differences. Thus our approach was twofold. First, we intentionally manipulated plasma E2 levels, as well as other sex factors, across a wide range. Second, we administered specific inhibitors of vasodilator pathways that are influenced by estrogen and possibly other sex factors to test the extent to which these pathways constitute mechanisms by which sex differences in exercise hyperemia might be expressed.
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METHODS |
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Four groups of Sprague-Dawley rats were used during the following experimental protocols: sham-operated males (n = 6, 364–446 g), sham-operated females (n = 5, 258–284 g), ovariectomized females (n = 5, 264–302 g), and ovariectomized females with estrogen replacement (n = 6, 218–274 g). Each animal was familiarized with locomotion on a rodent treadmill (model 1010 Modular Treadmill, Columbus Instruments, Columbus, OH) before undergoing the experimental protocols. All procedures complied with National Institutes of Health guidelines and were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Iowa.
Surgical Preparation
All animals were obtained at 12 wk of age. Each animal underwent either a sham operation or ovariectomy (with or without estrogen replacement) and was allowed a 4-wk recovery period. After the administration of anesthesia (2% isoflurane inhalation), a midline abdominal incision was made during the ovariectomy procedure to locate the uterus and ovaries. The junction between the uterus and each ovary was ligated, followed by ovary excision. The abdominal incision was then closed in layers. Sham-operated rats underwent a similar procedure without removal of the ovaries. In ovariectomized females with estrogen supplementation, a small incision was made in the skin on the neck for insertion of a time-release estrogen pellet (0.72 mg 17-estradiol/pellet, 60-day release, Innovative Research of America) then closed and sutured. Buprenorphine (0.03 mg/kg sq) was given postoperatively for control of pain. During the subsequent recovery period, approximately once per week each animal was required to complete short bouts (<1 min) of treadmill locomotion at various speeds (5–25 m/min) and grades (–10–10°). The goal of this protocol was to promote treadmill familiarization without eliciting significant exercise training responses.
Flow probe insertion was adapted from the methods presented for rats by Sheriff and Hakeman (22). After anesthetization (2% isofluorane inhalation), a midline abdominal incision was made slightly lateral to the original incision to position an ultrasonic transit-time blood flow transducer (model 1.5RB, Transonic, Ithaca, NY) around the terminal portion of the aorta. The probe cable was tunneled subcutaneously to a midscapular exit site. The animal was allowed to recover for 3–5 days or until an acceptable blood flow signal was acquired. Buprenorphine (0.03 mg/kg sq) was given postoperatively for control of pain.
On the day of an experiment, rats were anesthetized (2% isofluorane inhalation) for catheterization (PE-50 tubing) of a carotid artery for subsequent blood pressure measurement and drug induction. Catheter tubing was tunneled subcutaneously to a midscapular exit site, and the incision was closed in layers. One concern with carotid catheterization is that it may elicit baroreceptor-mediated reflex adjustments in cardiovascular control mechanisms. However, hexamethonium bromide (an inhibitor of autonomic neurotransmission) was administered before experimentation, and this would eliminate the efferent actions of baroreflex-mediated changes in autonomic function elicited by carotid catheterization as well as any potential sex differences in baroreflex sensitivity that could influence cardiovascular function (5, 15). Animals were allowed sufficient recovery before further experimentation, generally 2–4 h.
Experimental Protocols
Before the experimental protocol was begun, the arterial catheter was connected to a pressure transducer (model P10EZ, Ohmeda, Madison, WI), which was then connected to a signal conditioner (model 660, Gould Instrument Systems, Valley View, OH). The flow transducer was connected to a flowmeter (model T106, Transonic). Signals were displayed on a chart recorder (model MT95K2, Astro-Med, West Warwick, RI) and written to a fixed disk of a microcomputer with the use of commercially available software (PONEMAH Physiology Platform, P3, Gould Instrument Systems). Data were digitized at 250 Hz. On completion of the setup procedures, the animal was placed on a rodent treadmill.
The main focus of this protocol was to determine whether estrogen modulated the contributions of NO and PG to cardiovascular responses to dynamic exercise. To eliminate the potentially confounding influence of autonomic adjustments in cardiovascular function during exercise, hexamethonium bromide (10 mg/kg body weight) was administered intra-arterially (carotid catheter) a minimum of 10 min before the first exercise bout. A supplemental dose of hexamethonium (5 mg/kg body weight) was given approximately every 60 min. Once baseline measures for terminal aortic blood flow (TAQ) and mean arterial pressure (MAP) were constant after hexamethonium administration, each animal completed four bouts of treadmill locomotion. Each bout consisted of 2 min of treadmill locomotion followed by 3 min of recovery. Individual bouts at 5, 7.5, 10, and 15 m/min (0% grade) were imposed in no regular order. The TAQ response in rats performing treadmill locomotion within this range of work rates is substantially complete within 30 s of the onset of locomotion (23).
Each animal was then given an intraperitoneal injection of indomethacin (5 mg/kg body wt, in dimethyl sulfoxide) to inhibit cyclooxygenase activity and therefore PG production. The efficacy of this dose in this species has been demonstrated previously (8, 25). Indomethacin was given before nitro-L-arginine methyl ester (L-NAME) because indomethacin has little effect on VC at rest (25), whereas L-NAME has large effects (18, 23); varying the order of drug administration might alter the results. A minimum of 30 min were allowed until baseline TAQ and MAP were stable. Animals then repeated the exercise protocol (2 min treadmill locomotion at 5, 7.5, 10, and 15 m/min, 0% grade, followed by 3 min recovery after locomotion at each treadmill speed).
To determine whether NO production could account for any residual differences in cardiovascular parameters after the indomethacin trials, each animal received an intra-arterial injection of L-NAME (10 mg/kg body weight) to inhibit NO synthase activity and was allowed a minimum of 10 min for cardiovascular parameters to stabilize. The efficacy of this dose of L-NAME was inferred from the large rise in MAP coupled with the large decrease in TAQ and hindlimb VC (e.g., Fig. 1). The exercise protocol was repeated.
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MAP and TAQ values were averaged over 1-s intervals, beginning before the onset of treadmill locomotion until the end of each exercise bout. To normalize the data to account for significant differences in body size for male and female rats, TAQ was expressed per 100 g of estimated hindlimb weight. On the basis of pilot studies in a separate group of rats, hindlimb body weight (weight of all tissue distal to the flow probe) was calculated as one-third of total body weight, and this value was not significantly different for male and female rats (data not shown). Because regional blood flow and systemic arterial pressure change in response to dynamic exercise, VC (which takes into account blood flow for a given perfusion pressure) was derived as an index to quantify adjustments in vascular tone. Hindlimb VC was calculated as the ratio of TAQ to MAP. Each animal's steady-state value for MAP, TAQ, and hindlimb VC was approximated by taking 15-s averages immediately before locomotion onset (baseline) and for the last 15 s of locomotion at each treadmill speed for hexamethonium, indomethacin, and L-NAME trials. On the completion of the entire exercise protocol, 
1 ml of whole blood was obtained from each animal for analysis of plasma E2 concentrations (chemiluminescence immunoassay; pathology laboratory at University of Iowa Health Center).
Statistical Analysis
To assess the overall contribution of the different treatments across the data set as a whole, a regression was done for each of the primary dependent variables (MAP, TAQ, hindlimb VC). Treatment effects were tested statistically by multiple linear regression (24). Both dummy variables and actual measured variables were used as independent variables to encode treatment effects analogous to a repeated-measures ANOVA (24). Dummy variables were used to encode for sex (0 for males, 1 for females) and whether the animal was ovariectomized (0 for not ovariectomized, 1 for ovariectomized). Also, dummy variables were used to encode for indomethacin treatment (0 for data collected before indomethacin, 1 for data collected after indomethacin) and for L-NAME treatment (0 for data collected before L-NAME, 1 for data collected after L-NAME). The actual quantitative values of plasma E2 and treadmill speed were also entered into the regression. For example, all values of MAP [equal to 22 rats x 8 conditions (4 work rates and each work rate's associated rest value) x 3 drug conditions (hexamethonium alone, hexamethonium + indomethacin, hexamethonium + indomethacin + L-NAME)], minus one rest and one 15 m/min value for one estrogen-supplemented ovariectomized rat after administration of both indomethacin and L-NAME (equal to 526 values), were entered into a single regression with dummy variables encoding sex, ovariectomy, indomethacin treatment, L-NAME treatment, and the actual measured values of plasma E2 and work rate. This was repeated for analysis of TAQ and hindlimb VC. Significance was accepted at P < 0.05.
It must be remembered that there is an important distinction for the apparent "strength" of a treatment effect (i.e., the numeric value of the regression coefficient for a particular treatment) between a dummy variable and an actual measured variable. For a dummy variable having a value of unity, all of the treatment effect is "lumped" into the numeric value of the regression coefficient. For example, if the regression coefficient for being female were –7 mmHg, then being female is associated with a 7-mmHg reduction in MAP. On the other hand, for actual measured variables, the strength of the treatment effect (i.e., the numeric value of the regression coefficient) reflects the strength of the treatment per unit of the measured variable. For example, if the numeric value of the regression coefficient for E2 were –0.07 mmHg·pg–1·ml–1, then the overall strength of the E2 treatment when plasma E2 concentrations equals 100 pg/ml would be –7 mmHg.
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RESULTS |
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MAP. The regression coefficients for the treatment effects for the data set as a whole are presented in Table 2 along with their associated P values. For MAP, all of the independent variables produced statistically significant treatment effects (Table 2). For the treatment effects encoded by dummy variables, L-NAME treatment was associated with the largest effect on MAP (+34.2 mmHg; P < 0.01). Ovariectomy raised MAP by 13.2 mmHg (P < 0.01) and indomethacin treatment raised MAP by 6.1 mmHg (P < 0.01). Conversely, the coefficient for the female dummy variable was –6.9 mmHg, indicating that being female lowered MAP by 6.9 mmHg (P < 0.01). There was also a significant treatment effect for E2 (–0.05 mmHg·pg–1·ml–1; P < 0.01). On the basis of the directionally opposite MAP response to exercise before and after L-NAME, (e.g., Fig. 1, A and B vs. C), a final dummy variable, equal to the product of the dummy variable encoding L-NAME and the actual measured variable reflecting work rate, was entered into the regression to test statistically for the apparent interaction of these two variables. Both work rate and the interaction dummy variable achieved statistical significance. The regression coefficient for work rate was +0.25 mmHg·m–1·min–1 (P < 0.01), indicating that MAP tended to increase by 2.5 mmHg for each 10 m/min increase in treadmill speed in Fig. 1, A and B. The regression coefficient for the dummy variable encoding the interaction between L-NAME and work rate was –1.1 mmHg·m–1·min–1 (P < 0.01), indicating that MAP tended to fall by 11 mmHg for each 10 m/min increase in treadmill speed (Fig. 1C).
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Hindlimb VC. For hindlimb VC, all of the independent variables were associated with statistically significant treatment effects. For the treatment effects encoded by dummy variables, L-NAME treatment was yet again associated with the largest effect [–0.0634 ml·min–1·100 g–1·mmHg–1 (conductance units); P < 0.01]. Ovariectomy reduced hindlimb VC by 0.0237 conductance unit (P < 0.01), and indomethacin reduced hindlimb VC by 0.0160 conductance unit (P < 0.01). Conversely, the coefficient for the dummy variable encoding female sex was +0.0112, indicating that being female raised hindlimb VC by 0.0112 conductance units (P < 0.05). There were also significant treatment effects (both P < 0.01) for E2 (+0.0003 conductance unit·pg–1·ml–1) and work rate (+0.0080 conductance unit·m–1·min–1).
Individual Drug Treatment Effects
MAP.
By and large, the pattern of the effects of the four treatments on MAP seen across the data set as a whole persisted across each drug condition individually. For example, the strength of the tendency of ovariectomy to increase MAP was similar under each drug condition individually (+13.7, +13.2, and +12.6 mmHg for hexamethonium, indomethacin, and L-NAME, respectively, all P < 0.001; Table 3). Similarly, female sex was associated with an 7 mmHg reduction in MAP across drug conditions (all P < 0.05; Table 4). Notably, the strength of the estrogen treatment effect on MAP seen during hexamethonium alone (–0.06 mmHg·pg–1·ml–1; P < 0.01) was reduced by one-third after administration of indomethacin (to –0.04 mmHg·pg–1·ml–1), and E2 no longer exerted a statistically significant effect (P = 0.09). L-NAME administration had little further effect on the influence of E2 on MAP (–0.04 mmHg·pg–1·ml–1; P = 0.06). Finally, the tendency for MAP to increase with rising work rate during hexamethonium alone (+0.23 mmHg·m–1·min–1; P = 0.16) and after indomethacin treatment (+0.28 mmHg·m–1·min–1 P = 0.07) did not achieve statistical significance under these conditions individually. L-NAME induced MAP to fall with rising work rate (–0.86 mmHg·m–1·min–1; P < 0.001).
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Hindlimb VC. Estrogen was associated with a statistically significant effect on hindlimb VC during hexamethonium alone (+0.0004 conductance unit·pg–1·ml–1; P < 0.001), and this effect persisted after administration of indomethacin (+0.0003 unit·pg–1·ml–1; P < 0.01). L-NAME administration eliminated the association between E2 and hindlimb VC (P = 0.18). The effect of ovariectomy on hindlimb VC seen across the data set as a whole persisted across the drug conditions individually (Tables 3 and 6). Female sex tended to increase hindlimb VC under each drug alone as it did for the data set as a whole, but these effects did not achieve statistical significance (Table 3). As expected, work rate was associated with significant effects on hindlimb VC across drug conditions (Table 3).
Finally, as a more explicit test of our hypotheses, we sought to test whether the extent to which indomethacin reduced the change in the increase in hindlimb VC in response to exercise was related to estrogen status. We found a highly significant treatment effect, indicating that the greater the plasma E2, the greater the reduction in the change in hindlimb VC after indomethacin (P < 0.001).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Endothelial-derived NO and prostacyclin are the primary intermediaries of flow-induced vasodilation in isolated skeletal muscle arterioles, because NO synthase inhibition and cyclooxygenase inhibition each attenuate the vasodilatory responses to increased luminal flow by 40–50% in male and female ovariectomized rats (13, 27). However, recent studies suggest that the relative contributions of NO and prostacyclin to flow-induced vasodilatory responses may exhibit sex specificity because, although the combination of NO synthase and cyclooxygenase inhibition in female and in estrogen-supplemented ovariectomized rats attenuated (by 50%), the vasodilatory response to increased luminal flow in isolated vessels from these animals, the remainder of the vasodilatory response was abolished after subsequent inhibition of endothelial-derived hyperpolarizing factors (9, 27). Therefore, it has been proposed that estrogen may influence the specific endothelial mediator used to elicit flow-induced vasodilation (7, 10 19), although it is not known whether this influences cardiovascular regulation during exercise conditions.
To determine whether the estrogenic influences on vascular regulation are mediated through PG and/or NO, we examined the vascular responses to dynamic exercise after different drug treatments (indomethacin, L-NAME) to inhibit PG and NO production. We employed treadmill locomotion, and, of course, different results might be found for other modes of exercise. During these trials, the autonomic nervous system was inhibited to eliminate compensatory changes in autonomic function secondary to drug administration (hexamethonium trials). In general, the influence that each independent variable exerted on the data set as whole tended to be maintained during the hexamethonium trials. Namely, being female and plasma E2 maintained their significant associations with the reduction in MAP. In addition, plasma E2 was associated with increased TAQ and hindlimb VC during hexamethonium trials, although the associations between being female and increased TAQ and VC were no longer significant. These findings indicate that, in the absence of autonomic neural inputs, estrogen significantly modulates vascular regulation independent of female sex.
Next, the influence of PG production on vascular regulation was inferred from trials in which cyclooxygenase was inhibited (indomethacin trials). After indomethacin administration, plasma E2 continued to modulate (increase) TAQ and hindlimb VC, although plasma E2 was no longer significantly associated with effects on MAP. Similar to the hexamethonium trials, being female did not influence TAQ or hindlimb VC during the indomethacin trials. Female sex, however, continued to be associated with reductions in MAP. It appears that the influence of E2 on MAP is at least partially dependent on PG production, because cyclooxygenase inhibition eliminated the significant association between E2 and MAP. In contrast, the strength (regression coefficient) of the association between E2 and TAQ (and hindlimb VC) was reduced after cyclooxygenase inhibition but not eliminated. The observed increase in TAQ and hindlimb VC associated with E2 is therefore not likely to be solely mediated through enhanced PG production. Furthermore, these results suggest that there is a reduction in MAP in females that is produced by some factor(s) in addition to the influence exerted by the ovaries and by estrogen. It was also interesting to note that being female was consistently associated with a reduction in MAP across all drug treatments, indicating that the unidentified factor(s) that lowers MAP operates in a manner independent of autonomic function, NO synthase, or cyclooxygenase.
To determine whether E2 modulates the vascular responses remaining after cyclooxygenase inhibition through NO-dependent processes in the present study, L-NAME was administered to inhibit NO production. After L-NAME, the positive associations between plasma E2 and hindlimb TAQ and VC were eliminated. E2, therefore, appeared to modulate TAQ and VC through NO-dependent pathways. In contrast, female sex was not significantly associated with TAQ or hindlimb VC under any drug condition (hexamethonium, indomethacin, L-NAME).
We found that TAQ was not modulated by female sex. Dynamic exercise can provide a substantial challenge to vascular regulation and may recruit numerous vascular regulatory mechanisms, dependent on exercise intensity, to sustain adequate O2 delivery. Therefore, under identical exercise conditions, it is not surprising that hindlimb TAQ values for males and females do not differ because overall cardiovascular regulation works to ensure that muscle blood flow is precisely matched with muscle metabolism.
Not surprisingly, work rate significantly influenced the vascular responses elicited during treadmill locomotion. Significant associations were evident between work rate and both TAQ and hindlimb VC after each drug treatment, indicating that factors other than PG or NO also determine vascular responses to changes in work rate. It is important to note, however, that work rate elicited differential responses in MAP according to drug treatment. During hexamethonium and indomethacin trials, no significant associations between work rate and MAP were indicated. On the basis of the regression coefficients, however, work rate tended to elicit (nonsignificant) increases in MAP after hexamethonium and indomethacin. NO synthase inhibition, however, characteristically increases arterial pressure at rest. The typical response to exercise after NO synthase inhibition, therefore, is a decrease in MAP, and this is indeed what we found. Work rate was negatively correlated with MAP during NO synthase inhibition (i.e., increases in work rate brought about significant decreases in MAP).
Plasma E2 in female rats varies dramatically over a 4-day estrus cycle, typically ranging from 17 pg/ml during the estrus (low estrogen) phase to 88 pg/ml in the proestrus (high estrogen) phase (4). Plasma E2 concentrations for male, female, and ovariectomized rats in the present study were similar to the estrus phase of the estrus cycle. Plasma E2 concentrations for sham-operated females ranged from 13 to 21 pg/ml. Although the ovariectomized rats (with or without E2 supplementation) demonstrated the expected changes in plasma E2 concentrations, the sham-operated females did not display variability in plasma E2 that would be expected during different phases of the estrus cycle, perhaps due to the timing of blood sample procurement (at the end of the experimental protocol) or recent surgical procedures (flow probe insertion) that may have impacted the estrus cycle. The estrogen-supplemented female rats exhibited plasma E2 concentrations greater than expected for the proestrus phase of the estrus cycle, as well as greater uterine weights despite smaller body sizes, supporting the assumption that estrogen provided significant treatment effects within this treatment group. Plasma E2 concentrations for the male rats were slightly greater than in sham-operated and ovariectomized female rats, as seen by others (1, 16)
Conclusions.
The primary purpose of this study was to determine whether estrogenic effects on NO and PG production contribute to differences in the vascular responses to treadmill locomotion for male and female rats. Our principle finding was that across all conditions, female sex was associated with reduced MAP and greater VC. Ovary removal reversed this pattern, and estrogen replacement restored the apparent female phenotype with respect to MAP and VC. Female sex, however, did not exert a significant effect on hindlimb TAQ. Further analysis revealed that plasma E2 modulated MAP, hindlimb TAQ, and VC across the data set as a whole. Furthermore, the estrogenic influences over MAP were eliminated after cyclooxygenase inhibition, suggesting estrogen modulated MAP in part through PG-dependent processes. In contrast, the significant influence of estrogen on TAQ and VC persisted after cyclooxygenase inhibition but was eliminated after NO synthase inhibition. On the basis of the overall findings of this study, estrogenic modulation of the vascular responses to dynamic exercise appear to be mediated through PG- and NO-dependent pathways, but this occurs independent of sex.
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GRANTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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throughout the 4-day estrous cycle of the rat. Endocrinology 94: 1704–1708, 1974.
. J Appl Physiol 91: 2391–2399, 2001.-Estradiol increases rat cerebrovascular prostacyclin synthesis by elevating cyclooxygenase-1 and prostacyclin synthase. Stroke 33: 600–605, 2002.This article has been cited by other articles:
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S. K. Nishiyama, D. W. Wray, and R. S. Richardson Sex and limb-specific ischemic reperfusion and vascular reactivity Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1100 - H1108. [Abstract] [Full Text] [PDF]
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 J. U. Gonzales, B. C. Thompson, J. R. Thistlethwaite, A. J. Harper, and B. W. Scheuermann Forearm blood flow follows work rate during submaximal dynamic forearm exercise independent of sex J Appl Physiol, December 1, 2007; 103(6): 1950 - 1957. [Abstract] [Full Text] [PDF]
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B. A. Parker, S. L. Smithmyer, J. A. Pelberg, A. D. Mishkin, M. D. Herr, and D. N. Proctor Sex differences in leg vasodilation during graded knee extensor exercise in young adults J Appl Physiol, November 1, 2007; 103(5): 1583 - 1591. [Abstract] [Full Text] [PDF]
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Z. F. Ba, A. Lu, T. Shimizu, L. Szalay, M. G. Schwacha, L. W. Rue III, K. I. Bland, and I. H. Chaudry 17beta-Estradiol modulates vasoconstriction induced by endothelin-1 following trauma-hemorrhage Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H245 - H250. [Abstract] [Full Text] [PDF]
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G. C. Sieck Commentary J Appl Physiol, August 1, 2004; 97(2): 748 - 748. [Full Text] [PDF]
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