AJP - Heart Information on EB 2010
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 275: H15-H22, 1998;
0363-6135/98 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kähönen, M.
Right arrow Articles by Pörsti, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kähönen, M.
Right arrow Articles by Pörsti, I.
Vol. 275, Issue 1, H15-H22, July 1998

Influence of gender on control of arterial tone in experimental hypertension

Mika Kähönen1,2, Jari-Petteri Tolvanen1,3, Kirsimarja Sallinen1, Xiumin Wu1, and Ilkka Pörsti1,4

1 Department of Pharmacological Sciences, Medical School, University of Tampere, FIN-33101 Tampere; and Departments of 2 Clinical Physiology, 3 Clinical Chemistry, and 4 Internal Medicine, Tampere University Hospital, FIN-33521 Tampere, Finland

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Endothelial dysfunction has been found to be less severe in female than in male spontaneously hypertensive rats (SHR), which could contribute to the gender differences observed in the extent and rate of progression of hypertension in SHR. However, the influence of gender on the roles of different endothelium-derived mediators in the arterial responses in hypertension have not been evaluated in detail. Therefore, contractile and relaxation responses of mesenteric arterial rings in vitro were studied in female and male SHR, with normotensive female and male Wistar-Kyoto rats (WKY) serving as controls. In norepinephrine (NE)-precontracted arterial rings, endothelium-dependent relaxations to ACh as well as endothelium-independent dilations to sodium nitroprusside were more pronounced in female than in male SHR, whereas relaxations to the beta -adrenoceptor agonist isoproterenol remained equally impaired in female and male SHR. The cyclooxygenase inhibitor diclofenac, which reduces the synthesis of dilating and constricting prostanoids, markedly enhanced the relaxations to ACh in male SHR but not in the other groups. The nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester attenuated the relaxations to ACh more effectively in female SHR and WKY than in the male groups. However, when endothelium-dependent hyperpolarization was prevented by precontracting the preparations with KCl, no significant differences were found in relaxations to ACh among the study groups. In conclusion, release of cyclooxygenase-derived constricting factors appeared to be more pronounced in male than in female SHR. In addition, the relative role of NO in endothelium-dependent arterial relaxation seemed to be higher in female than in male SHR, and relaxation induced by an NO donor also was more pronounced in female than in male SHR.

arterial smooth muscle; endothelium; spontaneously hypertensive rat; Wistar-Kyoto rat

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

PHYSIOLOGICAL LEVELS of 17beta -estradiol have been reported to potentiate endothelium-dependent vasodilation in postmenopausal women (14, 15), attenuate ACh-induced coronary constriction in women with coronary heart disease (10), and produce direct endothelium-independent relaxation of human coronary arteries in vitro (33). In addition, estrogen supplementation has been shown to improve endothelium-dependent flow-mediated vasodilation (26) and enhance basal nitric oxide (NO) release in the forearm vasculature (34). Thus estrogens seem to have beneficial influences on vascular tone, the effects of which could at least partially explain the gender differences in the incidence of cardiovascular events (11). However, testosterone has been shown to induce endothelium-dependent and -independent relaxations in the vasculature of experimental animals (7, 8, 42), suggesting that other steroid hormones may also have favorable effects on vascular function.

Previously, pulmonary arterial responses to prostaglandin F2alpha have been reported to differ in female and male rats (28). In addition, endothelium-dependent vasodilation appears to be more pronounced in female than in male experimental animals, an effect that has been attributed to differences in the function of the L-arginine-NO pathway (11). Recently, endothelial dysfunction was suggested to be less severe in the aorta of female than in that of male spontaneously hypertensive rats (SHR) (23), which could contribute to the gender differences observed in the progression of hypertension in these animals. In male SHR the impaired endothelial function has been attributed to enhanced formation of vasoconstricting prostanoids (16, 27), diminished release of NO from the endothelium (3), and reduced endothelium-dependent hyperpolarization (12, 20).

Because the effect of gender on the roles of different endothelium-derived mediators in the arterial responses in hypertension has not been evaluated in detail, the present study was designed to examine vascular contractile and relaxation responses in female and male SHR and Wistar-Kyoto rats (WKY). In particular, the influences of endothelium-derived autacoids on vascular tone were addressed. Here we report for the first time that the release of cyclooxygenase-derived constricting factors seemed to be higher in male than in female SHR, whereas the contribution of endothelium-derived NO to vascular relaxation appeared to be higher in female than in male SHR.

    MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Animals and experimental design. Female and male SHR (Okamoto-Aoki strain, n = 12 in each group) and WKY were obtained from Møllegaard's Breeding Centre (Ejby, Denmark). The rats were housed in an experimental animal laboratory (illuminated from 0600 to 1800, temperature 22°C) with free access to water and chow (Ewos, Södertälje, Sweden). The systolic blood pressures of conscious animals were measured at 28°C using the tail-cuff method (model 129 Blood Pressure Meter; IITC, Woodland Hills, CA). At the age of 20 wk the rats were decapitated and exsanguinated. The hearts were removed and weighed, and the superior mesenteric arteries were excised. The experimental design was approved by the Animal Experimentation Committee of the University of Tampere (Tampere, Finland).

Mesenteric arterial responses in vitro. Five successive sections (3 mm in length) of the mesenteric artery from each animal were cut. In the three most distal rings, the endothelium was left intact, and vascular endothelium was gently removed from the first two pieces (2). The rings were placed between hooks (diameter 0.3 mm) and suspended in an organ bath chamber (volume 20 ml) in PSS (pH 7.4) of the following composition (in mM): 119.0 NaCl, 25.0 NaHCO3, 11.1 glucose, 1.6 CaCl2, 4.7 KCl, 1.2 KH2PO4, and 1.2 MgSO4, aerated with 95% O2-5% CO2. The rings were initially equilibrated for 1 h at 37°C with a resting force of 1.5 g. The force of contraction was measured with an isometric force-displacement transducer and registered on a polygraph (FT03 transducer and model 7E polygraph; Grass Instruments, Quincy, MA). Normally, the presence of intact endothelium is confirmed by an almost complete relaxation to 1 µM ACh in 1 µM norepinephrine (NE)-precontracted rings, whereas no relaxation is observed in endothelium-denuded rings (2). However, in the study reported here, the responses to ACh in the SHR groups hardly attained 50% relaxation. Therefore, no vascular preparations were excluded from the study.

Endothelium-independent relaxation and contraction to 5-hydroxytryptamine. The responses of endothelium-intact preparations to sodium nitroprusside (SNP) and isoproterenol were cumulatively determined. The relaxations were elicited after precontraction with 1 µM NE, which resulted in ~60% of the maximal contraction in each group. The next drug concentration was added only after the previous level of relaxation was stable. Thereafter, the concentration-response curves for 5-hydroxytryptamine (5-HT) were cumulatively determined.

Relaxations to ACh after precontraction with NE. Responses to ACh were examined in endothelium-intact rings. The responses to ACh were repeated in the presence of 3 µM diclofenac, in the presence of diclofenac and 0.1 mM NG-nitro-L-arginine methyl ester (L-NAME), and in the presence of diclofenac, L-NAME, and 1 µM apamin [inhibitors of cyclooxygenase, NO synthase, and Ca2+-activated K+ channels (KCa), respectively].

Arterial relaxations to ACh and ADP after precontraction with KCl. Relaxations to ACh and ADP were examined in endothelium-intact rings precontracted with 50 mM KCl. The responses to ACh and ADP were repeated in the presence of 3 µM diclofenac and in the presence of diclofenac and 0.1 mM L-NAME.

K+ relaxation. The endothelium-denuded ring was contracted with 125 mM KCl (reference response). When the maximal contraction was fully developed, the ring was rinsed with PSS to restore resting tension. After 30 min, the rings were exposed to K+-free solution (pH 7.4; KH2PO4 and KCl were substituted with NaH2PO4 and NaCl, respectively). The omission of K+ induced gradual contractions, and after the response had reached a plateau, 1 mM K+ was readded and the subsequent relaxation evaluating the activity of Na+-K+-ATPase was registered (2). The K+-free contractions and relaxations to K+ repletion were repeated in the presence of 1 mM ouabain.

Ca2+ contraction. Ca2+ was omitted from the buffer solution, and endothelium-denuded rings were contracted with 10 µM NE to empty the Ca2+ stores. The rings were challenged again with 1 µM Ca2+-free buffer, and Ca2+ was returned to the organ bath in increasing concentrations (0.05 to 2.5 mM). NaCl was replaced with KCl on an equimolar basis.

The contractions to 5-HT were expressed in grams, and the EC50 for 5-HT in each ring was calculated as the percentage of maximal response. The Ca2+-contraction responses were presented as the percentages of maximal responses. The relaxations in response to K+ repletion, ADP, ACh, isoproterenol, and SNP were presented as percentages of preexisting contractile force. The EC25 or EC50 values for the three latter relaxants were calculated as percentages of 1 µM NE-induced precontraction with the use of a computer program and were presented as the negative logarithm (pD25, pD50), which values were also used in the statistical analysis. The EC25 for ACh and isoproterenol were calculated because maximal relaxations of SHR groups to these agonists did not reach 50% relaxation in the present study.

Drugs. The following drugs were used: acetylcholine chloride (ACh), ADP, apamin, diclofenac, isoproterenol, NG-nitro-L-arginine methyl ester hydrochloride (L-NAME), and 5-HT (Sigma Chemical, St. Louis, MO); and L-norepinephrine hydrogen L-tartrate and SNP (Fluka Chemie, Buchs, Switzerland). The stock solutions were made by dissolving the compounds in distilled water. All solutions were freshly prepared before use and were protected from light.

Analysis of results. Statistical analysis was carried out by one-way ANOVA supported by the Bonferroni test for pairwise comparisons among the test groups. When appropriate, ANOVA for repeated measurements was applied for data consisting of repeated observations at successive time points. All results are expressed as means ± SE. Differences were considered significant when P < 0.05.

    RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Blood pressure, heart weight, and body weight. The systolic blood pressures of male SHR were clearly higher than those observed in female SHR. Blood pressure levels were also slightly lower in female than in male WKY. Absolute heart weights and heart-to-body weight ratios were higher in both SHR groups compared with those in the normotensive control groups. Female SHR and WKY gained less weight than male SHR and WKY (Table 1).

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Experimental group data at close of study

Mesenteric arterial responses. The relaxations induced by ACh in endothelium-intact NE-precontracted (1 µM) mesenteric arterial rings were markedly impaired in female and male SHR compared with those in the two WKY groups (Fig. 1). Interestingly, the responses to ACh were more pronounced in female than in male SHR. Cyclooxygenase inhibition with diclofenac (3 µM) clearly improved relaxations to ACh in male SHR but did not significantly affect the responses in the female SHR and the WKY groups. The NO synthase inhibitor L-NAME (0.1 mM; in the presence of diclofenac) significantly diminished the relaxations of NE-precontracted rings to ACh in all groups (P < 0.001 in all groups), with the influence being more pronounced in female SHR and WKY groups than in their male control groups (Fig. 1). Apamin (1 µM), an inhibitor of KCa, slightly reduced the diclofenac- and L-NAME-resistant relaxations to ACh in both WKY groups (Fig. 1).


View larger version (27K):
[in this window]
[in a new window]
  		Fig. 1.   Relaxations to ACh in isolated endothelium-intact mesenteric arterial rings from male (bullet ) and female (black-square) spontaneously hypertensive rats (SHR) and male (open circle ) and female (square ) Wistar-Kyoto rats (WKY). Relaxations were induced after precontraction with 1 µM norepinephrine (NE) in absence (A) and in presence (B) of 3 µM diclofenac; in presence of diclofenac and 0.1 mM NG-nitro-L-arginine methyl ester (L-NAME; C); and in presence of diclofenac, L-NAME, and 1 µM apamin (D). Values are means ± SE; n = 10-12 rats in each group. * P < 0.05 by ANOVA for repeated measurements.

When endothelium-mediated hyperpolarization of arterial smooth muscle was eliminated by precontraction induced by depolarization with 50 mM KCl, no differences were found among the study groups in the relaxation responses induced by ACh (Fig. 2) or another endothelium-dependent agonist, ADP (data not shown). In the presence of diclofenac, the responses to ACh were augmented in male SHR but not in the other groups. The addition of L-NAME almost completely abolished the relaxations to ACh in all study groups during KCl-induced precontractions (Fig. 2).


View larger version (12K):
[in this window]
[in a new window]
  		Fig. 2.   Relaxations to ACh in isolated endothelium-intact mesenteric arterial rings from male (bullet ) and female (black-square) SHR and male (open circle ) and female (square ) WKY. Relaxations were induced after precontraction with 50 mM KCl in absence (A) and presence of 3 µM diclofenac (B), and in presence of diclofenac and 0.1 mM L-NAME (C). Values are means ± SE; n = 10-12 rats in each group. * P < 0.05 compared with male SHR by ANOVA for repeated measurements.

The responses to SNP, an agent that mediates arterial relaxation via the formation of exogenous NO and the subsequent accumulation of cGMP, were attenuated in male SHR compared with those in female SHR and the two WKY groups (Fig. 3 and Table 2). The vasorelaxations to the beta -adrenoceptor agonist isoproterenol in endothelium-intact arterial rings were comparably impaired in both SHR groups compared with those in the WKY groups (Fig. 3, Table 2). The maximal contractions elicited by K+-free solution were not statistically different among the study groups (maximal forces in male SHR, female SHR, male WKY, and female WKY: 1.3 ± 0.2, 0.8 ± 0.2, 0.9 ± 0.2, and 0.9 ± 0.1 g, respectively), with the exception of the comparisons between male SHR and female WKY (P = 0.045) and between male SHR and female SHR (P = 0.031). After the return of K+ to the organ bath following the K+-free precontractions, the rate of the subsequent relaxation was faster in WKY than in SHR groups (Fig. 3). Furthermore, K+ relaxation was effectively inhibited by the Na+-K+-ATPase inhibitor ouabain in all groups (Fig. 3).


View larger version (26K):
[in this window]
[in a new window]
  		Fig. 3.   Relaxations of endothelium-denuded mesenteric arterial rings from male (bullet ) and female (black-square) SHR and male (open circle ) and female (square ) WKY. Relaxations to sodium nitroprusside (A) and isoproterenol (B) were induced after precontraction with 1 µM NE, and relaxations to readdition of 1 mM K+ were induced after precontraction induced by K+-free buffer solution in absence (C) and presence (D) of 1 mM ouabain. Values are means ± SE; n = 10-12 rats in each group. * P < 0.05 by ANOVA for repeated measurements.

                              
View this table:
[in this window]
[in a new window]
  		Table 2.   Parameters of contractile and relaxation responses of isolated endothelium-intact arterial rings

The endothelium-intact vascular rings of both SHR groups showed higher sensitivity (i.e., pD50 values) to 5-HT compared with those of the corresponding WKY groups, whereas maximal contractile force generation to 5-HT was similar among the study groups. In addition, sensitivity to 5-HT was slightly higher in female than in male SHR (Table 2 and Fig. 4). The effect of organ bath Ca2+ concentration on NE-induced contractions, i.e., the Ca2+ sensitivity of the vascular rings during alpha -adrenoceptor stimulation, was corresponding in the four study groups (Fig. 4).


View larger version (14K):
[in this window]
[in a new window]
  		Fig. 4.   Contractions of mesenteric arterial rings from male (bullet ) and female (black-square) SHR and male (open circle ) and female (square ) WKY. A: contractions of endothelium-intact rings to 5-hydroxytryptamine. B: 1 µM NE-induced contractions in different organ bath Ca2+ concentrations in endothelium-denuded rings. Values are means ± SE; n = 10-12 rats in each group. * P < 0.05 for female SHR vs. other groups by one-way ANOVA supported by Bonferroni test.

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Impaired endothelium-dependent relaxation has been repeatedly observed in experimental hypertension (12, 20, 23, 29), and in the present study the relaxations to ACh in NE-precontracted rings also were attenuated in both female and male SHR. Interestingly, the responses to ACh were more pronounced in female than in male SHR, in accordance with recent findings (23). One plausible explanation for the attenuated endothelium-mediated relaxations in hypertension is enhanced release of endothelium-derived contracting factor(s) (EDCF) (27), the formation of which, most likely prostaglandin H2 or thromboxane A2 (TxA2), is increased by ACh in the mesenteric artery of male SHR (24). Previously, the endothelium-dependent vasoconstrictor responses in SHR have been shown to be blocked by cyclooxygenase inhibition (35), and treatment with a TxA2-prostaglandin endoperoxide-receptor blocker has completely restored endothelium-dependent dilation in vivo in male SHR (37). In the present study, diclofenac clearly enhanced the relaxations to ACh in male SHR and abolished the difference between female and male SHR, suggesting that cyclooxygenase-derived constricting prostanoids were indeed involved in the responses of male SHR. However, diclofenac was without significant effect on the relaxations to ACh in the other groups, whereby products of the cyclooxygenase pathway did not seem to play a significant role in the responses to ACh in the female SHR and in the WKY groups. Therefore, the release of contractile factors from the endothelium appeared to be more pronounced in male SHR than in the other groups. On the other hand, testosterone has been reported to increase TxA2-receptor density in cultured rat aortic smooth muscle cells (30), an effect that was more pronounced in the male than in the female study group (31). Thus another possibility for the present findings is that the sensitivity of arterial smooth muscle to the contractile factors was higher in male SHR.

In the present study, systolic blood pressures of male SHR were clearly higher than those in age-matched female SHR. In accordance, previous reports have shown that hypertension develops more rapidly and becomes more severe in male than in female SHR (17, 23). Interestingly, the production of EDCF has been shown to closely parallel the increase in blood pressure in SHR (18). Therefore, the lower blood pressure in female than in male SHR may be attributed to lower release of endothelial contractile factors in the female animals. Lower body weight in the female SHR provides another explanation for the lower blood pressures in these rats.

Inhibition of NO synthesis by L-NAME effectively diminished relaxations to ACh in both SHR groups, whereas the responses in the both WKY groups were slightly but significantly attenuated by L-NAME, in accordance with previous findings (20, 25). Thus these findings indicate that there was a significant NO-mediated component in endothelium-mediated relaxations of mesenteric arterial rings in all groups studied. Interestingly, the inhibitory effect of L-NAME on ACh-induced relaxation was more pronounced in female SHR and WKY than in the corresponding male groups, thus suggesting that the relative role of NO in endothelium-mediated relaxation was higher in the female animals. Indeed, more pronounced endothelium-dependent vasodilation in normotensive female than in male experimental animals has been attributed to differences in the function of the L-arginine-NO pathway (11, 22). In addition, estrogen enhanced basal NO release in the forearm vasculature in perimenopausal women (34), and treatment of male SHR with estrogen augmented ACh-induced relaxation to levels observed in female controls (21), an effect that was attributed to the modulation of the L-arginine-NO pathway (11). Thus favorable influences of estrogen on NO release could contribute to the gender differences in the present study, reflected as more pronounced inhibitory effects of L-NAME on endothelium-dependent relaxation in the female rats.

In the study reported here, WKY groups showed distinct L-NAME-resistant dilations to ACh, suggesting that factors other than NO contributed to these responses. Indeed, ACh has been shown to cause hyperpolarization of arterial smooth muscle that remains resistant to both NO synthase and cyclooxygenase inhibition (13). Therefore, a substance termed endothelium-derived hyperpolarizing factor (EDHF) has been proposed as a vasoactive autacoid of endothelial origin (9). EDHF has been described to be an endogenous K+-channel opener, but the nature of K+ channels opened by EDHF has not been fully characterized. Apamin, a blocker of KCa, has been found to reduce the L-NAME-insensitive relaxation in rat mesenteric artery, and apamin together with charybdotoxin completely abolishes these responses (38). In contrast, the ATP-sensitive K+-channel blocker glyburide was found to be ineffective (13, 32). These findings indicate that EDHF relaxes mesenteric arteries mainly by activating KCa. In the present study, apamin somewhat attenuated the L-NAME- and diclofenac-resistant relaxation to ACh in WKY groups, thus suggesting that this relaxation was mediated at least partially via arterial KCa.

The membrane depolarization induced by precontracting the arterial preparations with KCl has been reported to eliminate the action of EDHF (1). Interestingly, no significant differences were found among the present study groups in response to ACh and ADP when the precontractions were induced by KCl. The fact that the relaxations to ACh in KCl-precontracted rings were comparable among the study groups, whereas those induced in NE-precontracted rings were markedly reduced in hypertensive compared with normotensive rats, suggests that hyperpolarization induced by ACh was reduced in both SHR strains. In the presence of diclofenac, the relaxations to ACh and ADP were again augmented in male SHR but not in the other groups. Moreover, the relaxations to ACh and ADP in KCl-precontracted preparations of all groups were practically abolished by L-NAME, suggesting that NO and EDHF were indeed responsible for the observed dilator responses to these agonists.

Arterial relaxations to the beta -adrenoceptor agonist isoproterenol were comparably impaired in both SHR groups compared with those in the WKY groups. However, arterial relaxations elicited by SNP were more pronounced in female than in male SHR, suggesting that the sensitivity of arterial smooth muscle to NO was higher in the female group. Exogenous NO has been shown to hyperpolarize guinea pig uterine artery (36) and rat mesenteric artery (13), whereas the KCa blockers charybdotoxin and tetraethylammonium have been shown to decrease relaxation to NO in guinea pig pulmonary arterial and tracheal smooth muscle (4). Thus augmented function of KCa in smooth muscle could partially explain the enhanced relaxation to the SNP in female SHR in this study.

Taken together, inhibition of cyclooxygenase with diclofenac eliminated the difference in the ACh-induced relaxation between female and male SHR. Thus the release of cyclooxygenase-derived constricting factors appeared to be more pronounced in the male hypertensive animals. In addition, the inhibitory effect of L-NAME on ACh-induced relaxation was more pronounced in female SHR and WKY than in the corresponding male groups, suggesting that the relative role of NO in endothelium-mediated relaxation was higher in the female rats. Furthermore, prevention of hyperpolarization by precontractions induced by KCl eliminated the difference in the ACh-induced arterial relaxation among the study groups. Because NO has been proposed to directly activate KCa (5), the deviations in endothelium-mediated relaxation among the groups in this study may partially have resulted from differences in hyperpolarization of arterial smooth muscle. This conclusion is supported by the fact that the relaxations elicited by SNP were higher in female SHR and in both WKY groups compared with those in male SHR, indicating enhanced sensitivity of arterial smooth muscle to relaxation via NO. Interestingly, the mechanism of 17beta -estradiol-induced endothelium-independent arterial dilation has been found to involve opening of KCa via cGMP-dependent phosphorylation (41). In addition, 17beta -estradiol-induced elevation of basal NO release from endothelium has been suggested to activate KCa in coronary arterial smooth muscle (40). Thus the favorable influences of estrogens on NO-mediated smooth muscle hyperpolarization through KCa provide a possible mechanism by which gender affects arterial dilation in experimental hypertension.

Vascular Na+-K+-ATPase function was evaluated indirectly by K+ repletion in response to K+-free medium-induced precontractions (2), because the return of K+ activates the Na+-K+-ATPase, which repolarizes the cell membrane and thus relaxes smooth muscle (6). The rate of K+ relaxation also reflects general smooth muscle relaxation mechanisms (e.g., contractile protein dephosphorylation, Ca2+ sequestration, and extrusion) (19), but previous results suggest that the K+ relaxation rate is indicative of Na+-K+-ATPase activity in the rat mesenteric artery (2). Previous studies on K+ relaxation have yielded conflicting results (2, 39). However, in the present study, the K+ relaxation rate was markedly slower in SHR than in WKY groups. The more pronounced K+ relaxation in WKY than in SHR groups suggests increased recovery rate of ionic gradients across the cell membrane, probably via differences in the function of Na+-K+-ATPase among the study groups. This conclusion is supported by the fact that K+ relaxation was effectively inhibited by the Na+-K+-ATPase inhibitor ouabain in all study groups. Enhanced function of Na+-K+-ATPase would also favor hyperpolarization of arterial smooth muscle in the normotensive groups.

In conclusion, the release of cyclooxygenase-derived constricting factors appeared to be more pronounced in male than in female SHR. In addition, the relative role of NO in endothelium-dependent arterial relaxation was higher in female than in male SHR, possibly via a hyperpolarization mechanism. Finally, endothelium-independent NO-mediated relaxation was also more pronounced in female than in male hypertensive rats. Taken together, the control of arterial tone was clearly affected by gender in the present model of genetic hypertension.

    ACKNOWLEDGEMENTS

This study was supported by the Aarne Koskelo Foundation, the Finnish Cultural Foundation, Pirkanmaa Fund, the Väinö and Hilkka Kiltti Foundation, the Medical Research Fund of Tampere University Hospital, and the University of Tampere (Tampere, Finland).

    FOOTNOTES

Address for reprint requests: M. Kähönen, Medical School, Dept. of Pharmacological Sciences, Univ. of Tampere, PO Box 607, FIN-33101 Tampere, Finland.

Received 24 July 1997; accepted in final form 13 March 1998.

    REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

1.   Adeagbo, A. S. O., and C. R. Triggle. Varying extracellular [K+]: a functional approach to separating EDHF- and EDNO-related mechanisms in perfused rat mesenteric arterial bed. J. Cardiovasc. Pharmacol. 21: 423-429, 1993[Medline].

2.   Arvola, P., I. Pörsti, P. Vuorinen, A. Pekki, and H. Vapaatalo. Contractions induced by potassium-free solution and potassium relaxation in vascular smooth muscle of hypertensive and normotensive rats. Br. J. Pharmacol. 106: 157-165, 1992[Medline].

3.   Berkenboom, G., D. Brekine, P. Unger, K. Grosfils, M. Staroukine, and J. Fontaine. Chronic angiotensin-converting enzyme inhibition and endothelial function of rat aorta. Hypertension 26: 738-743, 1995[Abstract/Free Full Text].

4.   Bialecki, R. A., and C. Stinson-Fisher. KCa channel antagonists reduce NO donor-mediated relaxation of vascular and tracheal smooth muscle. Am. J. Physiol. 268 (Lung Cell. Mol. Physiol. 12): L152-L159, 1995[Abstract/Free Full Text].

5.   Bolotina, V. M., S. Najibi, P. J. Palacino, and R. A. Cohen. Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 368: 850-853, 1994[Medline].

6.   Bonaccorsi, A., K. Hermesmeyer, O. Aprigliano, C. B. Smith, and D. F. Bohr. Mechanism of potassium relaxation of arterial muscle. Blood Vessels 14: 261-276, 1977[Medline].

7.   Costarella, C. E., J. N. Stallone, G. W. Rutecki, and F. C. Whittier. Testosterone causes direct relaxation of rat thoracic aorta. J. Pharmacol. Exp. Ther. 277: 34-39, 1996[Abstract/Free Full Text].

8.   Chou, T. M., K. Sudhir, S. J. Hutchison, E. Ko, T. M. Amidon, P. Collins, and K. Chatterjee. Testosterone induces dilation of canine coronary conductance and resistance arteries in vivo. Circulation 94: 2614-2619, 1996[Abstract/Free Full Text].

9.   Cohen, R. A., and P. M. Vanhoutte. Endothelium-dependent hyperpolarization beyond nitric oxide and cyclic GMP. Circulation 92: 3337-3349, 1995[Free Full Text].

10.   Collins, P., G. M. C. Rosano, P. M. Sarrel, L. Ulrich, S. Adamopoulos, C. M. Beale, J. G. McNeill, and P. A. Poole-Wilson. 17beta -Estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation 92: 24-30, 1995[Abstract/Free Full Text].

11.   Farhat, M. Y., M. C. Lavigne, and P. W. Ramwell. The vascular protective effects of estrogen. FASEB J. 10: 615-624, 1996[Abstract].

12.   Fujii, K., M. Tominaga, S. Ohmori, K. Kobayashi, T. Koga, Y. Takata, and M. Fujishima. Decreased endothelium-dependent hyperpolarization to acetylcholine in smooth muscle of the mesenteric artery of spontaneously hypertensive rats. Circ. Res. 70: 660-669, 1992[Abstract/Free Full Text].

13.   Garland, C. J., and G. A. McPherson. Evidence that nitric oxide does not mediate the hyperpolarization and relaxation to acetylcholine in the rat small mesenteric artery. Br. J. Pharmacol. 105: 429-435, 1992[Medline].

14.   Gilligan, D. M., D. M. Badar, J. A. Panza, A. A. Quyyumi, and R. O. Cannon III. Acute vascular effects of estrogen in postmenopausal women. Circulation 90: 786-791, 1994[Abstract/Free Full Text].

15.   Gilligan, D. M., A. A. Quyyumi, and R. O. Cannon III. Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women. Circulation 89: 2545-2551, 1994[Abstract/Free Full Text].

16.   Hutri-Kähönen, N., M. Kähönen, X. Wu, J.-P. Tolvanen, K. Sallinen, and I. Pörsti. Ramipril therapy improves arterial dilation in experimental hypertension. Cardiovasc. Res. 33: 188-195, 1997[Medline].

17.   Iams, S. G., and B. C. Wexler. Inhibition of the development of spontaneous hypertension in SH rats by gonadectomy or estradiol. J. Lab. Clin. Med. 10: 608-616, 1979.

18.   Iwama, Y., T. Kato, M. Muramatsu, H. Asano, K. Shimizu, Y. Toki, Y. Miyazaki, K. Okumura, H. Hashimoto, T. Ito, and T. Satake. Correlation with blood pressure of the acetylcholine-induced endothelium-derived contracting factor in the rat aorta. Hypertension 19: 326-332, 1992[Abstract/Free Full Text].

19.   Johns, A., P. Leijten, H. Yamamoto, K. Hwang, and C. Van Breemen. Calcium regulation in vascular smooth muscle contractility. Am. J. Cardiol. 59: 18A-23A, 1987[Medline].

20.   Kähönen, M., H. Mäkynen, X. Wu, P. Arvola, and I. Pörsti. Endothelial function in spontaneously hypertensive rats: influence of quinapril treatment. Br. J. Pharmacol. 115: 859-867, 1995[Medline].

21.   Kauser, K., and G. M. Rubanyi. 17beta -Estradiol attenuates endothelial dysfunction in male spontaneously hypertensive rats (Abstract). J. Am. Coll. Cardiol. 23: 295A, 1994.

22.   Kauser, K., and G. M. Rubanyi. Gender difference in bioassayable endothelium-derived nitric oxide release from isolated rat aortae. Am. J. Physiol. 267 (Heart Circ. Physiol. 36): H2311-H2317, 1994[Abstract/Free Full Text].

23.   Kauser, K., and G. M. Rubanyi. Gender difference in endothelial dysfunction in the aorta of spontaneously hypertensive rats. Hypertension 25: 517-523, 1995[Abstract/Free Full Text].

24.   Lang, M. G., G. Noll, and T. F. Lüscher. Effect of aging and hypertension on contractility of resistance arteries: modulation by endothelial factors. Am. J. Physiol. 269 (Heart Circ. Physiol. 38): H837-H844, 1995[Abstract/Free Full Text].

25.   Li, J., K. A. Bian, and R. D. Bukoski. A non-cyclo-oxygenase, non-nitric oxide relaxing factor is present in resistance arteries of normotensive but not spontaneously hypertensive rats. Am. J. Med. Sci. 307: 7-14, 1994[Medline].

26.   Liebermann, E. H., M. D. Gerhard, A. Uehata, B. W. Walsh, A. P. Selwyn, P. Ganz, A. C. Yeung, and M. A. Creager. Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann. Intern. Med. 121: 936-941, 1994[Abstract/Free Full Text].

27.   Lüscher, T. F., and P. M. Vanhoutte. Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension 8: 344-348, 1986[Abstract/Free Full Text].

28.   Maddox, Y. T., J. G. Falcon, M. Ridinger, C. M. Cunard, and P. W. Ramwell. Endothelium-dependent gender differences in the response of the rat aorta. J. Pharmacol. Exp. Ther. 240: 392-395, 1987[Abstract/Free Full Text].

29.   Mäkynen, H., M. Kähönen, X. Wu, P. Arvola, and I. Pörsti. Endothelial function in deoxycorticosterone-NaCl hypertension: effect of calcium supplementation. Circulation 93: 1000-1008, 1996[Abstract/Free Full Text].

30.   Masuda, A., R. Mathur, and P. V. Halushka. Testosterone increases thromboxane A2 receptors in cultured rat aortic smooth muscle cells. Circ. Res. 69: 638-643, 1991[Abstract/Free Full Text].

31.   Matsuda, K., R. S. Mathur, M. E. Ullian, and P. V. Halushka. Sex steroid regulation of thromboxane A2 receptors in cultured rat aortic smooth muscle cells. Prostaglandins 49: 183-196, 1995[Medline].

32.   McPherson, G. A., and J. Angus. Evidence that acetylcholine mediated hyperpolarization of the rat small mesenteric artery does not involve the K+ channel opened by chromakalim. Br. J. Pharmacol. 103: 1184-1190, 1991[Medline].

33.   Mügge, A., M. Riedel, M. Barton, M. Kuhn, and P. R. Lichtlen. Endothelium independent relaxation of human coronary arteries by 17beta -oestradiol in vitro. Cardiovasc. Res. 27: 1939-1942, 1993[Medline].

34.   Sudhir, K., G. L. Jennings, J. W. Funder, and P. A. Komesaroff. Estrogen enhances basal nitric oxide release in the forearm vasculature in perimenopausal women. Hypertension 28: 330-334, 1996[Abstract/Free Full Text].

35.   Takase, H., Y. Dohi, M. Kojima, and K. Sato. Changes in the endothelial cyclo-oxygenase pathway in resistance arteries of spontaneously hypertensive rats. J. Cardiovasc. Pharmacol. 23: 326-330, 1994[Medline].

36.   Tare, M., I. A. Parkington, H. A. Coleman, T. O. Neild, and G. J. Dusting. Hyperpolarization and relaxation of arterial smooth muscle caused by nitric oxide derived from the endothelium. Nature 346: 69-71, 1990[Medline].

37.   Tesfamariam, B., and M. L. Ogletree. Dissociation of endothelial cell dysfunction and blood pressure in SHR. Am. J. Physiol. 269 (Heart Circ. Physiol. 38): H189-H194, 1995[Abstract/Free Full Text].

38.  Waldron, G. J., and C. J. Garland. Effect of potassium channel blockers on L-NAME insensitive relaxations in rat small mesenteric artery (Abstract). Can. J. Physiol. Pharmacol. 72, Suppl. 1: 115, 1994.

39.   Webb, R. C., and D. F. Bohr. Potassium relaxation of vascular smooth muscle from spontaneously hypertensive rats. Blood Vessels 16: 71-79, 1979[Medline].

40.   Wellman, G. C., A. D. Bonev, M. T. Nelson, and J. E. Brayden. Gender differences in coronary arterial diameter involve estrogen, nitric oxide, and Ca2+-dependent K+ channels. Circ. Res. 79: 1024-1030, 1996[Abstract/Free Full Text].

41.   White, R. E., D. J. Darkow, and J. L. Lang. Estrogen relaxes coronary arteries by opening BKCa channels through a cGMP-dependent mechanism. Circ. Res. 77: 936-942, 1995[Abstract/Free Full Text].

42.   Yue, T., K. Chatterjee, C. Beale, P. A. Poole-Wilson, and P. Collins. Testosterone relaxes rabbit coronary arteries and aorta. Circulation 91: 1154-1160, 1995[Abstract/Free Full Text].

Am J Physiol Heart Circ Physiol 275(1):H15-H22
0002-9513/98 $5.00 Copyright © 1998 the American Physiological Society


This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
J. C. Sullivan, J. L. Pardieck, D. Doran, Y. Zhang, J.-X. She, and J. S. Pollock
Greater fractalkine expression in mesenteric arteries of female spontaneously hypertensive rats compared with males
Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H1080 - H1088.
[Abstract] [Full Text] [PDF]

Home page
 Ther Adv Cardiovasc DisHome page
P. D. Patel and R. R. Arora
Review: Endothelial dysfunction: A potential tool in gender related cardiovascular disease
Therapeutic Advances in Cardiovascular Disease, April 1, 2008; 2(2): 89 - 100.
[Abstract] [PDF]

Home page
 J. Appl. Physiol.Home page
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]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
J. Palacios, E. T. Marusic, N. C. Lopez, M. Gonzalez, and L. Michea
Estradiol-induced expression of Na+-K+-ATPase catalytic isoforms in rat arteries: gender differences in activity mediated by nitric oxide donors
Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1793 - H1800.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. M. Orshal and R. A. Khalil
Gender, sex hormones, and vascular tone
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2004; 286(2): R233 - R249.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
A. P. McKee, D. A. Van Riper, C. A. Davison, and H. A. Singer
Gender-dependent modulation of alpha 1-adrenergic responses in rat mesenteric arteries
Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1737 - H1743.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
H. L. Xu, R. A. Santizo, H. M. Koenig, and D. A. Pelligrino
Chronic estrogen depletion alters adenosine diphosphate-induced pial arteriolar dilation in female rats
Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H2105 - H2112.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
K. G. Lamping and F. M. Faraci
Role of Sex Differences and Effects of Endothelial NO Synthase Deficiency in Responses of Carotid Arteries to Serotonin
Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 523 - 528.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kähönen, M.
Right arrow Articles by Pörsti, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kähönen, M.
Right arrow Articles by Pörsti, I.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online