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This Article Abstract Full Text (PDF) All Versions of this Article: 91/1/261    most recent expphysiol.2005.032060v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Giménez, J. Articles by Hernández, I. Search for Related Content PubMed PubMed Citation Articles by Giménez, J. Articles by Hernández, I. Related Collections Vascular

¹ Department of Physiology, Facultad de Medicina, Universidad de Murcia, Spain

	Abstract

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We investigated the role of oestrogen in the function and structure of the microcirculation of female spontaneously hypertensive rats (SHRs), and evaluated the effect of 17ß-oestradiol on their cardiovascular response to pharmacological agents that block the formation of angiotensin II. Ten-week-old SHRs were randomly assigned to the following groups: intact, ovariectomized, and ovariectomized treated with 17ß-oestradiol (1.5 mg delivered over 60 days) and/or captopril (5 mg kg^–1 day^–1 for 8 weeks). Systolic blood pressure was determined from the time of ovariectomy up to 18 weeks of age, at which time endothelial function and microvascular density in skeletal muscle were evaluated. Both 17ß-oestradiol and captopril prevented development of hypertension in ovariectomized rats. Furthermore, coadministration of both drugs had a greater antihypertensive effect than either one alone. Acetylcholine-induced vasodilatation was impaired in ovariectomized SHRs, and the response was improved by treatment with 17ß-oestradiol and/or captopril. In addition, 17ß-oestradiol replacement in ovariectomized rats enhanced the effect of captopril on acetylcholine-induced vasodilatation. Ovariectomized rats also showed lower microvascular density than intact rats, an effect that was prevented by 17ß-oestradiol replacement or captopril treatment and, to a significantly larger extent, by coadministration of both. We concluded that both 17ß-oestradiol and captopril attenuated the development of hypertension and improved the impairment in microvascular density of ovariectomized SHRs. Moreover, when simultaneously administered, oestradiol and captopril had an additive effect on blood pressure and the microvasculature.

(Received 30 August 2005; accepted after revision 7 November 2005; first published online 10 November 2005)
Corresponding author I. Hernandez: Departamento de Fisiología, Facultad de Medicina, Universidad de Murcia, Campus de Espinardo, 30100, Murcia, Spain. Email: isabelhg{at}um.es

	Introduction

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The development of hypertension both in animal models and in humans is accompanied by impaired endothelial function and rarefaction of arterioles and capillaries (Vicaut, 2003). In this regard, oestrogens have been shown to enhance endothelial-dependent relaxation of arterial rings from different species and different vascular beds, including the aorta and coronary, skeletal muscle, mesenteric and cerebral arteries (Tostes et al. 2003). While recent clinical trials suggest that oestrogen administration after development of cardiovascular disease does not prevent the occurrence of secondary events (Grady et al. 2002; Hulley et al. 1998), the use of hormonal therapy after the menopause had no harmful effects on coronary heart disease when the therapy started in the early postmenopausal period (Hodis et al. 2003). Much of the discrepancy between studies may be due to the different age of patients, and the type of hormonal compound and route of administration used. Human studies have, however, shown that oestrogen replacement increases brachial and coronary blood flow, and decreases both coronary resistance and peripheral vascular tone (Losordo & Isner, 2001). Besides its effects on endothelial function, the actions of oestrogen on the microvascular net are also of potential interest. In this sense, oestrogen has been shown to induce endothelial cell proliferation and migration, and to increase the expression of vascular endothelial growth factor (Losordo & Isner, 2001). Ovariectomy, however, reduces skeletal muscle neovascularization after ischaemia, an effect that can be prevented by oestrogen replacement (Kyriakides et al. 2001). Thus, a protective effect of oestrogen on vascular rarefaction might possibly be contributing to prevent increased vascular resistance in hypertension. Although oestrogen seems to improve vascular function, the effect of this hormone on blood pressure is not clear. Harrison-Bernard et al. (2003) and Reckelhoff et al. (2000) have reported that ovariectomy does not affect the development of hypertension in SHRs. In women, blood pressure has been reported to decrease, increase or remain unchanged after oestrogen treatment, depending on the oestrogenic preparation type and dose, and on how blood pressure is measured (Harrison-Bernard & Raij, 2000; Dubey et al. 2002).

Like oestrogen, angiotensin-converting enzyme (ACE) inhibitors improve endothelial function (Rodrigo et al. 2001) and have been described to reduce microcirculation rarefaction in different tissues (Vicaut, 1999). Several studies indicate the existence of gender-related differences with regard to the antihypertensive effect of renin–angiotensin system (RAS) inhibitors in SHRs (Nigro et al. 1997; Silva-Antonialli et al. 2000) and humans (Preston et al. 2002; Safar et al. 2002), which suggests a beneficial interaction between oestrogen and the antihypertensive effect of ACE inhibitors. After the menopause, oestrogen deficiency promotes overexpression of Angiotensin Type I (AT₁) receptors and increased ACE activity, which may contribute to increased hypertension and cardiovascular risk in postmenopausal women (Tostes et al. 2003). In addition, it has recently been proposed to use ACE inhibitors as a preventive drug intervention in women with a high risk of coronary heart disease (Mosca et al. 2004). Consequently, the study of RAS inhibition in the presence and absence of oestrogen may be of particular interest.

The purpose of this study was to test the hypothesis that ovariectomy leads to impairment of endothelium-dependent microvascular relaxation and microvascular rarefaction in SHRs, and to investigate the potential contribution of oestrogens and the RAS to these effects. To that end, we evaluated: (a) the effects of ovariectomy on a number of parameters, including systolic blood pressure, tissue vascular resistance in response to acetylcholine and sodium nitroprusside in skeletal muscle, and microvascular density in gracilis muscle samples; (b) the impact of oestradiol replacement on ovariectomy-induced changes; and (c) the effect of ACE inhibition on ovariectomized rats in the presence or absence of oestradiol.

	Methods

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Experiments were performed on a total of 33 virgin female SHRs. Ten-week-old rats were anaesthetized with ketamine (30 mg kg^–1 I.M.) and xylazine (20 mg kg^–1 I.M.), and their ovaries exposed and either removed (n = 27) or left intact (n = 6, intact group). Ovariectomized (OVX) rats were in turn divided into four groups: OVX (n = 6, rats with no further treatment); OVX + E₂ [n = 7, rats given a subcutaneous implant of pellets (Innovative Research of America, Sarasota, FL, USA) containing 17ß-oestradiol (1.5 mg delivered over 8 weeks)]; OVX + CAP (n = 7, rats chronically treated with captopril (5 mg kg^–1 day^–1) in tap water); and OVX + CAP + E₂ (n = 7, rats treated with captopril and 17ß-oestradiol for 8 weeks). All procedures were in accordance with the recommendations of the Council of Europe on care and use of animals. Approval for these experiments was obtained in advance from the Animal Ethics Committee of the University of Murcia.

Blood pressure measurements

Systolic blood pressure (SBP) was measured in conscious, resting animals, by non-invasive tail-cuff plethysmography (LE 5002 Storage Pressure Meter, Letica Scientific Instruments, Barcelona, Spain), starting at 11 weeks of age, when the animals had recovered from the surgery. Seven days before the beginning of the experiment, rats were trained every 2 days for SBP measurements. Measurements were performed in an isolated room under controlled light and temperature conditions. Animals were placed in boxes for 15 min, and at least three consecutive pressure determinations were made for each animal, the average of these being recorded as the SBP for that animal. Blood pressure measurements were performed 1, 2, 3, 5, 7 and 8 weeks after ovariectomy.

Laser-Doppler flowmetry

Eighteen-week-old rats were anaesthetized by intramuscular injection of ketamine (30 mg kg^–1, Rhône Merieux) and intraperitoneal injection of thiopentone (Pentothal, 50 mg kg^–1, Abbott Laboratories). A catheter (PE-50) was inserted into the right carotid artery to measure mean arterial pressure (MAP). A small skin incision was made on the right leg to expose the underlying muscle tissue (biceps femoralis; Hernandez & Greene, 1995). The muscle was carefully dissected free from the skin with smooth scissors. After the muscle layer was freed from its connective tissue on the underside of the skin, a window was constructed with warm agar (37°C). This window was filled with warm physiological saline solution (37°C). The hindlimb was fixed in place on a specially designed heated table. Assessment of tissue blood flow was obtained with a Periflux Pf3 laser-Doppler perfusion monitor (Perimed, Stockholm, Sweden). After an equilibration period of 1 h, basal values of MAP and tissue blood flow were registered. Acetylcholine was locally administered at three different doses: 10^–6 10^–5 and 10^–4 M, and its effect on blood pressure and tissue blood flow registered. Muscle blood flow was allowed to stabilize after each dose. In order to evaluate differences in the vasodilatation response caused by anatomical rarefaction, sodium nitroprusside was locally applied at a dose (10^–4 M) known to cause maximum vasodilatation. Tissue vascular resistances were calculated from mean arterial pressure and tissue blood flow, and reported as millimetres of mercury per laser periflux unit (LPU).

Study of microcirculation density

Following blood flow measurements and while the rats were still under anaesthesia, the gracilis muscle was removed and rinsed in PSS, after which the animals were killed by administration of thiopentone (Pentothal, 200 mg kg^–1 I.V.). Muscle samples were incubated with FITC-labelled Grifonia simplicifolia I lectin (Sigma) as previously described (Hernandez et al. 1992). This procedure selectively stains all microvessels with a diameter over 10 µm, preferentially arterioles and capillaries versus venules, regardless of perfusion status. After exposure to lectin, sections were rinsed five times in PSS and mounted on microscope slides with mounting medium (Sigma Diagnostics). Stained microvessels were viewed with an epifluorescence microscope (World Precision Instruments) coupled to a cooled charge-coupled device camera (Cool snap, RS Photometric). Ten fields from each one of two samples were analysed in each animal. Microvascular density was measured by counting labelled microvessel intersections with a 40 µm computer-generated grid overlying the microscope field, which was displayed on a computer monitor at 250x using imaging software (Karl-Zeiss 300).

Data analysis

All values are reported as means ± S.E.M. Systolic blood pressure and response to acetylcholine were analysed by two-way ANOVA for repeated measures, and a post hoc Fisher's least-significant difference test was used to determine differences between means if a statistically significant effect was found. Responses to sodium nitroprusside and microvascular density were analysed by one-way ANOVA using a completely randomized design. As before, a post hoc Fisher's analysis was performed on statistically significant effects to detect differences between the groups. Values of P < 0.05 were considered statistically significant.

	Results

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Effect of ovariectomy on SHR endothelial function, microcirculation density and systolic blood pressure

Time-related changes in systolic blood pressure are shown in Fig. 1. At 11 weeks of age, i.e. 1 week after ovariectomy, SBP was 161 ± 8, 157 ± 6 and 165 ± 5 mmHg in intact, ovariectomized and ovariectomized plus oestradiol groups, respectively. The evolution of systolic blood pressure was not significantly different in intact versus ovariectomized rats, although in the former group it increased to a slightly lower value (187.7 ± 3.6 compared to 202.3 ± 8.3 mmHg, n.s.). Oestradiol treatment prevented the SBP increase in ovariectomized rats (161.5 ± 7.4 mmHg; P < 0.01).

View larger version (15K): [in this window] [in a new window]   Figure 1.  Time-related systolic blood pressure (SBP) changes measured by tail-cuff plethysmography in intact (Intact), ovariectomized (OVX), and ovariectomized treated with 17ß-oestradiol (OVX + E2) SHRs Measures were performed 1, 2, 3, 5, 7 and 8 weeks after ovariectomy or sham surgery. Values are expressed as means ± S.E.M. *P < 0.05 versus week 1. P < 0.05 versus OVX group.

View larger version (14K): [in this window] [in a new window]   Figure 2.  Tissue vascular resistance changes in intact, ovariectomized and ovariectomized SHRs treated with 17ß-oestradiol after local application of 10–6, 10–5 or 10–4M acetylcholine (A) and after local application of 10–4M sodium nitroprusside (B) Values are expressed as means ± S.E.M. *Significant differences from ovariectomized SHRs (P < 0.05).

View larger version (11K): [in this window] [in a new window]   Figure 3.  Number of microvessel intersections marked with FITC-labelled lectin from intact and ovariectomized SHRs and ovariectomized SHRs treated with 17ß-oestradiol Values are expressed as means ± S.E.M. *Significant differences from ovariectomized SHRs (P < 0.05).

Figure 4 illustrates SBP changes in ovariectomized rats treated with captopril or captopril + 17ß-oestradiol. Captopril prevented the development of hypertension, with animals displaying an average SBP value of 135.9 ± 3.4 mmHg at the end of the experiment. 17ß-Oestradiol enhanced the antihypertensive effect of captopril, lowering the SBP value to 119 ± 3 mmHg (P < 0.05).

View larger version (21K): [in this window] [in a new window]   Figure 4.  Time-related SBP changes measured by tail-cuff plethysmography in intact, ovariectomized (OVX), ovariectomized treated with captopril (OVX + CAP), and ovariectomized treated with captopril plus 17ß-oestradiol (OVX + CAP + E2) SHRs Measurements were performed 1, 2, 3, 5, 7 and 8 weeks after ovariectomy. Values are expressed as means ± S.E.M. *Significant differences versus week 1; versus OVX; versus ovariectomized SHRs treated with captopril alone (all P < 0.05).

View larger version (26K): [in this window] [in a new window]   Figure 5.  Tissue vascular resistance changes in intact, ovariectomized (OVX), ovariectomized treated with captopril (OVX + CAP), and ovariectomized treated with captopril plus 17ß-oestradiol (OVX + CAP + E2) SHRs after local application of 10–6, 10–5 or 10–4M acetylcholine (A) and after local application of 10–4M sodium nitroprusside (B) Values are expressed as means ± S.E.M. *P < 0.05 versus ovariectomized SHR; P < 0.05 versus ovariectomized SHRs treated with captopril.

View larger version (48K): [in this window] [in a new window]   Figure 6.  Number of microvessel intersections marked with FITC-labelled lectin from intact, ovariectomized (OVX), ovariectomized treated with captopril (OVX + CAP), and ovariectomized treated with captopril plus 17ß-oestradiol (OVX + CAP + E2) SHRs Values are expressed as means ± S.E.M. *P < 0.05 versus ovariectomized SHRs; P < 0.05 versus ovariectomized SHRs treated with captopril.

	Discussion

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The lower response of ovariectomized rats to 10^–4 M acetylcholine could be due to impaired endothelial function. In this sense, previous studies report that ovariectomized SHRs show reduced vasodilatation in response to shear stress in skeletal muscle arteries (Huang et al. 1997), as well as a diminished response to carbachol in aortic rings in the absence of oestradiol (Wassmann et al. 2001), which suggests a beneficial effect of oestrogen on endothelial function. Other authors (Hernandez et al. 2000; Wassmann et al. 2001) have suggested that reduced NO availability, due to a higher level of reactive oxygen species, could be responsible for the impaired response of ovariectomized rats to endothelium-dependent vasodilator agents. In this sense, Delgado et al. (1999) reported that N-acetylcysteine, a free radical scavenger, could reverse aortic ring endothelium dysfunction associated with ovariectomy. In addition, because ACh-mediated vasodilatation was accompanied by a reduced response to sodium nitroprusside, it cannot be excluded that vascular smooth muscle from ovariectomized rats might have a lower sensitivity to NO. However, previous studies in our laboratory have shown that aortic rings from ovariectomized rats do display a lower response to acetylcholine, but not sodium nitroprusside, than those from intact rats (Delgado et al. 1999), suggesting an abnormal endothelium function rather than decreased vascular smooth muscle sensitivity to NO.

The results of the present study, however, provide two pieces of evidence involving an effect of oestrogen on the microvascular net structure during the development of hypertension in SHRs. First, ovariectomy decreased the maximally vasodilated vascular resistance response to local application of sodium nitroprusside, an effect that was prevented by chronic oestradiol replacement. Second, ovariectomized rats had a significantly lower microvascular density than intact rats, and oestradiol replacement was again able to prevent this. In the present study, there appears to be no significant effect of ovariectomy on blood pressure; however, differences close to 15 mmHg were found between intact and ovariectomized animals. The lack of statistical significance may be due to blood pressure variability in rats with intact ovaries that were not cycling. In contrast, oestradiol replacement in ovariectomized SHRs prevented the systolic blood pressure increase and inhibited microvascular rarefaction. In this regard, the possibility was raised that the blood pressure difference may account for the lower microvascular density. From the results of this study, however, it should also be noted that ovariectomized animals showed a significantly greater microvascular density decrease than intact animals did, although no significant hypertension evolution differences were found between both groups. In this sense, besides decreasing blood pressure, there would be additional mechanisms for oestradiol to exert its protective effects on the vasculature.

In agreement with our results, previous studies have reported a frontal cortex capillary density (Jesmin et al. 2003) and left ventricle coronary capillary density (Jesmin et al. 2002) reduction after ovariectomy in middle-aged female rats, prevented in both cases by oestradiol treatment. This might be due to an oestrogen angiogenic effect that could be partly mediated by an enhancement of endothelial precursor cells (Strehlow et al. 2003) and gene expression of vascular endothelium growth factor (Karas et al. 1996). Moreover, oestrogens seem to play an important role in neovascularization by upregulating angiogenesis (Kyriakides et al. 2001) and increasing capillary volume density in the myocardium (Lamping et al. 2003), where ovariectomy has been described to reduce ischaemia-induced neovascularization.

Recently, Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women (Mosca et al. 2004) recommends, among other strategies, the use of ACE inhibitors in high-risk women. Thus, understanding the interaction among oestrogen and ACE inhibitors is of potential interest. In our experiments, chronic ACE inhibition decreased blood pressure and improved impaired endothelial function in SHRs, as reported by others (Rodrigo et al. 2001). Captopril appears to reduce blood pressure not only by reducing the formation of angiotensin II, but also by increasing vasodilator factors like bradykinin and NO. According to this, other authors, like us, have shown that nitric oxide synthesis inhibition reduces the antihypertensive effect of captopril (Ruiz et al. 1994; Cachofeiro et al. 1995). Furthermore, this effect may be explained by a reduction of angiotensin II-induced superoxide generation leading to increased NO bioavailability, thus increasing the response to acetylcholine of animals treated with captopril (Wassmann et al. 2001).

Aside from the sexual dimorphism in the effect of ACE inhibition on endothelial function that has been described, the effect of ACE inhibition on the microvascular net remains controversial. Thus, ACE inhibition has been reported to prevent microvascular rarefaction in SHR myocardium and skeletal muscle (Vicaut, 1999), but it seems to reduce microvascular density in renal hypertension models (Wang & Prewitt, 1990; Levy et al. 2001). In our model of ovariectomized SHRs, captopril administration ameliorated hypertension-induced microvascular rarefaction; however, since captopril prevented the development of hypertension, the involvement of some kind of pressure-dependent mechanism in this effect cannot be excluded.

In our study, the combined impact of oestradiol and captopril on blood pressure was more effective in preventing hypertension than captopril alone. These results are in agreement with previous data showing that enalapril reduces blood pressure to normotensive levels in 70% of females compared to 45% of males (Nigro et al. 1997), suggesting a sexually dimorphic response to the hypotensive effect of ACE inhibition in SHRs. It has also been reported that oestradiol can restore the beneficial effect of moexipril on systolic blood pressure in ovariectomized SHRs (Pelzer et al. 2002). In addition to previous studies from Silva et al. (2000), showing that chronically administered losartan rendered aortas from female SHRs more sensitive to sodium nitroprusside than those from male SHRs, a recent study by Liu and coworkers showed that 17ß-oestradiol and an AT₁ receptor blocker synergistically attenuated the vascular injury response in mice (Liu et al. 2002). These studies raise a number of pressing questions, including whether 17ß-oestradiol and ACE inhibitors also have a synergistic or additive effect in lowering blood pressure and reducing vascular damage in hypertensive states. In our experiments, ovariectomized rats treated with oestradiol and captopril displayed a stronger microvascular response to sodium nitroprusside and higher microvascular density than ovariectomized rats treated with captopril alone. The stronger effect of oestradiol and captopril together on microvascular density could be due to the more pronounced antihypertensive action that was observed when they were administered together. Nonetheless, other factors could explain our results. For example, ACE inhibition exerts a bradykinin-mediated angiogenic action on the microvascular net (Silvestre et al. 2001), and it is known that oestrogen enhances the expression (Madeddu et al. 1997) and plasma levels (Nogawa et al. 2001) of bradykinin B2 receptor, so captopril may have a greater effect in the presence of oestrogen.

In summary, our results show that oestrogen and ACE inhibitors have a beneficial blood pressure lowering effect in ovariectomized SHRs, which is accompanied by an improvement of microvascular density. Furthermore, coadministration of oestradiol and captopril had an additive effect on blood pressure and microvascular function and density. These results support the notion that ACE inhibition and its combination with oestrogen replacement might be useful for the treatment of cardiovascular disease associated with the menopause.

View larger version (81K): [in this window] [in a new window]   Figure 7.  Representative photomicrographs of gracilis muscle microvascular bed from intact, ovariectomized (OVX), ovariectomized treated with 17ß-oestradiol (OVX + E2), ovariectomized treated with captopril (OVX + CAP), and ovariectomized treated with captopril plus 17ß-oestradiol (OVX + CAP + E2) SHRs

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	Acknowledgements

 
This work was supported by grants from the Ministry of Education and Culture of Spain (PM98-0058; BFI2002-00641; BFI2003-00618) and The Seneca Foundation (PI-65/00/00790/FS/01; PB/37/FS/02).

This Article Abstract Full Text (PDF) All Versions of this Article: 91/1/261    most recent expphysiol.2005.032060v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Giménez, J. Articles by Hernández, I. Search for Related Content PubMed PubMed Citation Articles by Giménez, J. Articles by Hernández, I. Related Collections Vascular