Hyper‐reactivity of cerebral arteries from ovariectomized rats: therapeutic benefit of tamoxifen

Abstract

1 An increased incidence of systemic hypertension has been documented in postmenopausal women and identified as an independent risk factor in the development of cerebrovascular stroke. The present study examined whether cerebrovascular reactivity was increased in the hypertensive ovariectomized rat, and explored the potential therapeutic benefit of the partial estrogen receptor agonist tamoxifen. 2 Female Sprague -Dawley rats were subjected to bilateral ovariectomy (OVX, n ¼ 16) or a sham operation (n ¼ 8). At 6-week postsurgery, rats were anesthetized to assess ventricular contractility and blood pressure. In a second series of experiments, OVX rats (n ¼ 8) were given tamoxifen starting 3 weeks postsurgery, and continued for 3 weeks. At the end of each protocol, the middle cerebral artery was harvested and rings were mounted in wire-myographs to measure isometric tension. 3 Systolic arterial pressure (SAP) was significantly increased (Po0.05) in the OVX rat (17478 mmHg), as compared to sham (13576 mmHg). The resting tension of isolated cerebral arteries from OVX rats (186715 mg) was significantly elevated (Po0.05), as compared to sham (12979 mg). Phenylephrine treatment did not elicit a constriction of cerebral arteries isolated from sham rats, whereas a potent response (Po0.05) was observed in OVX rats. Nitric oxide (NO) synthase inhibition with L-NNA led to a limited contraction in sham rats (873% of E max ), whereas a significant (Po0.05) increase was observed in OVX rats (34712% of E max ). Lastly, vascular sensitivity (pD 2 ) to sodium nitroprusside was significantly increased (Po0.05) in OVX rats, as compared to sham. 4 Tamoxifen therapy normalized the resting tension of isolated cerebral arteries from OVX rats, abrogated phenylephrine-mediated contraction, and modestly reduced SAP. By contrast, tamoxifen treatment of OVX rats did not attenuate L-NNA-mediated contractile response of cerebral arteries. 5 These data demonstrate that the cerebral artery isolated from the OVX rat was associated with an exaggerated vasoconstrictor response to phenylephrine, and altered NO-dependent vascular reactivity. The administration of tamoxifen to OVX rats normalized cerebral artery reactivity to phenylephrine. These findings provide the impetus to examine the potential therapeutic benefit of the partial estrogen receptor agonist tamoxifen to reduce the incidence of cerebrovascular stroke in postmenopausal women.

Tamoxifen treatment of myocardial infarcted female rats exacerbates scar formation

“…The class of compounds referred to as SERMs possess partial estrogen activity and mimic the beneficial effect of the endogenous hormone on bone resorption and circulating HDL levels [3,12,19]. In addition, TAM therapy normalized the exaggerated cerebral vascular reactivity to norepinephrine in ovariectomized female rats [29]. However, during the early phase of remodeling in post-MI female rats, TAM administration increased infarct size and the underlying mechanism may have been related in part to the attenuation of new vessel growth.…”

“…To examine the effect of TAM, a dose of 10 mg kg −1 per day was added to standard rat chow (12-24 h postsurgery), and continued for a period of 3 weeks. The dose of TAM employed in the present study was previously shown to normalize the exaggerated cerebral artery response to norepinephrine in the ovariectomized female rat [29]. During the 3-week protocol, rats were weighed every 2 days to adjust dosage according to changes in body weight (BW).…”

Gender-Specific Alteration of Adrenergic Responses in Small Femoral Arteries From Estrogen Receptor-β Knockout Mice

“…25 Because responses to PE are similar in aortas from ER␤KO and WT male mice, 4 it would also appear that the observed defect is a characteristic of small arteries alone. Indeed, PE responses have also been shown to be similar in aortas from WT, ER␤KO, and ER␣KO female mice after OVX and 17␤-estradiol supplementation.…”

“…This was unlikely to be attributable to increased basal synthesis of endothelium-derived vasodilators because PE-, NE-, and U46619-induced constrictions were unaffected by inhibitors of NOS and COX. An increased basal tension after NOS inhibition in isolated small arteries has been attributed to the endogenous synthesis of ET-1, 41,42 and increased basal tension in response to NOS inhibitor in cerebral arteries from OVX rats was associated with hypertension, 25 which could be prevented by ET A inhibition. 43 Therefore, observed AR abnormality could theoretically be achieved through increased basal ET-1 synthesis, but this requires verification by further investigations.…”

Endothelin-1-Induced Pulmonary Vasoreactivity Is Regulated by ET_A and ET_B Receptor Interactions

“…Experiments were conducted on isolated arteries of 1–2 mm length and 150–200 µm diameter using a wire myograph as previously reported [12]. They were set up on a myograph with a resting tension of 80–100 mg and bathed in a physiological salt solution containing the following composition (m M ): NaCl, 119; KCl, 4.7; KH 2 PO 4 , 1.18; MgSO 4 , 1.17; NaHCO 3 , 1.17; CaCl 2 , 1.16; EDTA, 0.023; glucose, 10.…”