Hyper-reactivity of cerebral arteries from ovariectomized rats: therapeutic benefit of tamoxifen.
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=16) or a sham operation (n=8). At 6-week postsurgery, rats were anesthetized to assess ventricular contractility and blood pressure. In a second series of experiments, OVX rats (n=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 (P<0.05) in the OVX rat (174+/-8 mmHg), as compared to sham (135+/-6 mmHg). The resting tension of isolated cerebral arteries from OVX rats (186+/-15 mg) was significantly elevated (P<0.05), as compared to sham (129+/-9 mg). Phenylephrine treatment did not elicit a constriction of cerebral arteries isolated from sham rats, whereas a potent response (P<0.05) was observed in OVX rats. Nitric oxide (NO) synthase inhibition with L-NNA led to a limited contraction in sham rats (8+/-3% of Emax), whereas a significant (P<0.05) increase was observed in OVX rats (34+/-12% of Emax). Lastly, vascular sensitivity (pD2) to sodium nitroprusside was significantly increased (P<0.05) 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.
Centre de Recherche de l'Institut de Cardiologie de Montréal, Montreal, Quebec, Canada.
Eric
E
Thorin
Mylan
M
Pham-Dang
Robert
R
Clement
Isabelle
I
Mercier
Angelino
A
Calderone
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002536:Cerebral Arteries / Q000187:drug effects* / Q000502:physiology; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000187:drug effects; D019335:Nitroarginine / Q000494:pharmacology; D010052:Ovariectomy; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D014662:Vasoconstrictor Agents; D013629:Tamoxifen; D010656:Phenylephrine; D019335:Nitroarginine; D019001:Nitric Oxide Synthase