Estrogen augments cyclopiazonic acid-mediated, endothelium-dependent vasodilation.
The modulatory effects of chronic estrogen treatment on the responses to cyclopiazonic acid, an endoplasmic reticulum Ca2(+)-ATPase inhibitor, were studied in rings of aorta and the isolated perfused kidney of the rat. Rings of aorta were obtained from the following groups of age-matched rats (i) male, (ii) female, and two groups of rats implanted with a subcutaneous pellet (iii) ovariectomized, placebo-treated, (iv) ovariectomized, 17beta-estradiol-treated (0.5 mg/pellet/21 days). In phenylephrine (2 microM) pre-contracted rings with intact endothelium, cyclopiazonic acid (10(-7) to 3 x 10(-5) M) produced endothelium-dependent relaxations in a concentration-dependent manner. The cyclopiazonic acid dilation as a percentage loss of phenylephrine tone was greater in aortic rings from female (72.9 +/- 2.4%) and estrogen-treated rats (65.5 +/- 4.8%) compared to those from male (51.5 +/- 3.4%) or ovariectomized rats (40.8 +/- 3.9%) (P < 0.05, one-way analysis of variance (ANOVA)). These relaxation responses of cyclopiazonic acid were converted to contractions by pre-treatment with an inhibitor of nitric oxide (NO) synthase, N(omega)-nitro-L-arginine methyl ester (L-NAME, 200 microM; 30 min). There were no differences in cyclopiazonic acid-induced contractions of aortas excised from either estrogen-treated or untreated-ovariectomized rats. In perfused kidneys, cyclopiazonic acid (10(-5) M) caused a larger decrease in perfusion pressure in kidneys from female rats (110 +/- 0.4 mmHg) than it did in kidneys from male rats (80 +/- 0.6 mmHg). These results demonstrate that cyclopiazonic acid causes a greater endothelium-dependent dilation in estrogen-treated ovariectomized and control female rats, possibly due to unmasking of estrogen-enhanced Ca2+ entry into the endothelial cells.
Rahimian
R
R
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Van Breemen
C
C
Karkan
D
D
Dube
G
G
Laher
I
I
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D004958:Estradiol / Q000097:blood* / Q000494:pharmacology; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D010656:Phenylephrine; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D007211:Indoles; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D004958:Estradiol; D019331:NG-Nitroarginine Methyl Ester; C000543:cyclopiazonic acid