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 th e rat. Rings of aorta were obtained from the following groups of age-m atched rats (i) male, (ii) female, and two groups of rats implanted wi th a subcutaneous pellet (iii) ovariectomized, placebo-treated, (iv) o variectomized, 17 beta-estradiol-treated (0.5 mg/pellet/21 days). In p henylephrine (2 mu M) pre-contracted rings with intact endothelium, cy clopiazonic acid (10(-7) to 3 x 10(-5) M) produced endothelium-depende nt relaxations in a concentration-dependent manner. The cyclopiazonic acid dilation as a percentage loss of phenylephrine tone was greater i n 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 ovariect omized rats (40.8 +/- 3.9%) (P < 0.05, one-way analysis of variance (A NOVA)). These relaxation responses of cyclopiazonic acid were converte d to contractions by pre-treatment with an inhibitor of nitric oxide ( NO) synthase, N-omega-nitro-L-arginine methyl ester (L-NAME, 200 mu M; 30 min). There were no differences in cyclopiazonic acid-induced cont ractions of aortas excised from either estrogen-treated or untreated-o variectomized 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 ovariectomi zed and control female rats, possibly due to unmasking of estrogen-enh anced Ca2+ entry into the endothelial cells.