Multiple Mechanisms are Involved in the Acute Vasodilatory Effect of 17β-Estradiol in the Isolated Perfused Rat Heart

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Abstract
The purpose of this study was to define the dose-dependent effects of 17β-estradiol on coronary flow and cardiac function in isolated rat hearts and to identify the mechanisms involved in its vasodilator action. Hearts from female and male Wistar rats were perfused at constant pressure (100 mm Hg). Stereoisomer specificity and the mechanism of vasodilation by 17β-estradiol were examined in female rat hearts. Function was measured by a left ventricular (LV) balloon and coronary flow (CF) with an ultrasonic flowmeter. 17β-Estradiol at 10−6, 5 × 10−6, and 10−5M increased CF in female hearts by 5 ± 2, 27 ± 4 (p < 0.05 vs. baseline), and 40 ± 4% (p < 0.05 vs. baseline), respectively. The effect of 17β-estradiol in hearts from male rats was similar but less pronounced compared with females [ΔCF 8 ± 3, 19 ± 3 (p < 0.05 vs. baseline)] and 25 ± 7% (p < 0.05 vs. baseline; p < 0.05 vs. female 17β-estradiol). Maximum vasodilation by the stereoisomer 17α-estradiol was significantly smaller [ΔCF 5 ± 3, 4 ± 3 (p < 0.05 vs. female 17β-estradiol) and 14 ± 1% (p < 0.05 vs. baseline; p < 0.05 vs. female 17β-estradiol)] for 10−6, 5 × 10−6, and 10−5M. Pretreatment with the NO-synthesis inhibitor Nω-methyl-L-arginine (10−4M) had no effect on the maximal vasodilator response to 17β-estradiol (10−5M) [ΔCF 36 ± 6% (p < 0.05 vs. baseline)]. When hearts were pretreated with the prostaglandin-synthesis inhibitor diclofenac (10−6M), the maximal vasodilator effect of 17β-estradiol was partially attenuated [ΔCF 12 ± 7% (p < 0.05 vs. female 17β-estradiol)]. Similarly, pretreatment with the K+ATP-blocker glibenclamide (10−6M) partially inhibited the maximal vasodilator effect of 17β-estradiol [ΔCF 22 ± 6% (p < 0.05 vs. baseline; p < 0.05 vs. female 17β-estradiol)]. Pretreatment with the Ca2+ channel antagonist nifedipine (7.2 × 10−8M) completely blocked the vasodilator effect. In isolated perfused rat hearts, 17β-estradiol induced marked acute coronary vasodilation; this effect is in part gender specific, and in female hearts, largely stereoisomer specific. The dilator effect is mediated predominantly by calcium channel blockade, but prostaglandin release and K+ATP channel activation also are involved. In the isolated perfused rat heart, NO production does not contribute to the acute vasodilator effect of 17β-estradiol.