Activation of Ca2+-independent nitric oxide synthase by 17β-estradiol in post-ischemic rat heart

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Abstract
Background: Nitric oxide (NO) donors or facilitation of endogenous NO production is cardioprotective. This study sought to determine whether enhanced myocardial NO production might contribute to estrogen-induced cardioprotection. Methods: Ca2+-dependent and Ca2+-independent NOS activities (pmol min−1 mg−1 protein), NOS protein expression (quantitative immunoblot), cGMP content (pmol mg−1 protein) and LV work (Joules) were measured in hearts isolated from ovariectomized rats that were either untreated or treated chronically with 17β-estradiol (0.25 mg, 21 day release formulation). Results: After 14 days, serum levels of 17β-estradiol were 6±1 and 135±16 pg ml−1 in untreated and 17β-estradiol-treated animals, respectively. After 60 min aerobic working mode perfusion, Ca2+-dependent NOS (untreated, 1.47±0 36; 17β-estradiol 1.13±0.25) and Ca2+-independent NOS (untreated, 0.45±0.24; 17β-estradiol, 0.41±0.21) activities, eNOS and iNOS proteins and cGMP content (untreated, 0.64±0.08; 17β-estradiol, 0.76±0.12) were not different in the two groups. After 60 min low-flow (0.5 ml min−1) ischemia and 30 min reperfusion, Ca2+-dependent NOS activities were again similar (untreated, 1.25±0.23; 17β-estradiol, 0.78±0.27). However, after reperfusion, Ca2+-independent NOS activity (untreated, 0.39±0.10; 17β-estradiol, 1.36±0.36) was 3.5-fold higher (P=0.008) and cGMP content (untreated, 0.30±0.03; 17β-estradiol, 0.49±0.07) was 1.6-fold higher (P=0.017) in hearts from 17β-estradiol-treated animals. Although pre-ischemic function was similar, recovery of post-ischemic LV work was 2-fold greater (P=0.024) in the 17β-estradiol group. Conclusion: The ability of ischemia and reperfusion in combination with chronic 17β-estradiol to increase Ca2+-independent NOS activity and cGMP content supports a role for enhanced myocardial NO signaling in 17β-estradiol-induced cardioprotection.

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