Regulation of the Vascular Responses to Endothelin-1: Effects of Gender and Chronic Physiological Concentrations of 17β-Oestradiol

1. An interaction between endothelium-derived factors and sex hormones appears likely since gender differences occur in cardiovascular disorders in which endothelial dysfunction is implicated. We examined the influence of oestrogen and/or gender on endothelin-1 (ET-1) generation, and the expression and function of ET receptors in rats.
2. Female Sprague-Dawley rats (10 wks) comprised four groups: gonadally intact or ovariectomised and replaced with 17β-oestradiol (E2), tamoxifen or placebo for 6-8 weeks. Total RNA was extracted from aortae of the female rats and from age-matched males (n=7 per group). Ribonuclease protection assay was used to
measure prepro-ET-1. ETA receptor mRNA expression was quantified by competitive RT-PCR. Parallel studies using aortic ring preparations examined functional responses to ET-1 (10-10 to 3x10-7M) in intact and endothelium-denuded vessels (n=6-8 per group).
3. 17β-E2 attenuated the contractile response to ET-1 in both intact (EC50 = 1.2±0.3 x 10-8M for 17β-E2 versus 3.6±1.0 x 10-9M for placebo, P=0.02; and 4.3±1.3 x 10-9M for males, P=0.04) and denuded (EC50 = 6.5±2.6 x 10-9M for 17β-E2 versus 1.8±0.5 x 10-9M for placebo, P=0.008; and 1.6±0.2 x 10-9M for males, P=0.002) aortic rings.
4. No significant differences in plasma ET-1 concentrations, prepro-ET-1 mRNA or ETA receptor mRNA levels were observed between the groups.
5. Our results demonstrate that chronic physiological levels of oestrogen reduce the contractile response to ET-1 in both intact and denuded aortic rings by a mechanism other than altered vascular expression of ETA and ET-1. This effect of oestrogen may contribute to its cardioprotective action in women.