Sex steroid hormones differentially regulate nitric oxide synthase and arginase activities in the proximal and distal rabbit vagina.

Abstract

Nitric oxide synthase (NOS) and arginase have been shown to regulate nitric oxide (NO) production reciprocally in genital tissues. In animal models, NO is an important regulator of vaginal blood flow and vaginal wall contractility. In this study, we investigated the modulation of NOS and arginase activities by estrogens and androgens in the proximal and distal rabbit vagina. In intact control animals, total NOS activity was higher in the proximal (528+/-78 pmol/mg protein) than the distal (391+/-44 pmol/mg protein) vagina. However, arginase activity was higher in the distal (206+/-8 nmol/mg protein) than the proximal (64+/-5 nmol/mg protein) vagina. Ovariectomy enhanced NOS activity in the proximal but not distal vagina with concomitant decrease in arginase activity in both the proximal and distal vagina. In ovariectomized rabbits, replacement with 5alpha-dihydrotestosterone (DHT) or Delta5-androstenediol (Adiol) increased NOS activity beyond that observed in ovariectomized rabbits receiving vehicle. In contrast, DHT and Adiol treatment reduced arginase activity more than that of the ovariectomized rabbits receiving vehicle. Testosterone exhibited inconsistent effects on NOS and arginase activity in the distal and proximal vagina. Estradiol replacement in ovariectomized animals reduced NOS activity in the proximal vagina down to levels that were comparable to intact control animals. However, estradiol positively modulated arginase activity in the distal vagina. Western blot analyses indicated that in the proximal vagina, neural NOS protein levels paralleled the changes observed in enzyme activity. These observations suggest that steroid hormones differentially regulate NOS and arginase activities of the proximal and distal regions of the vagina. Although estrogen treatment reduced total NOS activity in proximal vagina, estrogens are known to enhance vaginal blood flow. This paradoxical observation may be explained by differential regulation of n-NOS and e-NOS in the proximal and distal vagina. We suggest that changes in vaginal blood flow and compliance may depend on the endocrine status and the levels of circulating androgens and estrogens.