Induction of calcium-dependent nitric oxide synthases by sex hormones.

Abstract

We have ex ed the effects of pregnancy and sex hormones on calciumdependent and m-independent nitric oxide synthas (NOSs) in the guinea pig. Pregnancy (near term) caused a >4-fold iase in the activity of cacium-dependent NOS in the uterine artery and at least a doubling in the heart, kidney, skeletal muscle, esophagus, and cerebeflum. The increase in NOS activity in the cerebellum during pregnanc was nhibited by the estn-receptor antagonittam len. Treatment with a ol (but not p rone) also i ed calcium-dependent NOS activity in the tissues examined from both females and males. Testosterone a calcium-dependent NOS only in the cerebeflum. No sign nt change in calcium-independent NOS acv was observed either during pregency or after the admiration f any sex hormone. Both pregan and estradol treatment increased the amount of mRNAs for NOS Isogymes eNOS and nNOS in skeletal muscle, 8 that the ireases in NOS activity result from enzyme induction. Thus both eNOS and nNOS are subject to rution by esten, an action that could explain some of the changes that occur during pegn and some gender differences in physiology and pa polg.Nitric oxide (NO) synthases (NOSs) constitute a family of isozymes that catalyze the oxidation of L-arginine to NO and citrulline. First identified in the vascular endothelium (1, 2), NO synthesis has subsequently been shown to play important roles in the regulation of vascular and gastrointestinal tone, in cell-mediated cytotoxicity against bacteria and tumors, and in a variety of central and peripheral nervous system activities (for review, see ref.3). NOSs can be divided into two functional classes based on their sensitivity to calcium (3). The cytokine-or bacterial product-inducible isoenzyme iNOS binds calmodulin tightly at resting intracellular calcium concentrations. The constitutive forms, isozymes eNOS (originally described in endothelial cells) and nNOS (originally described in neuronal tissue), bind calmodulin in a reversible and calcium-dependent fashion. The mechanisms by which their synthesis is controlled are unknown.The cDNA species encoding the rat, mouse, and human nNOS, the human and bovine eNOS, and iNOS from several species and cell types have been cloned and sequenced (4-17). ref. 28). This protection is lost with the onset of menopause or after surgical castration. This observation could be linked to reports that NO might slow the development ofatherosclerosis by inhibiting the proliferation of smooth muscle cells while stimulating endothelial cell proliferation (29,30).We therefore decided to investigate the hypothesis that sex hormones could regulate constitutive NOSs. We tested this in female and male guinea pigs by determining the effect of pregnancy on NOS activity and by measuring both NOS activity and NOS mRNA before and after sex hormone therapy. MATERIALS AND METHODSHartley guinea pigs of similar chronological age were obtained from a commercial breeder (Charles River Breeding Laboratories): males and nonpregnant females (600-700 g) and pregnant females of >5...

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