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Zonal Expression of Endothelial Nitric Oxide Synthase in Sheep and Rhesus Adrenal Cortex

Perinatal Research Laboratories, Department of Obstetrics/Gynecology, University of Wisconsin (J.K.P., I.M.B.), Madison, Wisconsin 53715; and Department of Population Health and Reproduction, University of California School of Veterinary Medicine (F.M., A.J.C.), Davis, California 95616

Address all correspondence and requests for reprints to: Dr. Ian M. Bird, 7E Meriter Hospital, 202 South Park Street, Madison, Wisconsin 53715. E-mail: imbird{at}facstaff.wisc.edu

There is mounting evidence that nitric oxide (NO) may inhibit adrenal steroidogenesis by binding to the heme group of P450 enzymes, particularly the rate-limiting steps cholesterol side-change cleavage P450, aldosterone synthase P450, and 17-hydroxylase/C_17/20-lyase P450. Using immunohistochemistry, nitrotyrosine was detectable throughout the ovine adrenal cortex, and endothelial NO synthase (eNOS) was further identified in zona glomerulosa (ZG) and at a higher level throughout the zona fasciculata, increasing toward the medulla. Caveolin-1, 90-kDa heat shock protein, ERK-1/2, and Akt, all known and proposed regulators of eNOS activity, were detected throughout the ovine adrenal cortex. Western immunoblotting confirmed the identity of these proteins as well as the absence of neuronal NOS, inducible NOS, caveolin-2, and caveolin-3. Through dual immunostaining we further identified for the first time a zona intermedia without strong staining for 17-hydroxylase/C_17/20-lyase P450 or angiotensin II type 1 receptor, but positive for eNOS. Rhesus adrenals also stained positively for eNOS, but staining was seen only in the ZG and zona reticularis. We conclude that eNOS may play a role in controlling zone-specific aldosterone synthase vs. 11ß-hydroxylase activities of the single CYP11B gene in sheep. In the rhesus monkey, NO may modulate ZG aldosterone synthase, but it is not needed for control of the distinct 11ß-hydroxylase in the zona fasciculata. In the zona reticularis, however, eNOS may control C₁₉ steroid production at the level of 17-hydroxylase vs. 17,20-lyase activity otherwise unopposed by 3ß-hydroxysteroid dehydrogenase.

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