Steroid-producing cells regulate arterial tone of adrenal cortical arteries.

Adrenal blood flow is coupled to adrenal hormone secretion. ACTH increases adrenal blood flow and stimulates the secretion of aldosterone and cortisol in vivo. However, ACTH does not alter vascular tone of isolated adrenal cortical arteries. Mechanisms underlying this discrepancy remain unsolved. The present study examined the effect of zona glomerulosa (ZG) cells on cortical arterial tone. ZG cells (10(5) to 10(7) cells) and ZG cell-conditioned medium relaxed preconstricted adrenal arteries (maximal relaxations = 79 +/- 4 and 66 +/- 4%, respectively). In adrenal arteries coincubated with a small number of ZG cells (0.5-1 x 10(6)), ACTH (10(-12) to 10(-8) m) induced concentration-dependent relaxations (maximal relaxation = 67 +/- 4%). Similarly, ACTH (10(-8) m) dilated (55 +/- 10%) perfused arteries embedded in adrenal cortical slices. ZG cell-dependent relaxations to ACTH were endothelium-independent and inhibited by high extracellular K(+) (60 mm); the K(+) channel blocker, iberiotoxin (100 nm); the cytochrome P450 inhibitors SKF 525A (10 microm) and miconazole (10 microm); and the epoxyeicosatrienoic acid (EET) antagonist 14,15-EEZE (2 microm). Four EET regioisomers were identified in ZG cell-conditioned media. EET production was stimulated by ACTH. We conclude that ZG cells release EETs and this release is stimulated by ACTH. Interaction of endocrine and vascular cells represents a mechanism for regulating adrenal blood flow and couples steroidogenesis to increased blood flow.

Autoradiographic evidence that zona glomerulosa and capsular vessels of the human adrenal cortex are provided with different subtypes of adrenomedullin receptors.

Frozen sections of normal adrenal glands, obtained from patients undergoing unilateral nephrectomy for kidney cancer, were labeled in vitro with human [125I]ADM(1-52). Autoradiography and quantitative densitometry showed the presence of abundant ADM(1-52) binding sites in both zona glomerulosa (ZG) and capsular vessels, which were displaced with about the same efficiency by cold ADM(1-52) and rat ADM(1-50). The selective calcitonin gene-related peptide type 1 (CGRPI) ligand CGRP(8-37) eliminated, although less efficiently than ADMs, [125I]ADM(1-52) binding in the ZG, but not in the capsular vessels. These findings suggest the existence of different receptor subtypes for ADM in the human adrenal cortex. The CGRP(8-37)-sensitive receptors located in the ZG may mediate the well-known inhibitory effect of ADM on aldosterone secretion, while the CGRP(8-37)-insensitive receptors present in the capsular vessel may be involved in the ADM-induced rise in adrenal blood flow.

Adrenic acid metabolites as endogenous endothelium-derived and zona glomerulosa-derived hyperpolarizing factors.

Adrenic acid (docosatetraenoic acid), an abundant fatty acid in the adrenal gland, is identical to arachidonic acid except for 2 additional carbons on the carboxyl end. Adrenic acid is metabolized by cyclooxygenases, cytochrome P450s, and lipoxygenases; however, little is known regarding the role of adrenic acid and its metabolites in vascular tone. Because of its abundance in the adrenal gland, we investigated the role of adrenic acid in vascular tone of bovine adrenal cortical arteries and its metabolism by bovine adrenal zona glomerulosa cells. In adrenal cortical arteries, adrenic acid caused concentration-dependent relaxations, which were inhibited by the epoxyeicosatrienoic acid antagonist 14,15-epoxyeicosa-5(Z)-enoic acid and the cytochrome P450 inhibitor SKF-525A. The large-conductance calcium-activated potassium channel blocker iberiotoxin or removal of the endothelium abolished these relaxations. Reverse-phase high-pressure liquid chromatography and liquid chromatography/mass spectrometry isolated and identified numerous adrenic acid metabolites from zona glomerulosa cells, including dihomo-epoxyeicosatrienoic acids and dihomo-prostaglandins. In denuded adrenal cortical arteries, adrenic acid caused concentration-dependent relaxations in the presence of zona glomerulosa cells but not in their absence. These relaxations were inhibited by SKF-525A, 14,15-epoxyeicosa-5(Z)-enoic acid, and iberiotoxin. Dihomo-16,17-epoxyeicosatrienoic acid caused concentration-dependent relaxations of adrenal cortical arteries, which were inhibited by 14,15-epoxyeicosa-5(Z)-enoic acid and high potassium. Our results suggest that adrenic acid relaxations of bovine adrenal cortical arteries are mediated by endothelial and zona glomerulosa cell cytochrome P450 metabolites. Thus, adrenic acid metabolites could function as endogenous endothelium-derived and zona glomerulosa-derived hyperpolarizing factors in the adrenal cortex and contribute to the regulation of adrenal blood flow.