Abstract-Hypertension is a prominent feature of patients with Cushing's disease and ectopic adrenocorticotropic hormone (ACTH) syndrome, who have elevated ACTH levels. Chronic administration of ACTH (1-24) also raises blood pressure in humans. This effect has been postulated to be due to ACTH-induced increases in cortisol secretion in the adrenal gland. It is well known that cortisol increases vascular tone by potentiating the vasoconstrictor action of a number of pressor hormones. In the present study, we show direct evidence that human aortic endothelial cells possess the ACTH receptor. 11␤-Dehydrogenation, converting cortisol to its inactive metabolite, cortisone, mediated by vascular 11␤-hydroxysteroid dehydrogenase type 2 is essential for the control of vascular tone, and the reduced activity may be relevant to the pathogenesis of hypertension. We found that ACTH (1-24) dose-dependently decreased the gene expression and enzyme activity of 11␤-hydroxysteroid dehydrogenase type 2 in these cells, and the decrease was partially abolished by a selective ACTH receptor antagonist. This may indicate that ACTH potentiates the action of cortisol through its direct effect on the vasculature. Therefore, the present study provides important information for understanding the mechanism of ACTH-induced hypertension. A drenocorticotropic hormone (ACTH) is the main hormone that regulates glucocorticoid synthesis and secretion in mammals by binding to specific receptors on the adrenal cortex. The ACTH receptor (ACTH-R) gene has been cloned, and the predicted amino acid sequence has demonstrated that this receptor is one of the smallest of the 7 transmembrane domain receptors identified to date. 1 This receptor is expressed in the adrenal cortex but has been recently identified in extra-adrenal tissues such as human skin 2 and mouse adipose tissue. 3 Previous studies showed that the administration of ACTH (1-24) caused an increase in blood pressure in normotensive and hypertensive subjects, whereas no change was observed in patients with adrenal insufficiency, 4 and the effect of ACTH (1-24) was mimicked by cortisol. 5 Thus, the rise in pressure has been believed to be due to ACTH-induced increases in cortisol secretion in the adrenal gland. 6 It has been shown that the direct effect of cortisol on vascular tone plays a significant role in the rise in pressure, because the steroid may raise pressure in the absence of any classic glucocorticoid effects (increases in plasma volume or urinary sodium retention). 7 Cortisol increases vascular tone by potentiating the vasoconstrictor action of a number of pressor hormones, including ␣-adrenergic agonists and angiotensin II. 8,9 In addition to the hormonal effect, ACTH has been suggested to have direct effects on vascular tone. In hypovolemic and hemorrhagic shock in humans, acute intravenous administration of ACTH (1-24) promptly restores blood pressure without any effect on heart rate. 10 However, little is known concerning the existence of ACTH-R in the vasculature.11␤-Hydroxyster...

Nephrogenic diabetes insipidus (NDI) is characterized by resistance of the kidneys to the action of arginine vasopressin (AVP); X-linked recessive NDI is caused by an inactivating mutation of the vasopressin type-2 (V2) receptor. Several missense mutations in the first or second extracellular loop of the V2 receptor have been reported, and some of these mutant receptors were confirmed to have reduced affinities for ligand binding. We detected a novel V2 receptor gene mutation, a substitution of cysteine for arginine-104 (R104C) located in the first extracellular loop of the V2 receptor, in a patient with congenital NDI. Functional analysis by transient expression studies with COS-7 cells showed binding capacity of R104C mutant diminished as 10% of wild type, but binding affinity was strong rather than wild type. In the result of AVP stimulation studies, maximum cAMP accumulation of R104C decreased as 50% of wild type. On the other hand, a designed mutant receptor, substituted serine for arginine-104 as a model of modified R104C mutant receptor removed the influence of the sulfhydryl group in cysteine-104, recovered binding capacity up to 50% of wild type and maximum cAMP accumulation as 82% of wild type. Our study demonstrated that the R104C mutation of the V2 receptor was a cause of NDI. The mechanism of renal resistance to AVP was the reduction of ligand binding, and adenylyl cyclase activation depended on the V2 receptor. In addition, we confirmed that the sulfhydryl group of the cysteine-104 caused most part of R104C mutant receptor dysfunction.

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Leukocytosis, Carcinomatous pleuritis, Rapid increase of pleural effusion CSF) in both serum and pleural effusion were high, indicating that the tumor cells produced G-CSF, but immunohistochemical examination of the tumor cells did not show any positive staining for and G-CSF monoclonal antibody. Carcinomatous pleuritis in this case had an unusual character, perhaps related to the leukocytosis.