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Estradiol-17# administration to young (10-to 12-week-old) rabbits to produce the "estrogen-dominated" uterus increased the uterine contractile response to both oxjtocin and methacholine in vitro. In "progesterone-dominatel" uteri, obtained from rabbits that received progesterone for 4 days after estrogen pretreatment, the contractile response to oxytocin in vitro was selectively abolished; the response to methacholine was unaffected. Parallel changes were observed in the concentration (but not affinity) of specific sites in uterine microsomal membranes that bind 1111oxytocin with selectivity features expected for oxytocin receptors. fluence on the affinity of these sites. A sublethal dose of actinomycin D, administered over a 24-hr period to rabbits pretreated with estradiol for 4 days, likewise reduced specific oxytocin binding; additive effects were not observed when progesterone and actinomycin D were administered together. These results suggest that the regulatory effects of estrogens and progesterone upon the rabbit uterine contractile response to oxytocin are achieved, at least in part, by the opposing actions of these steroids in regulating the number of oxytocin receptors in smooth muscle cells. Estradiol increased the concentration of uterine oxytocin receptors; the maintenance of high receptor levels appears to depend upon the continuous de novo synthesis of oxytocin receptors. In contrast, progesterone, like actinomycin D, appears to act at the nuclear locus to repress synthesis of oxytocin receptors.

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The investigation was undertaken to evaluate the direct stimulatory effects of neurohypophyseal hormones upon adenylate cyclase activity in a cellfree, particulate fraction derived from the kidney medulla of various mammalian species. The relative affinity of neurohypophyseal hormones for the receptor component of the adenylate cyclase system (as defined by the concentration of hormone required for half-maximal stimulation) had the order [8-argininel-vasopressin > [8-lysinel-vaso-pressin >> oxytocin (AVP > LVP >> OT) for rat, mouse, rabbit, and ox; in the pig, the order was LVP > AVP >> OT. The relative affinities of the three hormones in rat and pig cyclase systems were found to correspond with the relative antidiuretic potencies of these hormones in the intact rat and pig. These findings show that the renal receptor for neurohypophyseal hormones in a particular species exhibits the highest affinity for the specific antidiuretic hormone that occurs naturally in that species.Some of the molecular requirements for the stimulation of rabbit adenylate cyclase were defined by studies of several neurohypophyseal analogs possessing structural changes in positions 1, 2, 3, 4, 5, 8, and 9.This investigation introduces the particulate preparation of renal medullary adenylate cyclase as a tool for the analysis of neurohypophyseal hormone-receptor interactions and indicates that this preparation can be adapted to serve as an in vitro bioassay system for antidiuretic hormonal activity.The mammalian antidiuretic hormones (vasopressins) promote water reabsorption from the nephron by increasing the permeability to water of the distal convoluted tubules and collecting ducts (1, 2). There is substantial evidence that vasopressins and related analogs act via the adenylate cyclase-cycic AMP system in the mammalian kidney as well as in amphibian membranes, namely, (a) 3': 5'-cyclic AMP mimics the effects of vasopressin upon isolated kidney tubules (2) and amphibian urinary bladders (3); (b) neurohypophyseal hormones stimulate adenylate cyclase in membrane preparations derived from renal medulla of dog (4), rat (5-7), mouse (6), rabbit (6,(8)(9)(10), and hamster (11), and from the epithelium of toad bladder (12, 13); and (c) the stimulation of toad bladder adenylate cyclase effected by a set of neurohypophyseal peptides can be correlated with the hydroosmotic response evoked by these peptides in the intact bladder (12). Abbreviations: AVP, [8-argininel-vasopressin (Biochenistry, 6, 362 (1967)]. 1693The availability of adenylate cyclase preparations from renal medulla makes it possible to study vasopressin action in a cell-free system, with the elimination of many of the factors (14) that complicate the bioassay of antidiuretic activity in the whole animal. This paper presents: (a) properties of particulate vasopressin-sensitive preparations of adenylate cyclase from the renal medulla of rat, mouse, rabbit, ox, and pig; (b) a comparison of the relative stimulatory effects on these cyclase systems of the natural mammalian...

It has been established in bovine capsule strippings, consisting mainly of zona glomerulosa tissue, that labeled progesterone, deoxycorticosterone and corticosterone are all converted to radioactive aldosterone. Analysis of the data indicates that at least 50 % of the aldosterone produced is derived from corticosterone; under certain conditions, with the addition of high concentrations of corticosterone, the percentage pathway is at least 92 % Progesterone studied at varying concentrations under similar conditions of incubation is a major precursor of both aldosterone and corticosterone; there is some possibility that aldosterone may be formed, to a minor extent, via a pathway not involving progesterone. Labeled deoxycorticosterone is also converted to aldosterone, and it seems likely, though not established by the present studies, that it is the intermediate between progesterone and corticosterone; thus the major sequence appears to be progesterone → deoxycorticosterone → corticosterone → aldosterone. Although the precursors of progesterone have not been demonstrated in incubations with capsule strippings, it has been found that homogenates prepared mainly from zone glomerulosa tissue can convert cholesterol to corticosterone and hence presumably to aldosterone. The route between cholesterol and corticosterone probably involves progesterone but this has not been established. The significance of these findings in relation to in vivo results has been briefly discussed.