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Involvement of AVP in several pathological states is now established and specific modulation of the different AVP receptor subtypes (V1a, V1b and V2) offers new clinical perspectives for treating major diseases. Recent years have marked a turning point with the design and the use of the first nonpeptide vasopressin receptor antagonists expressing various selectively profile. In that field, we report here the characterization of SR 121463A a highly selective, orally-active antagonist of vasopressin V2 receptors in several models in vitro and in vivo. This compound displayed competitive nanomolar affinity for V2 receptors in various species including man and exhibited a highly selective AVP V2 profile. In vitro, SR 121463A potently antagonized AVP-stimulated adenylyl cyclase activity in human kidney preparations (Ki = 0.26 +/- 0.04 nM) without any intrinsic agonistic effect. In normally-hydrated rats, SR 121463A induced dose-dependent powerful and long-lasting aquaresis after intravenous (0.003 to 0.3 mg/kg) or oral (0.03 to 10 mg/kg) administration. The action of SR 121463A is purely aquaretic with no changes in urine Na+ and K+ excretions unlike that of known diuretic agents such as furosemide or hydrochlorothiazide. In vasopressin-deficient Brattleboro rats, SR 121463A is devoid of any V2 antidiuretic agonist properties. In addition, this compound potently antagonized DDAVP extrarenal V2 effects on hemostasis factor release (FVIII, vW and t-PA) in dogs (ID50 approximately 10 micrograms/kg i.v.). Thus, SR 121463A is the most potent and selective, orally-active V2 antagonist yet described. It is a useful ligand for exploring V2 receptors and the therapeutical usefulness of pure V2 aquaretic agents in several water-retaining diseases and congestive heart failure.

The RT6 alloantigenic system of the rat has originally been defined on T lymphocytes of the peripheral lymphatic organs and has been considered to be selectively expressed on mature peripheral T cells. Studying NK cells and intestinal intraepithelial lymphocytes (IEL), we have now found that both cell types also express RT6 and that the expression patterns found for IEL and NK cells were markedly different from each other and also from the expression pattern previously described for T cells of the peripheral lymphatic organs. In lymph nodes, spleen, and blood both RT6- and RT6+ T cells have been found and the density of RT6 expression on the positive cells has been shown to vary over a broad range. In contrast more than 98% of intestinal IEL stained for RT6 and the RT6 density was about tenfold higher than on strongly positive T cells of the peripheral lymphatic organs. Furthermore, the same high RT6 density was also found on IEL of athymic nude rats althogh these cells, to a large extent, lacked other T cell markers. This probably indicates that RT6 expression is an early event in the maturation of intestinal IEL which can occur already before the expression of T cell-specific membrane molecules. The conclusion that the expression of RT6 may be differently regulated in IEL and other T cell populations was further substantiated by the observation that RT6 was also present on IEL of diabetes-prone BB rats which are known to lack RT6 positive T cells in peripheral lymphatic organs. For NK cells still another pattern of RT6 expression was found. Unlike peripheral T cells and IEL, only a small subset of NK cells in blood and spleen expressed RT6. The percentage of RT6 positive cells was increased by in vitro stimulation of isolated NK cells with high concentrations of recombinant rat IL-2 indicating that RT6 expression may be associated with an activated state in NK cells. Taken together, these findings demonstrate that the expression of RT6 is not restricted to T cells and is differently regulated in normal peripheral T cells, intestinal IEL, and NK cells. Since it has recently been demonstrated that the RT6 gene contains two functional promoter regions with major structural disparity it is very likely that the distinct patterns of RT6 expression in different cell types reflect the differential use of the two promoters. The development of this complex control of RT6 expression in evolution may have been driven by a beneficial effect resulting from the use of the RT6 molecular function by several different lymphocyte populations.

Insulin-dependent diabetes mellitus (IDDM) is believed to be an autoimmune disease, characterized by lymphocytic infiltration of the islets and the presence of islet cell autoantibodies. Autoimmunity may result from an intrinsically abnormal immune system, primary alterations of the target beta cell or both. However, the initial event that causes the beta cell-specific autoimmunity remains unknown. Our recent experimental results showed that islet grafts from neonatal BB rats remained intact without insulitis when transplanted into the renal subcapsular space of acutely diabetic BB rats. In contrast, islet grafts from adult BB rats (which had been treated with silica for the prevention of insulitis) revealed severe insulitis and were rapidly destroyed. These results suggest that the delayed expression of a beta cell-specific autoantigen may result in the initiation of beta cell-specific autoimmunity. The islet cell-specific 37 kd autoantigen is not expressed early in the life of BB rats, but is expressed at around 30 days of age. This islet-specific autoantigen might be recognized and attacked by the immune effectors. In contrast, nondiabetic Wistar Furth rats express the autoantigen from birth.