Vasopressin (AVP) is not only a potent antidiuretic and vasoconstrictor hormone but it also stimulates platelet aggregation, blood coagulation factors, glucose release, and fibroblast proliferation. All these actions may mediate the involvement of AVP in the development of arterial hypertension and atherosclerosis. To substantiate this working hypothesis and complete our knowledge on AVP regulation and mechanisms of action, we propose to conduct the following research lines: 1) The exploration in normal and hypertensive rats (genetically and DOCA-salt hypertensive models) of the regulation of both types of AVP receptors during alterations of dietary sodium intake, of circulating AVP concentration and of blood pressure. The cellular responsiveness to AVP in these animals will be tested at the vascular (pressor dose-response curve) and renal (adenylate cyclase activity) levels. 2) The study of the interactions of the human platelet AVP receptors with the guanine nucleotide regulatory protein, phospholipase C, phospholipase A2 and the Na+/H+ exchanger. 3) The purification of the human platelet V1 vascular AVP receptor by detergent solubilization, gel chromatography, high pressure liquid chromatography, affinity chromatography, photoaffinity cross linking and amino acid sequencing. The long term objective of our research is to: 1) Determine the role played by AVP in the development of arterial hypertension and atherosclerosis. 2) Clone human AVP receptors and describe the molecular defect present in nephrogenic diabetes insipidus 3) Help to develop orally active drugs antagonizing AVP actions in human diseases such as arterial hypertension, cardiac failure and liver cirrhosis.
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