VASOPRESSIN EFFECT IN DISORDERS OF RENAL CONCENTRATION

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The effect of the hormone vasopressin (VP) to increase renal collecting tubular water permeability is critical in the maintenance of body water homeostasis. The hydroosmotic effect of VP is dependent upon intracellular generation of 3 feet 5feet-cyclic adenosine monophosphate (cAMP). In some mammalian cyclic nucleotide systems, generation of cAMP is a complex process involving a hormone receptor, stimulatory (Ns) and inhibitory (Ni) guanidine nucleotide regulatory proteins and the catalytic subunit of adenylate cyclase. In the present studies, the role and interaction of the VP receptor, the putative Ns and Ni regulatory proteins and the catalytic subunit of adenylate cyclase in mediating the osmotic water permeability effect of VP will be examined. These studies will be carried out in microdissected rabbit cortical collecting tubules in which osmotic water flux and adenylate cyclase will be measured. First the effect of probes which selectively stimulate or inhibit the VP receptor (stimulation with VP, inhibition with d(CH2)5Tyr(Et)-VAVP), the Ns unit (stimulation with cholera toxin), the Ni unit (stimulation with guanosine 5 feet-(Beta Gamma-imsido)triphosphate, inhibition with pertussis toxin) and the catalytic subunit (stimulation with forskolin, inhibition with 2 feet, 5 feet dideoxyadenosine) on basal and VP-stimulated osmotic water flux and adenylate cyclase will be performed. Subsequently the effect of altered cationic (Mg++, Mn++, Na+, K+, Li+) tubular environment and toxic and ischemic renal injury on collecting tubular physiologic and biochemical response to VP will be examined. If defects in VP responses are observed, osmotic water flux and adenylate cyclase responses to the above noted probes will allow assessment of the pathogenetic role and site of altered cAMP generation. Together these studies will contribute to our understanding of the mechanism of hydroosmotic effect of VP on mammalian collecting tubule in health and disease.