This program project grant contains 5 research proposals centered around the role of AVP in physiologic and pathophysiologic states. These projects are designed to naturally follow the prior project. The description of the non-osmotic pathways of AVP release is among the most inclusive of this project's previously contributions. Arterial vasodilatation or decreased cardiac output constitute two signals for arterial underfilling, with activation of neurohormonal reflexes causing sodium and water retention. The mechanism(s) underlying vasodilatation in pregnancy and cirrhosis however remain undefined. The possibility that there are alterations in endothelium dependent relaxing factors, nitric oxide in particular, will be tested in animal models by a combination of in vivo systems, measurement of vasoactive hormones, in vitro measurements of vascular reactivity and molecular assessment of constitutive and activated forms of nitric oxide synthase. The osmotic and non-osmotic release of AVP will be studies in small cell lung cancer (SCLC) cell lines by examining the promoter region of the AVP gene and the effect of agents that alter AVP release in this system. These experiments are a continuation of our observations on hypothalamic mRNA in AVP release in various models associated with AVP release and are likely to define the genetic locus whereby these pathways initiate gene transcription. Also, the abnormality in transport and processing of the gene product present in central diabetes insipidus will be investigated. Another project will examine signalling pathways in vascular smooth muscle cells following stimulation by growth promoting agents. Distinct patterns of growth are characteristic of pathophysiologic states. Interaction between growth stimuli and the phenotypic state of the cells will be investigated using vasoconstrictors which promote hypertrophy, and PDGF which promotes hyperplasia. The role of G-proteins, protein kinases and phospholipases in mediating the effect of these agents will be examined. These studies will identify the molecular events responsible for the patterns of growth associated with atherosclerosis (hyperplasia) and hypertension (hypertrophy). The other major target tissue is the kidney where AVP affects the critical determinants of sodium and water excretion. The present experiments further define AVP action in the collecting tubule by following up our studies on hormonal signalling in the inner medulla and the mechanisms of hormone resistance in nephrogenic diabetes insipidus. The distribution of V1. V2, and oxytocin receptors, the role of protein kinase A in water and sodium reabsorption, the analysis of second messengers and kinases with adenylyl cyclase agonists and the study of AVP resistance in the settings of high Ca and Li will be included. Finally, SCLC is one of the most coupled to these receptors and the role of AVP in cell growth will be examined in order to define the AVP-stimulated proliferation mechanisms in this common lung tumor and thus these studies could have long term pharmacologic implications. The above projects will further the understanding of AVP in physiologic and pathophysiologic states.
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