The overall goal of this project is the characterization of membrane events initiated by aldosterone secretagogues and to determine their role in mediating the abnormalities in steroid secretion observed in experimental hypertension. The stimulating effect of angiotensin II (AII) on aldosterone secretion is blunted in adrenal zona glomerulsa (ZG) cells in spontaneously hypertensive rats compared to normotensive rats. The mechanism of this inhibition is not known. This grant will test the hypothesis that the abnormalities in SHR involve functional modifications of K(+) channels or their modulation by AII through defined second messengers. The secretagogues, AII and ACTH, influence distinct messenger systems and may exhibit different effects on membrane channels in normotensive and hypertensive rats. Therefore, channel-regulating mechanisms involving different second messengers systems under the influence of these secretagogues will be compared in normotensive and hypertensive rats. The main experimental approaches use a combination of the whole cell/patch-clamp configurations and a newly designed ultra-low volume, hanging-drop patch-clamp technique as well as affinity-purified antibodies directed against different G-protein subunits.
The specific aims of the project are to investigate the effects of AII and ACTH on K(+) channels in ZG cells, to explore the involvement of distinct second messengers in the modulation of these channels and to compare the effects of secretagogues on K(+) channels in ZG cells from normotensive and hypertensive rats. The results from these studies should substantially increase our understanding of the membrane events involved in signal transduction during stimulation of aldosterone biosynthesis and of derangements in this regulation in experimental hypertension.
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