RENOVASCULAR CA2+ CHANNEL EXPRESSION IN HYPERTENSION

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DESCRIPTION (Verbatim from the application): The goal of this project is to provide the first profile of the disease-specific expression of L-type Ca2+ channels in renovascular smooth muscle membranes of the SHR. Early results using Western methods show an increased expression of pore-forming alpha1c subunit of the L-type Ca2+ channel in renal arterial muscle membranes of adult SHR compared to normotensive WKY rats. This alteration was associated with an enhanced Ca2+-dependent resting tone in isolated renal arteries. It appears, however, that the alpha1c subunit is not upregulated in renovascular muscle membrane of 4 week old prehypertensive SHR. These findings provide the first direct evidence that elevated systemic blood pressure in vivo may induce a disease-specific population of L-type Ca2+ channels in renal arterial smooth muscle that can profoundly affect arterial diameter. In this regard, the renal circulation of humans with essential hypertension also develops an elevated vascular resistance, which is sensitive to block by L-type Ca2+ channel blockers. This response is thought to represent a critical protective mechanism to prevent glomerular hypertension and injury. Based on our early findings, this new 3-year project will begin to compare the subunit composition, regulation, and physiological role of L-type Ca2+ channels in renovascular smooth muscle membranes between 4 and 12 week-old SHR and age-matched WKY by: (a) examining Ca2+ channel function in isolated renal arteries, (b) measuring Ca2+ current density in patch-clamped renovascular smooth muscle cells, (c) using ribonuclease protection assays, Western blots, and immunoprecipitation methods to define the molecular mechanisms that induce the disease-specific expression of L-type Ca2+ channel subunits during pressure elevation, and (d) apply these same experimental approaches to examine if L-type Ca2+ channel changes are normalized when systemic blood pressure is lowered in adult SHR rats by oral antihypertensive drugs. Notably, the identification of a unique Ca2+ channel profile in the renal circulation during essential hypertension may provide an important diagnostic tool for predicting susceptibility to pressure-induced renal disease, and new gene or drug therapies designed to alter this Ca2+ channel profile may provide a novel approach to reduce renal injury during systemic hypertension.