Traditionally it was believed that all aldosterone was synthesized in the zona glomerulosa of the adrenal cortex under the regulation of the renin-angiotensin system, ACTH, sodium, potassium and other less important factors. There is now evidence from several laboratories including ours that steroidogenic enzymes required for aldosterone synthesis are expressed in endothelium, vascular smooth muscle cells and the brain. These tissues are also capable of synthesizing aldosterone, albeit at a much lower level than the adrenal. There is recent evidence that the expression of aldosterone synthase and synthesis of aldosterone in the heart is regulated by the same factors as in the adrenal gland. We have cloned the rat 21-hydroxylase and have confirmed its expression and that of the aldosterone synthase and 11beta-hydroxylase in the rat heart. We found about 10 times more aldosterone in heart than blood, 65 percent of which is an aldosterone-monoacetate. Our preliminary data indicate that this aldosterone is acetylated at the 20 position which fixes the structure in the bicyclical acetal mode, a conformation believed to be the most active because it is more planar. Over 20 years ago it was shown that the aldosterone-monoacetate is far more potent as an antinatriuretic agent than aldosterone. We propose to study the regulation of the expression of the mRNA for enzymes of aldosterone synthesis and enzymatic activity of aldosterone synthase and 11beta-hydroxylase during the development of 4 models of hypertension associated with significant cardiac remodeling, including renovascular (2 kidney clip), angiotensin II infusion, and the genetic models, the SHR-SP and Dahl Salt Sensitive. The effect of converting enzyme inhibition, which results in prevention and regression of cardiac hypertrophy in the models, on steroidogenic enzyme mRNA levels will also be assessed. The generation of aldosterone and aldosterone-monoacetate will be measured in isolated perfused hearts in vitro from control and hypertensive animals. The type of aldosterone-monoacetate will be determined. The rate of hydrolysis in blood and the subcellular distribution and receptor binding affinity in the heart of aldosterone-monoacetate will also be measured and compared to its parent compound. These studies will characterize the cardiac renin-angiotensin-aldosterone system which is implicated clinically and experimentally in pathological cardiac remodeling, as well as a mechanism for amplification of aldosterone action by monoacetylation.
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