It has been demonstrated that parathyroid hormone (PTH) is a potent vasodilator acting directly on specific vascular beds. In this proposal, the following studies will be carried out: (1) Elucidation of the cellular mechanism of the vascular action of PTH. The involvement of intracellular cyclic AMP and calcium movement across the cell membrane will be studied. Rat tail artery which is sensitive to PTH will be analyzed for its cyclic AMP content with a radioimmunoassay. The effects of PTH and its analogs will be studied. The low affinity lanthanum resistant pool of calcium will be determined and the effects of PTH on basal and potassium chloride stimulated calcium uptake will be analyzed. The temporal relationship between vasodilation, calcium entry and intracellular cyclic AMP changes will be studied. (2) Studies of the molecular structure and vascular activity of PTH. Primary, secondary and tertiary structural changes of the peptide will be correlated with vascular activity changes produced by specific amino acid modifications. Such studies will be important for the design of agonists and antagonists and for understanding hypotensive peptides in general. (3) Investigation of the physiological and/or pathophysiological role of PTH in blood pressure regulation. Potent in vivo PTH antagonists will be sought and their effects will be determined in normotensive and hypertensive rats. There are three long term goals: (1) to understand the pharmacology of the vascualar action of PTH, (2) to provide information on the regulation of blood pressure in relation to calcium regulation and/or parathyroid disorder, and (3) to design small orally active hypotensive peptides based on our understanding of structure-activity relationships.
