These experiments will employ the isolated rabbit aorta and receptor binding assays to characterize the receptor sites for agonists and antagonists associated with the calcium channel in smooth muscle. These studies will: 1) employ a series of calcium entry blockers in the intact rabbit aorta and ligand binding studies with tritiated diltiazem and desmethoxyverapamil in smooth muscle membranes to characterize the different types of drug binding sites associated with the calcium channel and study he interaction between these sites; 2) characterize, with the aid of he isolated rabbit aorta and receptor binding techniques, the interaction between the alpha receptor and the binding site for the calcium channel agonist BAY K 8644. Successful completion of these experiments and confirmation of our hypotheses will enhance our understanding of the nature and types of drug binding sites associated with the smooth muscle calcium channel. Furthermore, these experiments will determine if these sites are capable of interacting and will aid in determining how binding at one site can affect binding of drug to a different site. Our studies will also shed light on the mechanism by which an exogenous calcium channel agonist can modulate the activity of agonists acting at the alpha 1 receptor on vascular smooth muscle. A better understanding of the interaction of calcium entry blocker with pharmacologic receptors is essential for the development of newer, safer, more potent and specific agents to treat cardiovascular disorders. Furthermore, increased understanding of these binding sites may aid in the development of agents to treat the non-cardiovascular disorders for which the calcium entry blockers are being investigated.
