The alpha1-adrenoceptor plays a vital role in sympathetic nervous system activity and the regulation of peripheral vascular function and blood pressure. This receptor is a member of the super family of G- protein coupled receptors and shares the common structural motif of seven membrane spanning regions and intracellular and extracellular domains. Four subtypes of the alpha1-adrenoceptor have been identified. Building on observations made during the current funding period and using an integrated approach we will test the hypothesis that multiple alpha1-adrenoceptors are involved in the regulation of the peripheral vascular system. These experiments will also quantitate the expression of the newly discovered alpha1D-adrenoceptor and test the hypothesis that this receptor plays a role in the regulation of the peripheral vascular system. We will blend modern molecular biological approaches with ligand binding and hemodynamic studies to gain a more complete understanding of the nature, distribution and regulatory functions of the alpha1-adrenoceptor subtypes. Specifically we will use radioligand binding techniques, mRNA analysis and in situ hybridization to quantitate the extent to which the alpha1-adrenoceptors are expressed on peripheral blood vessels. We will then assess the contribution of each of these subtypes to the regulation of systemic arterial blood pressure, total peripheral vascular resistance, regional vascular blood flow and regional vascular resistance. Our present state of knowledge suggests that there may be a very complicated pattern of vascular regulation potentially involving three receptors of alpha character. Upon completion of this project we will know the extent to which each of the alpha1-adrenoceptors is expressed on vascular smooth muscle and its involvement in the regulation of the peripheral vasculature. We will also gain a greater understanding of the basic mechanisms of blood pressure regulation. This information can then be applied to assessing for disturbances in these regulatory functions in disease states such as hypertension and coronary artery disease as well as stimulate the development of drugs and research tools specifically aimed at the receptor involved in vascular pathology.
|Porter, J E; Edelmann, S E; Waugh, D J et al. (1998) The agonism and synergistic potentiation of weak partial agonists by triethylamine in alpha 1-adrenergic receptor activation: evidence for a salt bridge as the initiating process. Mol Pharmacol 53:766-71|