Beta-adrenergic responsiveness may be reduced in the hypertensive state and could be an important factor in the pathogenesis and maintenance of hypertension. Preliminary studies have indicated reduced lymphocyte Beta-receptor affinity for agonist and Beta-adrenergic mediated adenylate cyclase activity in hypertensive subjects. The lymphocyte Beta-receptor is a readily accessible model for the human Beta-receptor complex. The proposed studies will attempt to correlate these biochemical changes in lymphocyte Beta receptors with functional alterations in both Beta-adrenergic modulated immune function in lymphocytes and Beta-adrenergic mediated vasodilation in vascular smooth muscle in man. Furthermore using radioligand binding and adenylate cyclase assays we will attempt to determine whether or not the reduction in lymphocyte Beta-receptor responsiveness in hypertensive subjects is a reversible defect using both in vivo and in vitro approaches. In order to localize the molecular site of this defect among the components of the lymphocyte Beta-receptor-adenylate cyclase complex in hypertensive subjects we will A) monitor for possible alterations in Beta-receptor structure using photoaffinity labelling of the Beta-receptor and SDS-gel electrophoresis and B) monitor possible functional alterations in the regulatory protein which couples the Beta-receptor to adenylate cyclase using reconstitution techniques. Altogether this proposal outlines a systematic, integrated approach to the study of altered Beta-receptor function in hypertension.
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