The reini-angiotensin system is important in the control of blood pressure, but its role in the pathogenesis of most forms of hypertension is uncertain. Existing evidence suggests that vascular responsiveness to angiotensin II (AII) is regulated by physiologic stimuli and perhaps may be pathologically altered in certain hypertensive disorders. The goal of the proposed research is to characterize the interaction between AII and its receptor in a hormonally-responsive tissue and to explore the mechanisms which influence cellular sensitivity. AII receptors in rat liver plasma membranes will be identified and characterized using radioligand binding techniques. Functional coupling of these receptors to cellular processes will be established by measuring glycogen phosphorylase stimulation and adenylate cyclase inhibition in intact, enzymatically-dissociated hepatocytes. The effects of cations and guanine nucleotides on receptor number and affinity will be determined to help define physiologic control mechanisms. AII receptors will be solubilized from affinity-labeled membranes and their physical-chemical properties determined by hydrodynamic and electrophoretic methods. Agonist-specific changes in molecular size, subunit composition and chemical reactivity will be sought to identify molecular changes attendant on receptor activation. Isolation and purification of AII receptors using affinity chromatography will be attempted from affinity-labeled and native membranes. If successful, anti-receptor antibodies will be generated in rabbits using micro-immunization techniques. These methods will be applied to animal models with physiologic and pathophysiologic alterations in renin-angiotensin system activity to test the hypothesis that cellular responsiveness is modulated by the A11 receptor. Possible changes in receptor expression (number, affinity) and activity (coupling to biochemical events) will be correlated with physiologic responsiveness to AII in these animals in an attempt to define molecular mechanisms involved. The methods developed during the proposed research should be readily applicable to the study of AII receptors in blood vessels, adrenal gland and other physiologic target organs of the renin-angiotensin system, and may provide insight into the pathophysiology of hypertensive disorders.
| Lavine, S J; Campbell, C A; Kloner, R A et al. (1988) Diastolic filling in acute left ventricular dysfunction: role of the pericardium. J Am Coll Cardiol 12:1326-33 |
