Considerable data have documented the key role the kidney plays in the pathophysiology of hypertension and of the likelihood that alterations in adrenergic response occur in experimental and clinical hypertension. We propose to test the hypothesis that changes in renal adrenergic receptors contribute to pathophysiologic manifestations of hypertension. In our recent work we have demonstrated that we can use radioligand binding techniques to identify and study regulation of the 4 principal subtypes of adrenergic receptors (Alpha1, Alpha2, Beta1, Beta2) in rat renal cortical membranes. In addition, we have developed in vitro autoradiography methods to study adrenergic receptors in kidney slices.
Our aims i n this proposal are to examine changes in receptor expression in vivo by using radioligand binding, in vitro autoradiography, kinetic modelling of binding data, and assessment of biochemical and functional responses. Other studies will examine agonist-mediated uncoupling of receptors and covalent modification in receptors by photoaffinity labelling. We will then use those techniques to assess changes in renal adrenergic receptors in 3 rat models of hypertension: SHR, DOCA-saline, and salt-sensitive Dahl hypertension, each of which may provide unique insights into the role of renal adrenergic receptors in this disease. Our long term goal is to define mechanisms whereby target cells regulate and are regulated by adrenergic receptors. The proposed studies whould provide new insights into mechanisms that operate in vivo to regulate adrenergic receptors and in particular to mechanisms regulating renal receptors in normal and hypertensive animals.
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