Cardiovascular & Renal: Methods for treating renin-related disorders with amylin antagonists

Abstract

Amylin Pharmaceuticals Inc: WO9405317-A, US5321008, WO9418571

Previously described amylin antagonists are claimed to ameliorate renin activity in subjects and have potential for the treatment of diseases such as congestive heart failure, syndrome X and hypertension. The amylin antagonists are peptidic in nature and selective for the amylin receptor over the calcitonin and/or calcitonin gene related peptide (CGRP) receptors.

In WO9405317 [101], subcutaneous administration of 100 μg of synthetic rat amylin to rats led to a 3 to 4-fold increase in plasma renin activity versus control levels that was statistically significant over the 4 hour duration of the experiment. Plasma renin activity was determined by specific radioimmunoassay for the generation of angiotensin I expressed as ng/ml/hr. Ad-ministratior of an amylin receptor specific antagonist, such as Ac-lAsn³⁰, Tyr³²]-calcitonin8–32(salmon), at t = -30 min (iv bolus) followed by a 1.0 mg/hr continuous iv infusion until t =120 min blocked the increase in plasma renin activity induced by the above dose of rat amylin. Similar results were obtained for other amylin antagonists, such as calcitonin8–32(salmcn) and Ac-[Glu¹⁵, Arg¹⁸, Val²⁷, Asn³⁰, Tyr³²]-amyling-18(human) calcitonin19–32(salmon).