Brain Angiotensin Generation Contributes to Renal Sympathetic Nerve Responses to Leptin

Abstract

Leptin acts in the brain to increase sympathetic nerve activity (SNA) in addition to reducing appetite and body weight. We recently demonstrated that pharmacologic blockade of brain angiotensin 1 receptors (AT1R) selectively attenuated SNA responses to intra-cerebroventricular (ICV) administration of leptin in rats without attenuating SNA responses to the melanocortin agonist MTII. We advanced the concept of a brain leptin-RAS interaction in regulation of SNA. To explore the mechanism, we measured angiotensin converting enzyme (ACE) and AT1aR mRNA in arcuate nucleus, paraventricular nucleus, and subfornical organ (SFO). Leptin increased ACE mRNA but only in the SFO, a site of functional leptin as well as angiotensin receptors. In the present study, we tested the hypothesis that ACE induced generation of brain angiotensin contributes to renal SNA responses to leptin. In anesthetized Sprague-Dawley rats, captopril, 12.5 ug ICV, blocked responses to angiotensin I, but not angiotensin II. Following ICV vehicle, leptin, 10 ug ICV, increased renal SNA by +141±38% (mean±SE). In contrast, following captopril ICV, leptin did not increase renal SNA (−14±17%). Captopril alone did not alter renal SNA. These studies support the concept of a brain RAS-leptin interaction and suggest that this interaction involves leptin-induced generation of brain angiotensin.