Apelin is a vasoactive peptide identified as the endogenous ligand of an orphan G protein-coupled receptor called APJ. Apelin and its receptor have been found in the brain and the cardiovascular system. Here we show that the apelin receptor mRNA is highly expressed in the glomeruli while its level of expression is lower in all nephron segments including collecting ducts that express vasopressin V2 receptors. Intravenous injection of apelin 17 into lactating rats induced a significant diuresis. Apelin receptor mRNA was also found in endothelial and vascular smooth muscle cells of glomerular arterioles. Apelin administration caused vasorelaxation of angiotensin II-preconstricted efferent and afferent arterioles as shown by an increase in their diameter. Activation of endothelial apelin receptors caused release of nitric oxide which inhibited angiotensin II-induced rise in intracellular calcium. In addition, it appears that apelin had a direct receptor-mediated vasoconstrictive effect on vascular smooth muscle. These results show that apelin has complex effects on the pre- and post glomerular microvasculature regulating renal hemodynamics. Its role on tubular function (if any) remains to be determined.

Abstract-Overactivity of the brain renin-angiotensin system has been implicated in the development and maintenance of hypertension. We reported previously that angiotensin II is converted to angiotensin III by aminopeptidase A in the mouse brain. We then used specific and selective aminopeptidase A inhibitors to show that angiotensin III is one of the main effector peptides of the brain renin-angiotensin system, exerting tonic stimulatory control over blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential candidate central nervous system target for the treatment of hypertension. Given this possible clinical use of aminopeptidase A inhibitors, it was, therefore, important to investigate their pharmacological activity after oral administration. We investigated RB150, a dimer of the selective aminopeptidase A inhibitor, EC33, generated by creating a disulfide bond. This chemical modification allows prodrug to cross the blood-brain barrier when administered by systemic route. Oral administration of RB150 in conscious DOCA-salt rats inhibited brain aminopeptidase A activity, resulting in values similar to those obtained with the brains of normotensive rats, demonstrating the central bioavailability of RB150. Oral RB150 treatment resulted in a marked dose-dependent reduction in blood pressure in DOCA-salt but not in normotensive rats, with an ED 50 in the 1-mg/kg range, achieved in Ͻ2 hours and lasting for several hours. This treatment also significantly decreased plasma arginine-vasopressin levels and increased diuresis, which may participate to the blood pressure decrease by reducing the size of fluid compartment. Thus, RB150 may be the prototype of a new class of centrally active antihypertensive agents. Key Words: aminopeptidase A inhibitors Ⅲ blood pressure Ⅲ brain renin-angiotensin system Ⅲ DOCA-salt rats Ⅲ hypertension H ypertension is a major cardiovascular risk factor, affecting Ϸ20% of the adult population, of which 95% have essential hypertension. Blockers of the systemic renin-angiotensin system (RAS), angiotensin (Ang) I-converting enzyme (ACE; EC 3.4.15.11) inhibitors or Ang II receptor type 1 (AT 1 ) antagonists, have since been shown to be efficient and safe for treating hypertension. 1 However, they may cause secondary effects, such as coughing, deterioration of renal function in cases of underlying renal artery stenosis, and, more rarely, angioedema. [2][3][4][5][6][7] In addition, these agents are not very effective in some patients, particularly African Americans, in whom high blood pressure (BP) is associated with low renin levels and a response to salt depletion. 8,9 The development of new classes of antihypertensive agents with different mechanisms of action, therefore, remains an important goal. In this way, because a brain RAS hyperactivity has been implicated in the development and maintenance of hypertension, 10 -13 its components could constitute interesting targets. Among the bioactive peptides of the brain RAS, Ang I...