Androgens potentiate renal vascular responses to angiotensin II via amplification of the Rho kinase signaling pathway

Objectives: This study assessed whether the Rho kinase signaling pathway contributes to androgenic amplification of angiotensin 11 (Ang 11) induced pressor and renal constrictor responses. Methods: Mean arterial pressure (MAP) responses to angiotensin 11 receptor I (AT1) inhibition were measured in conscious male New Zealand genetically hypertensive rats (NZGH) subjected to sham operation, castration or castration + testosterone replacement. MAP and renal vascular resistance (RVR) responses to Ang 11 were recorded with and without a Rho kinase inhibitor, fasudil, in anesthetized NZGH. Western blot was used to analyze target protein expression in the kidney. Results: MAP responses to AT I receptor inhibition and exogenous Ang 11 were attenuated in castrated NZGH. The increase in RVR (rum Hg/ml/min/g kidney) at the maximum dose of Ang 11 was significantly lower in castrated NZGH than in sham operated NZGH. Testosterone replacement restored RVR responses to Ang 11 in castrated rats. Fasudil treatment reduced both MAP and RVR responses to Ang 11 in each group. In addition, the differential MAP and RVR responses to Ang 11 amongst the three groups were significantly attenuated by Rho kinase inhibition. Western blot showed that Rho kinase protein expression was reduced by castration, while testosterone replacement restored the Rho kinase protein levels in castrated rats. The phosphorylation of myosin phosphatase target subunit I (MYPT1), a downstream target of Rho kinase, was also increased by androgens. Conclusions: Collectively, these results indicate that androgens potentiate Ang II-induced renal vascular responses, an effect mediated at least partly via up-regulation of the Rho kinase signaling pathway. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.