Original ArticleEffects of Long-term Blockade of Vasopressin Receptor Types 1a and 2 on Cardiac and Renal Damage in a Rat Model of Hypertensive Heart FailureIkeda, Tomoyuki MD*; Iwanaga, Yoshitaka MD*; Watanabe, Heitaro MD*; Morooka, Hanako MD*; Akahoshi, Yasumitsu BSc†; Fujiki, Hiroyuki PhD‡; Miyazaki, Shunichi MD*Author Information *Division of Cardiology, Department of Internal Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan; †Life Science Research Institute, Kinki University, Osakasayama, Japan; and ‡Otsuka Pharmaceuticals Co, Ltd, Tokushima, Japan. Reprints: Yoshitaka Iwanaga, MD, Division of Cardiology, Department of Internal Medicine, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama 589-8511, Japan (e-mail: firstname.lastname@example.org). Supported, in part, by Grants-in-aid from the Japan Society of the promotion of science (22590815). S. Miyazaki received research support from Daiichi-Sankyo Pharmaceutical Co, Ltd, Eisai Co, Ltd, Sanofi-Aventis KK, and Shionogi & Co, Ltd, but they played no role in conception, conduct, or analysis of this study. H. Fujiki is employee of Otsuka Pharmaceuticals Co, Ltd. The other authors report no conflicts of interest. Received June 09, 2015 Accepted July 16, 2015 Journal of Cardiovascular Pharmacology: November 2015 - Volume 66 - Issue 5 - p 487-496 doi: 10.1097/FJC.0000000000000300 Buy Metrics Abstract Abstract: The effects of chronic blockade of vasopressin type 1a receptors (V1aR) and the additive effects of a type 2 receptor (V2R) antagonist on the treatment of hypertension-induced heart failure and renal injury remain to be unknown. In this study, Dahl salt-sensitive hypertensive rats were chronically treated with a vehicle (CONT), a V1aR antagonist (OPC21268; OPC), a V2R antagonist (tolvaptan; TOLV), or a combination of OPC21268 and tolvaptan (OPC/TOLV) from the pre-hypertrophic stage (6 weeks). No treatment altered blood pressure during the study. Significant improvements were seen in median survival for the OPC and TOLV, and the OPC/TOLV showed a further improvement in Kaplan–Meier analysis. Echocardiography showed suppressed left ventricular hypertrophy in the OPC and OPC/TOLV at 11 weeks with improved function in all treatment groups by 17 weeks. In all treatment groups, improvements were seen in the following: myocardial histological changes, creatinine clearance, urinary albumin excretion, and renal histopathologic damage. Also, key mRNA levels were suppressed (eg, endothelin-1 and collagen). In conclusion, chronic V1aR blockade ameliorated disease progression in this rat model, with additive benefits from the combination of V1aR and V2R antagonists. It was associated with protection of both myocardial and renal damage, independent of blood pressure. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.