title: Effects of Long-term Blockade of Vasopressin Receptor Types 1a and 2 on Cardiac and Renal Damage in a Rat Model of Hypertensive Heart Failure.
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.
authors.affiliation: *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.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ikeda
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Iwanaga
authors.forename: Heitaro
authors.initials: H
authors.lastname: Watanabe
authors.forename: Hanako
authors.initials: H
authors.lastname: Morooka
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Akahoshi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujiki
authors.forename: Shunichi
authors.initials: S
authors.lastname: Miyazaki
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005355:Fibrosis; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000150:complications*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D020303:Rats, Inbred Dahl; D017483:Receptors, Vasopressin / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D000077602:Tolvaptan; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D010880:Piperidines; D015363:Quinolones; D017483:Receptors, Vasopressin; C582098:V1a vasopressin receptor, rat; C582099:V2 vasopressin receptor, rat; C068644:OPC 21268; D000077602:Tolvaptan