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: Tomoyuki Ikeda, Yoshitaka Iwanaga, Heitaro Watanabe, Hanako Morooka, Yasumitsu Akahoshi, Hiroyuki Fujiki, Shunichi Miyazaki
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 66 Issue 5 Pg. 487-96 (Nov 2015) ISSN: 1533-4023 [Electronic] United States
• PMID: 26248278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antidiuretic Hormone Receptor Antagonists
• Benzazepines
• Piperidines
• Quinolones
• Receptors, Vasopressin
• V1a vasopressin receptor, rat
• V2 vasopressin receptor, rat
• OPC 21268
• Tolvaptan

Topics

• Animals
• Antidiuretic Hormone Receptor Antagonists (pharmacology)
• Benzazepines (pharmacology)
• Disease Models, Animal
• Drug Therapy, Combination
• Fibrosis
• Gene Expression Regulation
• Heart Failure (drug therapy, etiology, genetics, metabolism, pathology, physiopathology)
• Heart Ventricles (drug effects, metabolism, pathology)
• Hemodynamics (drug effects)
• Hypertension (complications)
• Hypertrophy, Left Ventricular (etiology, metabolism, prevention & control)
• Kidney (drug effects, metabolism, pathology)
• Kidney Diseases (etiology, genetics, metabolism, pathology, prevention & control)
• Male
• Piperidines (pharmacology)
• Quinolones (pharmacology)
• Rats, Inbred Dahl
• Receptors, Vasopressin (drug effects, metabolism)
• Time Factors
• Tolvaptan
• Ventricular Function, Left (drug effects)
• Ventricular Remodeling (drug effects)