Chronic blockade of vasopressin type1a receptor and/or type2 receptor improves both cardiac and renal damage and dysfunction in hypertensive rats

Abstract

Background: Vasopressin (AVP) type 1a receptor (V1aR) antagonist could theoretically benefit heart failure (HF) patients by decreasing afterload and ameliorating remodeling. However, the conflicting results have been reported. Also, there is a concern that increased AVP may have detrimental effects through V1aR in HF patients treated with oral type 2 receptor (V2R) antagonist, tolvaptan. Therefore, we examined whether the chronic administration of V1a antagonist may exert beneficial effects and also its additive effects to tolvaptan treatment in rat hypertensive HF model. Methods and results: In Dahl salt-sensitive hypertensive rats, not only circulating AVP level, but also myocardial AVP and V1a receptor (V1aR), and renal V1aR and V2R expressions were significantly activated during the transition to HF (18-21 weeks). First, they were chronically treated with vehicle, V1aR antagonist (OPC21268), tolvaptan, or OPC21268 plus tolvaptan (combination) from pre-hypertrophic stage (6 weeks). All three treatments did not affect blood pressure. In OPC21268 and tolvaptan groups, the median survival time was significantly improved from 112 day (vehicle) to 141 day and 160 day, respectively. It was improved to a greater extent with the combined treatment (175 day). Echocardiography showed the improvement of fractional shortening (FS) was observed in all three treatment groups and the suppression of LV hypertrophy (LVH) only in OPC 21268 and combination groups. Furthermore, renal histopathologic damage (glomerulosclerosis and tubulointerstitial fibrosis) was ameliorated, and renal function (creatinine clearance) was also improved in all three treatment groups at HF stage. When these treatments were started at the established LVH phase (11 weeks), the improvement of survival was observed only in tolvaptan group and no additive improvement in the combined treatment. Conclusions: These findings suggest that V1aR blockade may ameliorate the development of LVH and HF in the treatment of hypertensive HF with renal injuries, and have limited effects starting after the establishment of LVH. Also, the chronic administration of both V1a and V2 antagonists exerts further beneficial effects. The underlying mechanism may be related to protection of myocardial and renal damages independent of blood pressure.