Abstract 8563: Chronic Administration of Oral Vasopressin Type 2 Receptor Blocker, Tolvaptan Exerts Both Myocardial And Renal Protective Effects in Rats with Hypertensive Heart Failure

Abstract

Background: During the diuretic therapy in heart failure (HF), the greatest concerns include additional activation of the neurohormonal cascade and renal injury. Although the recent clinical trials have shown the efficacy of the oral vasopressin (AVP) type 2 receptors (V2R) blocker, tolvaptan, the long-term effects on the myocardium and kidney in HF patients are not clear. Therefore, we tested chronic tolvaptan administration in rat hypertensive HF model and examined the chronic effects both on myocardium and kidney. Methods and Results: Dahl salt-sensitive hypertensive rats were given 8% high salt diet from 6 weeks of age. Not only circulating AVP level, but also myocardial AVP and V1a receptor (V1aR) expressions, and renal V1aR, V2R and aquaporin 2 (AQP2) expressions were significantly activated during the transition to HF (18-21 weeks of age). They were chronically treated with tolvaptan (30mg/kg/day) (Tolv group: n=21) or vehicle (n=22) from the LV hypertrophic stage (11 weeks of age) until 21 weeks. Chronic tolvaptan treatment persistently increased urine volume (94% increase) and decreased urine osmolality (43% decrease). Although there was no difference in blood pressure between the two groups, the survival rate in Tolv group was improved at 21 weeks of age from 45.5% to 81.0% (log rank test: p<0.01). At HF stage, LV fractional shortening was preserved (40.2% vs. 27.5%; p<0.05) and lung congestion was suppressed in Tolv group. Serum AVP level and plasma renin activity were not changed and mRNA levels of ANP, endothelin-1 (ET-1), AVP and V1aR in LV were significantly decreased in Tolv group. In contrast, renal histopathologic damage (glomerulosclerosis and tubulointerstitial fibrosis) was ameliorated, and renal function (creatinine clearance and sodium excretion) was improved in Tolv group at HF stage. Concomitantly, not only activation of AQP2, but also those of V2R, V1aR and ET-1 in kidney were significantly suppressed (p <0.05 in all). Conclusions: These results indicate chronic tolvaptan treatment has beneficial effects by preventing the progressions of both LV dysfunction and renal injury in hypertensive rats with HF. The underlying mechanism may be related to the prevention of local (myocardial and renal) neurohumoral activation.