Contribution of Endothelin-1 to Renal Vasoconstriction in Unilateral Ureteral Obstruction: Reversal by Verapamil

Abstract

Purpose In unilateral ureteral obstruction (UUO) vasoconstriction occurs both during and after release of UUO. ET-1, an endogenous peptide, causes marked vasoconstriction mediated by an increase in cytosolic calcium. We measured renal output of endothelin-1 (ET-1) in dogs with UUO and examined if the renal vasoconstriction that persisted after release of UUO could be reversed by a calcium antagonist, verapamil. Materials and Methods Hemodynamic and clearance experiments were performed in anesthetized mongrel dogs in three groups. Group 1 consisted of 9 dogs with sham-operation. Group 2 consisted of 7 dogs in whom ureteral obstruction was released 19 hours after UUO. Group 3 consisted of 5 dogs in whom verapamil was infused into the renal artery at two doses (5 and 10 micro g./kg./min., respectively) after release of UUO of 19-hour duration. ET-1 concentrations (measured by radioimmunoassay) were determined for renal venous and arterial plasma. Results In Group 1 renal venous plasma ET-1 level was 16.7 +/− 2.2, significantly lowered than 22.8 +/− 3.2 pg./ml. arterial plasma, indicating a net clearance of ET-1. In Group 2 and 3, renal venous plasma ET-1 levels (28.2 +/− 5.2 and 27.2 +/− 2.4 pg./ml., respectively) were significantly greater than those in arterial plasma (24.2 +/− 5.7 and 17.4 +/− 0.8 pg./ml., respectively), indicating a net output of ET-1 in the kidney. In addition, renal vasoconstriction occurred in Groups 2 and 3 as indicated by significantly lower renal blood flow and GFR than those in Group 1. In Group 3, intrarenal infusion of verapamil at two doses did not change arterial pressure but caused an ipsilateral, significant increase in RBF (from 132 +/− 17 to 184 +/− 19 and 180 +/− 16 ml./min., respectively) and dose-dependent increases in GFR (from 12 +/− 2 to 25 +/− 3 and 38 +/− 7 ml./min., respectively), associated with a profound dose-dependent ipsilateral diuresis and natriuresis. Conclusion Profound renal vasoconstriction in UUO was associated with an increase in renal production of ET-1, possibly contributing to renal vasoconstriction, and was reversed by intrarenal infusion of verapamil.