Relative Contributions of Endothelin Receptor Subtypes in Chronic Angiotensin II Induced Hypertension.
We previously showed that a selective ETA receptor antagonist, ABT627, completely normalized mean arterial pressure (MAP) in rats with chronic Ang II induced hypertension (AIH), indicating that endogenous endothelin (ET-1) plays a critical role in AIH. The goal of these experiments was to determine the relative contributions of ETA and ETB receptor activation to AIH. Male rats were chronically instrumented with arterial and venous catheters for drug injection and direct daily measurements of blood pressure and heart rate. Rats were maintained on high sodium intake, 6 mEq/day. Ang II was infused i.v. at 5 ng/min for 15 days; ET-1 antagonist was given during the middle 5 days. When injected acutely, A192621 (12 mg/kg 2x /day), a selective ETB receptor antagonist, gradually increased MAP over 1 hour in AIH rats but produced a biphasic increase in control rats over the same time. With 5-day dosing, A192621 significantly increased MAP in both AIH rats (130±9 to 158±8 mmHg) and uninfused control rats (110±3 to 129±7 mmHg). A192621 produced a significant decrease in water balance in both groups within 24 hours after start of drug administration, but had no effect on sodium balance. When injected acutely, A182086 (12 mg/kg 2x /day), an ETA/B receptor antagonist, produced a rapid drop in MAP in both groups to baseline levels over 1 hour. With 5-day dosing, A182086 significantly reduced, but did not normalize, MAP in AIH rats (138±3 to 127±7 mmHg). A182086 did not affect MAP in control rats (113±3 to 117±9 mmHg). A182086 did not affect water or sodium balance in either group. In conclusion, blockade of ETB receptors in AIH potentiates hypertension development, most likely through augmentation of ET-1 vasoconstriction. For this reason, ETA/B receptor blockade is less effective than ETA receptor blockade at decreasing MAP in chronic AIH. We found no evidence that ET-1 receptor activation in the kidney plays a role in AIH.