AT1 and TxA2/PGH2 receptors maintain hypertension throughout 2K,1C Goldblatt hypertension in the rat

Abstract

Angiotension II (ANG II) increases the generation of vasoconstrictor prostaglandin endoperoxides (PGH2) and thromboxane A2 (TxA2). Two-kidney, one-clip (2K,1C) Goldblatt hypertensive rats have an increased plasma renin activity (PRA) and ANG II level during the early, but not the late, phases of hypertension. Therefore, the aim of these studies was to compare the antihypertensive efficacy of an ANG II type I (AT1) and a TxA2/PGH2 receptor antagonist during different phases of 2K,1C hypertension. Rats were maintained on a fixed sodium intake for 3 days before and throughout the period of drug administration. These studies assessed the antihypertensive response to administration of the AT1 receptor antagonist losartan (20 mg.kg-1.day-1), the TxA2/PGH2 receptor antagonist ifetroban (20 mg.kg-1.day-1) or vehicle given for 3 days to rats with early (2-4 wk postclip), intermediate (10-12 wk postclip), and late (36-42 wk post-clip) 2K,1C hypertension and to two control groups of rats corresponding in age to the early or intermediate and the late 2K,1C groups. The mean arterial pressure (MAP) was measured directly with indwelling arterial cannulas. The MAP of sham-operated rats was 109 +/- 5 mmHg. In the early phase of 2K,1C hypertension, the MAP was increased to 143 +/- 6 mmHg, and it was increased further to 162 +/- 5 mmHg during the intermediate and to 179 +/- 4 mmHg during the late phase. The PRA, compared with age-matched controls, was increased during early and intermediate, but not late phase 2K,1C hypertension. Neither drug lowered blood pressure in control rats. However, both drugs significantly reduced the blood pressure in the early, intermediate, and late phases of 2K, 1C hypertension. At the end of 3 days of administration, blood pressure in early 2K, 1C rats given losartan was reduced to levels of control rats, but remained slightly elevated in other groups and in those receiving ifetroban. In conclusion, AT1 and TxA2/PGH2 receptors maintain hypertension throughout the evolution of 2K, 1C hypertension in the rat, despite changes in PRA.