ANTIHYPERTENSIVE ACTIVITY OF ABBOTT-81282, A NONPEPTIDE ANGIOTENSIN-II ANTAGONIST, IN THE RENAL HYPERTENSIVE RAT

ABBOTT-81282, utyl-N-[(2'-[1H-tetrazol-5yl]biphenyl-4-yl)methyl] amino }pyrimidine-5-carboxylic acid is a novel nonpeptide angiotensin II (AI I) antagonist. In vivo studies were performed to evaluate ABBOTT-81282 for its antihypertensive effect, pharmacological mechanism(s) of acti on, and cardiovascular safety. In the conscious renal artery-ligated ( RAL) hypertensive rat, a model of high renin hypertension, ABBOTT-8128 2 (1-10 mg/kg p.o. and 0.1-1.0 mg/kg i.v.) lowered mean arterial press ure (MAP) in a dose-dependent manner with the ED30 values of 2.2 mg/kg for p.o. administration and 6.08 mg/kg for i.v. administration. At 10 mg/kg p.o., ABBOTT-81282 lowered blood pressure in the RAL rat (DELTA MAP 66 +/- 9 mm Hg from control MAP 167 +/- 7 mm Hg, n = 6) to a normo tensive level (MAP, 115 +/- 5 mm Hg) for greater than 24 h and did not change heart rate. The i.v. administration of 1 mg/kg of ABBOTT-81282 also produced a sustained, long-lasting decrease (DELTAMAP 27-52 mm H g) in blood pressure that was significantly different from the vehicle group at 8 h postdosing (143 +/- 3 mm Hg, n = 4 for ABBOTT-81282 vs. 181 +/- 3 mm Hg, n = 6 for vehicle group, p < 0.01). When blood pressu re in the renal hypertensive rat was maximally lowered (AMAP 72 +/-9 m m Hg, n = 4) following the 1 mg/kg i.v. dose (cumulative) of ABBOTT-81 282, additional administration of captopril (3 mg/kg i.v.) produced no further decline in blood pressure. In the conscious normotensive rat, 10 mg/kg p.o. of ABBOTT-81282 had no effect on basal MAP (119 +/-3 vs . 115 +/- 4 mm Hg, pre- vs. 3.5 h postdosing, n = 4) and heart rate (3 64 +/- 18 vs. 363 +/- 14 beats/min, pre- vs. 3.5 h postdosing, n = 4) but inhibited the AII (0.1 mug/kg i.v.)-induced increase in MAP by 64- 70%, while the MAP responses to norepinephrine (0.3 mug/kg i.v.), vaso pressin (0.03 IU/kg i.v.) and bradykinin (3 mug/kg i.v.) remained inta ct. ABBOTT-81282 was also administered to conscious normotensive rats (n = 4) instrumented with ECG telemetry transmitters. At an i.v. dose of 10 mg/kg, which is 125 times greater than the i.v. ED30, ABBOTT-812 82 caused a minimal decrease (< 14%) in MAP and had no effect on ECG w aveforms. These data demonstrate that ABBOTT-81282 is a safe and effic acious antihypertensive agent with selective AII antagonism. ABBOTT-81 282 may have potential for clinical use in the treatment of hypertensi on.