EFFECT OF THE NOVEL ANGIOTENSIN-II TYPE-1 RECEPTOR ANTAGONIST L-158,809 ON ACUTE INFARCT EXPANSION AND ACUTE ANTERIOR MYOCARDIAL-INFARCTIONIN THE DOG

OBJECTIVES: To assess the effect of the angiotensin II type 1 receptor (AT1-R) antagonist L-158,809 on acute infarct expansion and left vent ricular (LV) function during acute anterior myocardial infarction. MET HODS: Dogs were randomized to receive intravenous L-158,809 (0.1 mg/kg bolus and 0.6 mu g/kg/min infusion) or vehicle beginning 1 h after pe rmanent left anterior descending coronary artery ligation and continue d for 48 h. In vivo LV remodelling and function (quantitative echocard iography) and hemodynamics over 48 h, and postmortem remodelling after 48 h were measured. RESULTS: L-158,809 produced 90% to 100% inhibitio n of the angiotensin II presser response during the infusions. With re spect to percentage changes over the 48 h in vivo, compared with vehic le controls, L-158,809 decreased mean arterial pressure (-20+/-4 versu s -9+/-2%, P=0.03) and left atrial pressure (-38+/-5 versus 25+/-6%, P <0.0001) but did not change heart rate. These unloading effects were a ssociated with a smaller percentage increase in infarct expansion inde x (-5+/-7% versus 27+/-2%, P=0.001) and LV diastolic volume (11+/-11% versus 52+/-6%, P=0.008), less shape deformation, fewer apical aneurys ms (0 versus 100%, P=0.0003), better global ejection fraction (49+/-2% versus 39+/-2%, P=0.005), less ST segment elevation and fewer Q waves . Also compared with vehicle controls, with L-158,809 postmortem infar ct size (19.8+/-2.4% versus 50.4+/-4.7% of risk region, P=0.0002) and expansion index (2.06+/-0.09 versus 2.76+/-0.18, P=0.006) were less an d thinning ratio greater (0.92+/-0.02 versus 0.60+/-0.05, P=0.0001). C ONCLUSIONS: The novel AT1-R antagonist L-158,809 produces significant AT1-R blockade, reduces LV loading, and effectively limits acute infar ct expansion and early LV remodelling during canine myocardial infarct ion.