Search

This study was undertaken to determine whether the myocardial infarct-sparing effect of ATL-146e, a selective adenosine A2A receptor agonist, persists without a rebound effect for at least 48 h and to determine the optimal duration of ATL-146e treatment in anesthetized dogs. Reperfusion injury after myocardial infarction (MI) is associated with inflammation lasting 24-48 h that contributes to ongoing myocyte injury. We previously showed that an ATL-146e infusion, starting just before reperfusion, decreased inflammation and infarct size in dogs examined 2 h after MI without increasing coronary blood flow. In the present study, adult dogs underwent 90 min of left anterior descending coronary artery occlusion. Thirty minutes before reperfusion, ATL-146e (0.01 [micro]g x [kg.sup.-1] x [min.sup.-1]; n = 21) or vehicle (n = 12) was intravenously infused and continued for 2.5 h (protocol 1) or 24 h (protocol 2). At 48 h after reperfusion hearts were excised and assessed for histological risk area and infarct size. Infarct size based on triphenyltetrazolium chloride (TTC) staining as a percentage of risk area was significantly smaller in ATL-146e-treated vs. control dogs (16.7 [+ or -] 3.7% vs. 33.3 [+ or -] 6.2%, P < 0.05; protocol 1). ATL-146e reduced neutrophil accumulation into infarcted myocardium of ATL-146e-treated vs. control dogs (30 [+ or -] 7 vs. 88 [+ or -] 16 cells/high-power field, P < 0.002). ATL-146e infusion for 24 h (protocol 2) conferred no significant additional infarct size reduction compared with 2.5 h of infusion. A 2.5-h ATL-146e infusion initiated 30 min before reperfusion results in marked, persistent (48 h) reduction in infarct size as a percentage of risk area in dogs with a reduction in infarct zone neutrophil infiltration. No significant further benefit was seen with a 24-h infusion. reperfusion injury; myocardial infarction

Angiotensin II type 2 receptor ([AT.sub.2]R) overexpression ([AT.sub.2]TG) attenuates left ventricular remodeling in a mouse model of anterior myocardial infarction (MI). We hypothesized that the beneficial effects of cardiac [AT.sub.2]TG are mediated via the bradykinin subtype 2 receptor ([B.sub.2]R). Fourteen transgenic mice overexpressing the [AT.sub.2]R ([AT.sub.2]TG mice), 10 mice with a [B.sub.2]R deletion ([B.sub.2]KO mice), 13 [AT.sub.2]TG mice with [B.sub.2]R deletion ([AT.sub.2]TG/[B.sub.2]KO mice), and 11 wild-type (WT) mice were studied. All mice were on a C57BL/6 background. Mice were studied by cardiac magnetic resonance imaging at baseline and days 1, 7, and 28 after MI induced by 1 h of occlusion of the left anterior descending artery followed by reperfusion. Short-axis images from apex to base were used to compare ventricular volumes and ejection fraction (EF). At baseline, end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) were lower and EF higher in [AT.sub.2]TG mice compared with the other three strains. Infarct size was similar between groups. No differences were observed in global remodeling parameters at day 28 between [AT.sub.2]TG and [AT.sub.2]TG/[B.sub.2]KO mice; however, EDVI and ESVI were lower and EF higher in both transgenic groups than in WT or [B.sub.2]KO mice. Both strains lacking [B.sub.2]R demonstrated increased collagen content and less hypertrophy in adjacent noninfarcted regions at day 28. Attenuation of postinfarct remodeling by overexpression of [AT.sub.2]R is not directly mediated via a [B.sub.2]R pathway. However, [B.sub.2]R does appear to have a role in the smaller cavity size and hyperdynamic function observed at baseline in [AT.sub.2]TG mice and in limiting collagen deposition during postinfarct remodeling. magnetic resonance imaging; remodeling

The relative contribution of the angiotensin II type 1 and 2 receptors ([AT.sub.1]-R and [AT.sub.2]-R) in postmyocardial infarction (MI) remodeling remains incompletely understood. We studied five groups of C57B1/6 mice after 1 h of left anterior descending artery occlusion-reperfusion: 1) wild type, untreated (n = 12); 2) wild type, treated with the [AT.sub.1]-R blocker losartan (10-20 mg x [kg.sup.-1] x [day.sup.-1] in drinking water) from day 1 to day 28 post-MI (n = 10); 3) cardiac overexpression of the [AT.sub.2]-R [[AT.sub.2]-transgenic (TG); n = 14]; 4) [AT.sub.2]-TG treated with losartan (n = 13); and 5) [AT.sub.2]-TG and null for the [AT.sub.1a]-R [[AT.sub.2]-TG/[AT.sub.1] knockout (KO); n = 10]. Cardiac magnetic resonance imaging (CMR) measured ejection fraction and left ventricular end-diastolic and end-systolic volume (EDVI and ESVI) and mass indexed to weight on days O, 1, 7, and 28 post-MI. Infarct size was measured on day 1 by late gadolinium-enhanced CMR. Regional myocyte hypertrophy and collagen content were measured on day 28 post-MI. Infarct size was similar among groups. Systolic blood pressure was lowest in [AT.sub.2]-TG/[AT.sub.1]KO. By day 28 post-MI, when corrected for baseline differences, EDVI and ESVI were higher and ejection fraction was lower in wild type than other groups. Ejection fraction was highest and EDVI and mass index were lowest in [AT.sub.2]-TG/[AT.sub.1]KO at day 28. The [AT.sub.2]-TG/[AT.sub.1]KO demonstrated less fibrosis in adjacent regions. Regional myocyte hypertrophy was similar in all groups. The [AT.sub.1]-R and [AT.sub.2]-R are intricately intertwined in post-MI remodeling. Pharmacological blockade of [AT.sub.1]-R is equivalent to [AT.sub.2]-R overexpression in attenuating post-MI remodeling. Genetic knockout of the [AT.sub.1a]-R is additive to [AT.sub.2]-R overexpression, due, at least in part, to blood pressure lowering. magnetic resonance imaging; angiotensin; myocardial infarction; receptors