AT1 receptor blockade limits myocardial injury and upregulates AT2 receptors during reperfused myocardial infarction.
Persistent left ventricular (LV) dysfunction after reperfused myocardial infarction (RMI) is a significant problem and angiotensin II (AngII) type 1 receptor (AT1R) blockers (ARBs) may limit reperfusion injury involving upregulation of AngII type 2 receptors (AT2R). To determine whether ARBs valsartan and irbesartan limit reperfusion injury and upregulate AT2R protein during RMI, we randomized dogs with anterior RMI (90 min ischemia; 120 min reperfusion) to 4 groups [valsartan (n = 6); irbesartan (n = 9); vehicle controls (n = 8); and sham (n = 6)] and measured serial in vivo hemodynamics, LV systolic and diastolic function, and inhibition of AngII pressor responses to the ARBs, and ex vivo infarct size, and regional AT1R and AT2R protein expression at the end of the reperfusion. Compared to the control group, both ARBs significantly limited the increase in left atrial pressure, promptly limited the deterioration of LV dP/dtmax, dP/dtmin, ejection fraction and diastolic function, limited infarct expansion and thinning, and limited infarct size. Importantly, both ARBs increased AT2R protein in the postischemic reperfused zone, with no change in AT1R protein. There were no changes in the sham group. The results suggest that limitation of myocardial injury associated with AT1R blockade combined with upregulation of AT2R protein expression contributes to the cardioprotective effects of ARBs during RMI. This beneficial effect of ARBs on persistent LV dysfunction after RMI should be evaluated in the clinical setting to determine the relative benefit of ARBs in patients who undergo reperfusion therapy for acute coronary syndromes.
Jugdutt
Bodh I
BI
Division of Cardiology, Department of Medicine, Faculty of Medicine and Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada. bjugdutt@ualberta.ca
Menon
Vijayan
V
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D000077405:Irbesartan; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D000068756:Valsartan; D020257:Ventricular Remodeling / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine; D000077405:Irbesartan