Effects of acute and chronic angiotensin receptor blockade on myocardial vascular blood volume and perfusion in a pig model of coronary microembolization.
Based on the reduction of ischemic cardiac events in clinical trials and experimental observations, inhibition of the effects of angiotensin II on coronary microcirculatory function may afford myocardial protection after injury. The immediate effects of intracoronary AT1 receptor blockade with irbesartan were examined in a pig model in the healthy myocardium and in acute ischemia induced by injection of 30-microm microspheres into the left anterior descending coronary artery (LAD). Electron-beam computed tomography was performed for in-vivo quantitative measurements of regional intramyocardial vascular blood volume (V(B)) and perfusion (F(M)), as well as left ventricular ejection fraction (LVEF) and muscle mass. Ratios of V(B) and F(M) in the anterior (LAD-supplied)/ inferior (control) myocardium were generated. At baseline, 0.2 mg/kg irbesartan injected into the LAD increased V(B) and F(M) ratios significantly by 27 +/- 8% and 51 +/- 13%, respectively. After anterior coronary microembolization, V(B) and F(M) ratios were 0.60 +/- 0.05 and 0.51 +/- 0.05, respectively, and were significantly increased by irbesartan (by 24 +/- 10% and by 36 +/- 11%, respectively). After 4 weeks of treatment with oral irbesartan (n = 7) or placebo (n = 7), an improved LVEF (56 +/- 4% v 44 +/- 4%, P = .046) was observed in irbesartan-treated animals, but no difference in LV end-diastolic volumes or muscle mass. Resting V(B) (0.95 +/- 0.06 v 0.76 +/- 0.06; P = .047) and F(M) (0.84 +/- 0.05 v 0.64 +/- 0.04; P = .016) ratios were significantly greater in irbesartan-treated animals. Using adenosine, there was a trend for higher V(B) and F(M) ratios in irbesartan- v placebo-treated animals. Therefore, in a pig model of acute myocardial ischemia, AT1 receptor blockade by irbesartan induced microvascular vasodilation and, ostensibly, conveyed myocardial protection. Long-term treatment with irbesartan resulted in moderate enhancements of resting V(B) and F(M) compared with placebo, suggesting a role for coronary microcirculatory effects of chronic AT1 receptor blockade in preserving LVEF.
Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota, USA. Axel.Schmermund@uni-essen.de
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A
Schmermund
L O
LO
Lerman
J A
JA
Rumberger
P E
PE
Lund
E A
EA
Pfeifer
P F
PF
Sheedy
E L
EL
Ritman
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001810:Blood Volume / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects*; D003328:Coronary Thrombosis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D000077405:Irbesartan; D008863:Microspheres; D017202:Myocardial Ischemia / Q000209:etiology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D013777:Tetrazoles; D003094:Collagen; D000077405:Irbesartan