Prevention of coronary vascular abnormalities early in reperfusion with TGF-beta may not prevent late coronary vascular injury.
Endothelial injury, manifest by increased protein leak and decreased endothelium-dependent relaxation, occurs during reperfusion after ischemia. Transforming growth factor-beta (TGF-beta) has been shown to improve endothelium-dependent relaxation and reduce infarct size after short periods (from 20 min to 4.5 h) of reperfusion even when administered 24 h before the ischemic period. However, whether this represents a transient delay in the process leading to endothelial injury or prevention of injury has not been clear. To examine this issue, we measured protein leak, an index of coronary microvascular permeability, and endothelium-dependent relaxation, a measure of coronary endothelial function, after brief (1-h) and lengthy (48-h) reperfusion periods in dogs treated 30 min before ischemia with TGF-beta (30 microg/kg, i.v.) and control dogs. The left anterior descending coronary artery (LAD) was ligated for 1 h followed by 1 h of reperfusion (n = 10) or 48 h of reperfusion (n = 12). Protein leak was assessed by a dual-isotope technique by using radiolabeled transferrin and erythrocytes, and endothelium-dependent relaxation was assessed in epicardial coronary rings by using adenosine diphosphate (ADP), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent dilator. In control animals, there was a marked increase in the protein leak index (PLI) in the infarct zone (8.3 +/- 1.4 in 1-h dogs, and 8.7 +/- 0.9 in 48-h dogs) compared with the nonischemic myocardium (3.1 +/- 0.8 at 1 h, and 3.8 +/- 0.9 at 48 h). In TGF-beta treated dogs, there was a marked improvement in PLI in the infarct zone in 1-h dogs (PLI, 4.1 +/- 1.1; p < 0.05; or a 50% reduction compared with untreated dogs). However, the 48-h dogs treated with TGF-beta failed to demonstrate an improvement in PLI (PLI, 8.5 +/- 0.9; p = NS). Endothelium-dependent relaxation was impaired in the LAD in control dogs, and treatment with TGF-beta failed to improve relaxation after 1 or 48 h of reperfusion. Microvascular permeability was increased and endothelium-dependent relaxation was decreased after ischemia at both 1 and 48 h of reperfusion. Pretreatment with TGF-beta reduced the increase in permeability at 1 h of reperfusion but not at 48 h.
Keller
M
M
Department of Medicine, University of Colorado Health Sciences Center and Veterans Affairs Medical Center, Denver 80262, U.S.A.
Kong
Y
Y
Robertson
A D
AD
Horwitz
L
L
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D003327:Coronary Disease / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology*; D004285:Dogs; D004562:Electrocardiography; D004730:Endothelium, Vascular / Q000473:pathology; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D009124:Muscle Proteins; D016212:Transforming Growth Factor beta; D014665:Vasodilator Agents; D009195:Peroxidase