Evidence for enhanced eNOS function in coronary microvessels during the second window of protection.
Nitric oxide (NO) derived from endothelial NO synthase (NOS) (eNOS) has been identified as a trigger for the second window of protection (SWOP), but its role as a mediator during the SWOP is a matter of debate. Eighteen mongrel dogs were chronically instrumented to measure left ventricular function, coronary blood flow, and wall thickening. Myocardial preconditioning was induced by 10 min coronary artery occlusion. After 24 h of reperfusion (during the SWOP), the hearts were excised. Coronary microvessels were isolated and incubated in presence of 1) the endothelium-dependent agonists carbachol and bradykinin, 2) the calcium ionophore A23187, and 3) the angiotensin-converting enzyme (ACE) inhibitors enalaprilat and ramiprilat. Nitrite, a metabolite of NO, was measured. Under baseline conditions, nitrite production in microvessels from SWOP was 30% higher than that from normal (96 +/- 4 vs. 74 +/- 3 pmol/mg, P < 0.01, respectively). Nitrite production in response to carbachol, bradykinin, and A23187 was also enhanced in microvessels from SWOP (P < 0.05). These enhanced responses were abolished by N(G)-nitro-l-arginine methyl ester (l-NAME) or the endothelial receptor-specific antagonists atropine and HOE-140. The level of eNOS protein in the SWOP myocardium was twofold higher than that in the non-SWOP myocardium. Nitrite production in response to the ACE inhibitors was greater in microvessels from SWOP. These effects were blocked by l-NAME, HOE-140, or dichloroisocoumarin (which inhibits kinin formation). We found that a brief ischemic episode induced delayed, enhanced NO production in coronary microvessels and an upregulation of eNOS protein. These findings suggest that eNOS is a mediator during the SWOP. The ability of ACE inhibitors to enhance NO release during the SWOP points to an additional clinical application for these drugs.
Kim
Song-Jung
SJ
Cardiac Physiology Research Lab, Section of Cardiology, Advocate Illinois Masonic Medical Center, 836 W. Wellington Ave., Suite 1247, Chicago, IL 60657, USA. kimso@uic.edu
Zhang
Xiaoping
X
Xu
Xiaobin
X
Chen
Alice
A
Gonzalez
Joaquin B
JB
Koul
Sharat
S
Vijayan
Kalpana
K
Crystal
George J
GJ
Vatner
Stephen F
SF
Hintze
Thomas H
TH
D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology; D003326:Coronary Circulation / Q000502:physiology*; D003331:Coronary Vessels / Q000502:physiology*; D004285:Dogs; D005260:Female; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D008833:Microcirculation / Q000502:physiology*; D009569:Nitric Oxide / Q000737:chemistry*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*
D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III