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J Thorac Cardiovasc Surg 2002;123:1074-1083
© 2002 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CSP)

Novel cardioprotective effects of tetrahydrobiopterin after anoxia and reoxygenation: Identifying cellular targets for pharmacologic manipulation

From the Division of Cardiac Surgery, Toronto General Hospital, Toronto, Ontario, Canada.

Supported by operating grants from the Heart and Stroke Foundation of Canada (R.D.W., V.R.) and Canadian Diabetes Association (R.D.W., V.R.). S.V. and P.W.M.F. are Fellows of the Canadian Institutes for Health Research (formerly MRC) and the Heart and Stroke Foundation of Canada. R.K.L. is a Career Investigator of the Heart and Stroke Foundation of Ontario. S.V. was selected as the Paul C. Samson Award Finalist (2001) for this research.

Read at the Twenty-seventh Annual Meeting of The Western Thoracic Surgical Association, San Diego, Calif, June 20-23, 2001.

Received for publication June 28, 2001. Revisions requested Sept 18, 2001; revisions received Oct 12, 2001. Accepted for publication Oct 24, 2001. Address for reprints: Richard D. Weisel, MD (E-mail: richard.weisel{at}uhn.on.ca), or Subodh Verma, MD, PhD, Division of Cardiac Surgery, Toronto General Hospital, 14-215, 200 Elizabeth St, Toronto, Ontario M5G 2C4, Canada.

Objectives: Contemporary cardioprotective strategies to prevent perioperative ischemia-reperfusion injury have focused on the L-arginine nitric oxide pathway. Tetrahydrobiopterin is an absolute cofactor required for the enzyme nitric oxide synthase and is thus a critical determinant of nitric oxide production. We hypothesized that ischemia-reperfusion results in diminished levels of tetrahydrobiopterin, which might represent a key cellular defect underlying endothelial and myocyte dysfunction after ischemia-reperfusion. To this aim, we examined the effects of tetrahydrobiopterin supplementation in (1) an in vivo experimental model of global ischemia-reperfusion and (2) an in vitro human ventricular heart cell model of simulated ischemia-reperfusion. Measures of endothelial function, oxidant production, cell survival, and cardiac function were used to assess outcome.
Methods: In study 1 Wistar rats were divided into one of 2 groups (n = 10 per group). One group received tetrahydrobiopterin (25 mg · kg^-1 · d^-1 for 7 days), and the other group served as the control group. Hearts were subjected to 30 minutes of ischemia followed by 30 minutes of reperfusion, and left ventricular developed pressure, left ventricular systolic pressure, and left ventricular end-diastolic pressure were determined by using the modified Langendorff technique. In study 2 we quantitated myocardial malondialdehyde, a marker of lipid peroxidation, in ventricular tissues from both groups of animals using butanol phase extraction and spectrophotometric analysis. In study 3 coronary vascular responses were determined in vascular segments of the left coronary artery in both groups of animals after ischemia-reperfusion. Endothelium-dependent and endothelium-independent vasodilatation to acetylcholine and sodium nitroprusside, respectively, were compared between groups. In study 4, using a human ventricular heart cell model of simulated ischemia-reperfusion, we studied the effects of tetrahydrobiopterin (20 µmol/L) on cellular injury (as assessed by means of trypan blue uptake).
Results: After ischemia-reperfusion, myocardial dysfunction was evidenced by a decrease in left ventricular developed pressure and an increase in left ventricular end-diastolic pressure (P = .01 compared with baseline). Hearts from tetrahydrobiopterin-treated rats exhibited protection against ischemia-reperfusion injury (left ventricular developed pressure: 74 ± 4 vs control 42 ± 8 mm Hg, P = .01; left ventricular end-diastolic pressure: 12 ± 3 vs 34 ± 7 mm Hg, P = .01). Furthermore, tetrahydrobiopterin treatment attenuated the rise in malondialdehyde levels after ischemia-reperfusion (P = .01). After reperfusion, coronary endothelial function to acetylcholine was attenuated (P = .003 vs sham-treated mice), whereas responses to sodium nitroprusside remained unchanged. Tetrahydrobiopterin-treated rats exhibited an improvement in acetylcholine-mediated vasorelaxation (P = .01 vs ischemia-reperfusion group). Cellular injury, as assessed by means of trypan blue uptake, was higher in human ventricular heart cells subjected to simulated ischemia-reperfusion; this effect was prevented with tetrahydrobiopterin treatment (P = .001).
Conclusions: Supplemental tetrahydrobiopterin provides a novel cardioprotective effect on left ventricular function, endothelial-vascular reactivity, oxidative damage, and cardiomyocyte injury after ischemia-reperfusion injury and might represent an important cellular target for future operative myocardial protection strategies.

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