Effect of tetrahydrobiopterin on selective endothelial dysfunction of epicardial porcine coronary arteries induced by cardiopulmonary bypass.
BACKGROUND
We hypothesized that cardiopulmonary bypass induces a selective alteration of the coronary arterial endothelial cell signal transduction which could be explained by a state of depletion and/or decreased activity of endogenous tetrahydrobiopterin (BH(4)). The aim of this study was to assess the effects of cardiopulmonary bypass and BH(4) on the endothelial function of epicardial coronary arteries in a swine model of cardiopulmonary bypass.


METHODS
Swine underwent 90 min of cardiopulmonary bypass alone (N=19) or in association with a brief cardioplegic arrest with (N = 6) or without (N = 5) in vivo BH(4) administration, followed by a 60-min period following weaning from cardiopulmonary bypass and were compared to a control group (N = 7). Endothelium-dependent relaxations of epicardial coronary artery rings were studied using standard organ chamber experiments in the presence or absence of in vitro BH(4) or superoxide dismutase (SOD) and catalase.


RESULTS
Cardiopulmonary bypass caused a statistically significant reduction of endothelium-dependent relaxations to serotonin (p < 0.0001), bradykinin (p < 0.001), UK14304 (p < 0.0001) and calcium ionophore (p < 0.01) in epicardial porcine coronary arteries. In vitro and in vivo BH(4) supplementation improved endothelium-dependent relaxations to serotonin and bradykinin, which were left unchanged by SOD-catalase administration. Cardiopulmonary bypass was associated with a decrease in nitric oxide availability (p = 0.002) and increased oxidative stress (p < 0.001), which were both restored by in vivo BH(4) administration (p < 0.001).


CONCLUSIONS
Treatment with BH(4) improves the endothelial dysfunction of porcine epicardial coronary arteries, restores nitric oxide availability and reduces the oxidative stress associated with cardiopulmonary bypass.
Stevens
Louis-Mathieu
LM
Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, Que. H1T 1C8, Canada.
Fortier
Simon
S
Aubin
Marie-Claude
MC
El-Hamamsy
Ismail
I
Maltais
Simon
S
Carrier
Michel
M
Perrault
Louis P
LP
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D003331:Coronary Vessels / Q000187:drug effects* / Q000503:physiopathology; D006152:Cyclic GMP / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D023421:Models, Animal; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D009569:Nitric Oxide / Q000032:analysis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010496:Pericardium / Q000187:drug effects / Q000503:physiopathology; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013482:Superoxide Dismutase / Q000494:pharmacology; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology
D018490:Serotonin Agents; D014665:Vasodilator Agents; D001708:Biopterins; D009569:Nitric Oxide; D012701:Serotonin; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; C003402:sapropterin; D006152:Cyclic GMP; D001920:Bradykinin