Tetrahydrobiopterin and antioxidants reverse the coronary endothelial dysfunction associated with left ventricular hypertrophy in a porcine model.
OBJECTIVE
Endothelium-dependent G-protein mediated relaxations of epicardial coronary arteries is impaired with left ventricular hypertrophy. The objective of this study was to assess the effect of L-arginine, BH(4) and the combination of two antioxidants, superoxide dismutase and catalase, on endothelium-dependent relaxations in a swine left ventricular hypertrophy model.


METHODS
Aortic banding was performed 3 cm above the coronary ostia. Vascular reactivity studies were performed in standard organ chamber experiments to assess the NO pathway in the presence of methyltetrahydropterin (a BH(4) analogue), L-arginine, superoxide dismutase and catalase.


RESULTS
There was a statistically significant increase in endothelium-dependent relaxation to serotonin and to bradykinin with methyltetrahydropterin and with superoxide dismutase plus catalase (P<0.05) but not with L-arginine compared to untreated coronary arteries from left ventricular hypertrophy animals. Plasma 3-nitrotyrosine level increased significantly from 918+/-122 to 1844+/-300 microM (P<0.05 vs. control) after 60 days of aortic banding. Endothelial dysfunction was not associated with a reduced expression of endothelial nitric oxide synthase 2 months after pressure overload left ventricular hypertrophy.


CONCLUSIONS
Treatment with BH(4) and antioxidants constitutes an interesting approach for the prevention of endothelial dysfunction in epicardial coronary arteries associated with left ventricular hypertrophy.
Malo
Olivier
O
Research Center, Montreal Heart Institute, Montreal, Quebec, Canada H1T 1C8.
Desjardins
Fanny
F
Tanguay
Jean-François
JF
Tardif
Jean-Claude
JC
Carrier
Michel
M
Perrault
Louis P
LP
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D001920:Bradykinin / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D003331:Coronary Vessels; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000097:blood / Q000503:physiopathology*; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000097:blood; D011622:Pterins / Q000494:pharmacology*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology; D013552:Swine; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000097:blood
D000975:Antioxidants; D015415:Biomarkers; D011622:Pterins; D012702:Serotonin Antagonists; D030421:Peroxynitrous Acid; D012701:Serotonin; C002744:3-nitrotyrosine; D014443:Tyrosine; D001120:Arginine; D007650:Ketanserin; C017523:6-methyltetrahydropterin; D002374:Catalase; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D001920:Bradykinin