Cytochrome p450 2C inhibition reduces post-ischemic vascular dysfunction.
Cytochrome p450 (CYP) inhibitors provide protection against myocardial infarction following both global and focal cardiac ischemia and reperfusion (I/R). We hypothesized that sulfaphenazole, an inhibitor of CYP2C6 and 9, also attenuates post-ischemic endothelial dysfunction by reducing CYP-mediated superoxide generation (which scavenges nitric oxide (NO)), thereby restoring NO bioavailability and vascular tone. Rat hearts were perfused in the Langendorff mode for 20 min in the presence, or absence, of sulfaphenazole and then subjected to 30 min global no-flow ischemia followed by 15 min reperfusion. Septal coronary resistance arteries were isolated and mounted on glass cannulae for measurements of luminal diameter. Preconstricted arteries were exposed to acetylcholine to elicit endothelium-dependent, NO-mediated vasodilation. Acetylcholine caused near maximal dilation in control tissues not subjected to I/R. Following I/R, endothelium-dependent vasodilation was reduced. Pretreatment with sulfaphenazole restored endothelial sensitivity to acetylcholine. Vasoresponsiveness to endothelium-independent vasodilators, sodium nitroprusside and isoproterenol, were also reduced following I/R. However, sensitivity to endothelium-independent vasodilators was not restored by pretreatment with sulfaphenazole. I/R-induced superoxide production was assessed by dihydroethidium staining of flash frozen hearts. Sulfaphenazole treatment significantly reduced superoxide production in arterial walls following I/R injury. We conclude that sulfaphenazole restores post-ischemic endothelium-dependent, NO-mediated vasodilation by reducing superoxide production, suggesting that CYP2C9 plays a key role in post-ischemic vascular dysfunction.
Hunter
Arwen L
AL
The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Room 166 Burrard Building, St. Paul's Hospital, University of British Columbia, 1081 Burrard St., Vancouver, British Columbia, Canada, V6Z 1Y6.
Bai
Ni
N
Laher
Ismail
I
Granville
David J
DJ
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000072467:Cytochrome P450 Family 2; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004996:Ethidium / Q000031:analogs & derivatives; D005456:Fluorescent Dyes; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007511:Ischemia / Q000150:complications*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000037:antagonists & inhibitors*; D013426:Sulfaphenazole / Q000494:pharmacology; D014652:Vascular Diseases / Q000209:etiology* / Q000517:prevention & control*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D017382:Reactive Oxygen Species; D013426:Sulfaphenazole; C067883:dihydroethidium; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D052250:Nitric Oxide Synthase Type III; C507848:CYP2C9 protein, rat; C089877:Cyp2c6v1 protein, rat; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase; D004996:Ethidium