Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Cytochrome p450 2C inhibition reduces post-ischemic vascular dysfunction. 1615 Jun 54

Cytochrome P450 (P450) enzymes play a significant role in promoting myocardial ischemia-reperfusion (I/R) injury. CYP2C9, an isoform of P450, is known to generate superoxide radicals in the reperfused heart. Sulfaphenazole (SPZ), a CYP2C9 inhibitor, has been shown to decrease I/R injury; however, the mechanism of cardioprotection by SPZ is not well elucidated. The objective of this study was to test whether SPZ mitigates myocardial I/R injury by scavenging reactive oxygen species (ROS). Isolated rat hearts were subjected to 30 min of global ischemia followed by 45 min of reperfusion. Hearts were perfused with SPZ and/or N(omega)-nitro-L-arginine methylester (L-NAME). Coronary flow (CF), left-ventricular developed pressure (LVDP), and rate-pressure product (RPP) were monitored. Superoxide and nitric oxide (NO) generation in the reperfused tissue was determined using fluorescence methods. Myocardial infarct size was measured using triphenyltetrazolium chloride staining. The SPZ-treated group showed a significant recovery of cardiac function compared with the untreated I/R group (CF, 53 versus 45%; LVDP, 48 versus 22%; RPP, 51 versus 20%). The infarct size was significantly reduced in the SPZ-treated group (15%) compared with the I/R control (42%). Coadministration of L-NAME with SPZ significantly attenuated the beneficial effects of SPZ. In addition, SPZ treatment showed significantly decreased superoxide levels and enhanced NO bioavailability in the reperfused heart. In conclusion, the protective effect of SPZ against I/R-mediated myocardial damage appears to be due to a reduction in the superoxide level caused by its inhibition of CYP2C9, as well as scavenging of oxygen free radicals generated in the reperfused heart.
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PMID:Cardioprotection by sulfaphenazole, a cytochrome p450 inhibitor: mitigation of ischemia-reperfusion injury by scavenging of reactive oxygen species. 1787 4