title: Factors mediating remote preconditioning of trauma in the rat heart: central role of the cytochrome p450 epoxygenase pathway in mediating infarct size reduction.
abstract: The present study further identified factors involved in the cardioprotective phenomenon of remote preconditioning of trauma (RPCT) with special emphasis on the role of the epoxyeicosatrienoic acids (EETs) in mediating this phenomenon. Remote preconditioning of trauma was produced by an abdominal incision only through the skin. Subsequently, all rats were subjected to 30 minutes of left coronary artery occlusion followed by 2 hours of reperfusion and the infarct size was determined. Remote preconditioning of trauma produced a reduction in infarct size expressed as a percentage of the area at risk from 63.0% ± 1.1% to 44.7% ± 1.4%; P < .01 versus control. To test the 3 major triggers of classical preconditioning in mediating RPCT, blockers of the bradykinin B2 receptor (B2BK), (S)-4-[2-[Bis(cyclohexylamino)methyleneamino]-3-(2-naphthalenyl)-1-oxopropylamino]benzyl tributyl phosphonium (WIN 64338, 1 mg/kg, iv), or HOE 140 (50 μg/kg, iv), the nonselective opioid receptor blocker, naloxone (3 mg/kg, iv), or the adenosine A1 receptor blocker, 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, 1 mg/kg, iv) were administered 10 minutes prior to RPCT. Only the 2 B2BK selective antagonists blocked RPCT (60.2% ± 1.1%, WIN 64338; 62.3% ± 2.0%, HOE 140). To test EETs in RPCT, we administered the EET receptor antagonist 14,15-Epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 2.5 mg/kg, iv) or the EET synthesis inhibitor, N-(Methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH, 3.0 mg/kg, iv) 10 minutes prior to RPCT. In both groups, the EET antagonists completely blocked RPCT (62.0% ± 0.8%, 14,15-EEZE; 61.8% ± 1.0%, MSPPOH). The EET antagonists also blocked the effect of B2BK activation. We also determined whether the sarcolemmal K(ATP) or the mitochondrial K(ATP) channel mediate RPCT by pretreating rats with 1-[5-[2-(5-Chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3 methylthiourea, sodium salt (HMR 1098) or 5-hydroxydecanoic acid (5-HD), respectively. Interestingly, 5-HD blocked RPCT (64.7% ± 1.3%), whereas, HMR 1098 did not (50.3% ± 1.3%). The 2 EET antagonists completely blocked capsaicin-induced cardioprotection. These results clearly suggest that EETs mediate RPCT-, bradykinin- and capsaicin-induced cardioprotection in rat hearts.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, WI 53226, USA. ggross@mcw.edu
authors.forename: Garrett J
authors.initials: GJ
authors.lastname: Gross
authors.forename: Anna
authors.initials: A
authors.lastname: Hsu
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gross
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Kasem
authors.initials: K
authors.lastname: Nithipatikom
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D006439:Hemodynamics; D019157:Ischemic Preconditioning, Myocardial; D054086:KATP Channels / Q000502:physiology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000502:physiology; D014970:Xanthines / Q000494:pharmacology
chemical_list: C494022:14,15-eicosa-5-enoic acid; D054086:KATP Channels; D014970:Xanthines; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; C051360:1,3-dipropyl-8-cyclopentylxanthine; D015126:8,11,14-Eicosatrienoic Acid; D002211:Capsaicin