Factors mediating remote preconditioning of trauma in the rat heart: Central role of the cytochrome P450 epoxygenase pathway in mediating infarct size reduction

Garrett J. Gross, Anna Hsu, Eric R. Gross, J R Falck, Kasem Nithipatikom

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 KATP or the mitochondrial KATP 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.

Original languageEnglish (US)
Pages (from-to)38-45
Number of pages8
JournalJournal of Cardiovascular Pharmacology and Therapeutics
Volume18
Issue number1
DOIs
StatePublished - Jan 2013

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Cytochrome P-450 Enzyme System
Wounds and Injuries
Capsaicin
Adenosine A1 Receptors
Coronary Occlusion
Opioid Receptors
Bradykinin
Naloxone
Reperfusion
Coronary Vessels
Salts
Sodium
Skin
Acids

Keywords

  • acute myocardial infarction
  • cardiac pharmacology
  • heart disease
  • ischemia-reperfusion injury

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Factors mediating remote preconditioning of trauma in the rat heart : Central role of the cytochrome P450 epoxygenase pathway in mediating infarct size reduction. / Gross, Garrett J.; Hsu, Anna; Gross, Eric R.; Falck, J R; Nithipatikom, Kasem.

In: Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 18, No. 1, 01.2013, p. 38-45.

Research output: Contribution to journalArticle

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N2 - 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 KATP or the mitochondrial KATP 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.

AB - 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 KATP or the mitochondrial KATP 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.

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