Tissue Kallikrein Is Involved in the Cardioprotective Effect of AT1-Receptor Blockade in Acute Myocardial Ischemia

  1. Erij Messadi-Laribi,
  2. Violaine Griol-Charhbili,
  3. Anne Pizard,
  4. Marie-Pascale Vincent,
  5. Didier Heudes,
  6. Pierre Meneton,
  7. François Alhenc-Gelas and
  8. Christine Richer
  1. INSERM U652/U872, Paris, France (E.M.-L., V.G.-C., A.P., M.-P.V., D.H., P.M., F.A.-G., C.R.); Université Paris-Sud, Le Kremlin-Bicêtre, France (E.M.-L., V.G.-C., C.R.); and Université de Paris-Descartes, Paris, France (D.H., P.M., F.A.-G.)
  1. Address correspondence to:
    Dr. Christine Richer-Giudicelli, INSERM U652/872, 15 rue de l'Ecole de Médecine, 75270 Paris, France. E-mail: christine.richer-giudicelli{at}u-psud.fr

Abstract

Angiotensin-converting enzyme inhibitors limit infarct size in animal models of myocardial ischemia reperfusion injury. This effect has been shown to be due to inhibition of bradykinin degradation rather than inhibition of angiotensin II formation. The purpose of this study was to determine whether angiotensin AT1 receptor blockade by losartan or its active metabolite EXP3174 protects against myocardial ischemia-reperfusion injury in mice and whether this protection is mediated by the kallikrein kinin system. We subjected anesthetized mice to 30 min of coronary artery occlusion followed by 3 h of reperfusion and evaluated infarct size immediately after reperfusion. Losartan (Los) or EXP3174 [2-n-butyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yI)methyl]imidazole-5-carboxylic acid] were administered 5 min before starting reperfusion at dosages determined by preliminary studies of blood pressure effect and inhibition of angiotensin pressor response. Compared with saline, both drugs significantly reduced myocardial infarct size by roughly 40% (P < 0.001). Pretreatment of mice with the selective AT2 receptor antagonist PD123,319 [S-(+)-1-([4-(dimethylamino)-3-methylphenyl]methyl)-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid] did not affect infarct size in the absence of losartan but abolished the reduction in infarct size provided by losartan. In tissue kallikrein gene-deficient mice (TK–/–), losartan no longer reduced infarct size. Pretreatment of wild-type mice with the B2 receptor antagonist icatibant reproduced the effect of TK deficiency. We conclude that AT1 receptor blockade provides cardioprotection against myocardial ischemia-reperfusion injury through stimulation of AT2 receptors. Kallikrein and B2 receptor are major determinants of this cardioprotective effect of losartan. Our results support the hypothesis of a coupling between AT2 receptors and kallikrein during AT1 receptor blockade, which plays a major role in cardioprotection.

Footnotes

  • This work was supported by INSERM, the Facultéde Médecine Paris-Sud 11, and the National Research Agency (Grant ANR-05-PCOD-027). E.M.-L. and V.G.-C. were supported by a fellowship from the Ministère de la Recherche et de la Technologie.

  • This study was performed in the European Vascular Genomics Network, a network of excellence supported by the European Community's Sixth Frame-work Program for Research Priority 1, “Life Sciences, Genomics and Biotechnology for Health” (Contract number LSHM-CT-2003-503254).

  • V.G.-C. and A.P. contributed equally to this work.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.124859.

  • ABBREVIATIONS: IR, ischemia-reperfusion injury; RAS, renin angiotensin system; ACE, angiotensin-converting enzyme; ACEI, angiotensinconverting enzyme inhibitor; AT1R, AT1 receptor; AT2R, AT2 receptor; ARB, AT1 receptor blocker; TK, tissue kallikrein; TK–/–, tissue kallikrein-deficient mice; TK+/+, wild-type littermates; AUC, area under curve; TTC, 2,3,5-triphenyltetrazolium chloride; IS, infarct size; AR, area at risk; LV, left ventricle; ANOVA, analysis of variance; MAP, mean arterial pressure; B1R, B1 receptor; B2R, B2 receptor; EXP3174, 2-n-butyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yI)methyl]imidazole-5-carboxylic acid; Ang II, angiotensin II; Los, losartan; ECG, electrocardiogram; PCR, polymerase chain reaction; HOE140, icatibant; PD123,319, S-(+)-1-([4-(dimethylamino)-3-methylphenyl]methyl)-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid.

    • Received April 24, 2007.
    • Accepted July 13, 2007.
« Previous | Next Article »Table of Contents

This Article

  1. Published online before print July 16, 2007, doi: 10.1124/jpet.107.124859 JPET October 2007 vol. 323 no. 1 210-216
  1. » Abstract
  2. Full Text
  3. Full Text (PDF)
  4. All Versions of this Article:
    1. jpet.107.124859v1
    2. 323/1/210 most recent

Classifications

Responses

  1. Submit a response
  2. No responses published

Current Issue

  1. November 2009, 331 (2)
  1. Current Issue
  1. Alert me to new issues of JPET