title: Selective kinin receptor agonists as cardioprotective agents in myocardial ischemia and diabetes.
abstract: Cardiac ischemia is a leading cause of death, especially in diabetic patients. The diabetic ischemic heart is resistant experimentally to established cardioprotective treatments. New pharmacological approaches to cardiac protection are warranted. The kallikrein-kinin system is involved in myocardial protection in ischemia. Respective roles of B1 (B1R) and B2 (B2R) receptors remain controversial. We tested whether pharmacological activation of kinin receptors may have therapeutic effect in cardiac ischemia-reperfusion in nondiabetic (NDiab) and diabetic (Diab) mice. We assessed effect on infarct size (IS) and signaling pathways involved in myocardial protection of potent selective pharmacological agonists of B1R or B2R given at reperfusion. In NDiab mice, a B2R agonist reduced IS significantly by 47%, similarly to ramiprilat or ischemic postconditioning, via activation of phosphoinositide 3 kinase/Akt pathway leading to inhibition of glycogen synthase kinase-3β (GSK-3β). B1R agonist had no effect on IS. In contrast, in Diab mice, the B2R agonist, ramiprilat, or ischemic postconditioning failed to reduce IS but a B1R agonist significantly reduced IS by 44% via activation of phosphoinositide 3 kinase/Akt and extracellular signal-regulated kinase 1/2, both leading to GSK-3β inhibition. Differential effect of B2R or B1R agonists in NDiab and Diab mice can be linked to inactivation of B2R signaling and induction of B1R in heart of Diab mice. Thus, a pharmacological B2R agonist is cardioprotective in acute ischemia in nondiabetic animals. B1R agonist overcomes resistance of diabetic heart to cardioprotective treatments. Pharmacological activation of B1R and B2R may become a treatment for diabetic and nondiabetic patients, respectively, in acute coronary syndromes.
authors.affiliation: INSERM U872, Research Center les Cordeliers, Paris, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Potier
authors.forename: Ludovic
authors.initials: L
authors.lastname: Waeckel
authors.forename: Marie-Pascale
authors.initials: MP
authors.lastname: Vincent
authors.forename: Catherine
authors.initials: C
authors.lastname: Chollet
authors.forename: Fernand
authors.initials: F
authors.lastname: Gobeil
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Christine
authors.initials: C
authors.lastname: Richer
authors.forename: Ronan
authors.initials: R
authors.lastname: Roussel
authors.forename: François
authors.initials: F
authors.lastname: Alhenc-Gelas
authors.forename: Nadine
authors.initials: N
authors.lastname: Bouby
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D043783:Receptor, Bradykinin B1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; C583125:bradykinin, (Hyp(3)-Thi(5)-(N)Chg(7)-Thi(8))-bradykinin; C583124:bradykinin, Sar-Lys-(Hyp(3)-Igl(5)-Phe(8))-desArg(9)-; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D001920:Bradykinin