PT  - JOURNAL ARTICLE
AU  - Potier, Louis
AU  - Waeckel, Ludovic
AU  - Vincent, Marie-Pascale
AU  - Chollet, Catherine
AU  - Gobeil, Fernand
AU  - Marre, Michel
AU  - Bruneval, Patrick
AU  - Richer, Christine
AU  - Roussel, Ronan
AU  - Alhenc-Gelas, François
AU  - Bouby, Nadine
TI  - Selective Kinin Receptor Agonists as Cardioprotective Agents in Myocardial Ischemia and Diabetes
AID  - 10.1124/jpet.113.203927
DP  - 2013 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 23--30
VI  - 346
IP  - 1
4099  - http://jpet.aspetjournals.org/content/346/1/23.short
4100  - http://jpet.aspetjournals.org/content/346/1/23.full
SO  - J Pharmacol Exp Ther2013 Jul 01; 346
AB  - 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.