Pharmacological Preconditioning in Type 2 Diabetic Rat Hearts: The Roles of Mitochondrial ATP-Sensitive Potassium Channels and the Phosphatidylinositol 3-Kinase-Akt Pathway

Abstract

1 AbstractPurpose: The authors examined whether olprinone, a phosphodiesterase type 3 inhibitor, or isoflurane, a volatile anesthetic, could protect the heart against myocardial infarction in type 2 diabetic rats and whether the underlying mechanisms involve protein kinase C (PKC), mitochondrial ATP-sensitive potassium (m-K ATP ) channels, or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway.Methods: All rats underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion.Wistar rats received isoflurane or olprinone before ischemia with or without the PKC inhibitor chelerythrine (CHE), the m-K ATP channel blocker 5-hydroxydecanoic acid (5HD), or the PI3K-Akt inhibitor LY294002 (LY). Goto-Kakizaki (GK) rats were randomly assigned to receive isoflurane or olprinone. In another group, GK rats received LY before the olprinone.Results: In the Wistar rats, both isoflurane (38 ± 11%) and olprinone (40 ± 11%) reduced infarct size as compared to the control (59 ± 8%). In the GK rats, olprinone (41 ± 9%) but not isoflurane (53 ± 11%) reduced infarct size as compared to the GK control (58 ± 14%). The beneficial effects of olprinone were blocked by LY (58 ± 14%). In the Wistar rats, CHE, 5HD, and LY prevented isoflurane-induced reductions of infarct size. On the other hand, LY but not CHE or 5HD prevented olprinone-induced reductions of infarct size.Conclusions: Olprinone but not isoflurane protects the heart against myocardial infarction in type 2 diabetic rats. The olprinone-induced cardioprotective effect is mediated by the PI3K-Akt pathway but not PKC or m-K ATP channels. (245 words)

Comparison of two sulfonylureas with high and low myocardial KATP channel affinity on myocardial infarct size and metabolism in a rat model of type 2 diabetes

“…Using an ex vivo model may explain our findings of smaller infarct size in GK compared with Wis rats, which is in contrast to results obtained with in vivo models [36,37]. Animals were subjected to acute SU treatment in the Langendorff model and not to in vivo long-term oral treatment, which may influence the effects observed here.…”

Roles of Cyclooxygenase 2 in Sevoflurane- and Olprinone-Induced Early Phase of Preconditioning and Postconditioning Against Myocardial Infarction in Rat Hearts

“…PDEIs are used for the treatment of heart failure, since these compounds have inotropic and vasodilatory effects via an increase in intracellular cAMP level in cardiomyocytes and vascular smooth muscles, and increase myocardial contractile force with less cardiac oxygen demand compared with catecholamines. It has been reported that the administration of olprinone before ischemia could lead to a reduction in myocardial infarct size in dogs 11 and rats 12,16 . Use et al 17 showed that milrinone, a PDE3-I, administered before ischemia or just after reperfusion, attenuates myocardial stunning in swine.…”

“…The methods used were as described in our previous report 12 . Male Sprague-Dawley rats weighing 455 ± 33 g (mean ± SD) and aged 14 ± 1 weeks were anesthetized with sodium pentobarbital, a 50 mg/kg intraperitoneal bolus, followed by intravenous infusion at 10-20 mg/kg/h.…”

Expressão do precondicionamento isquêmico em pacientes com diabetes mellitus tipo 2 e doença arterial coronariana

“…Há trabalhos que sugerem que o diabetes interfere negativamente sobre o PI (37,(42)(43)(44)50,51) , enquanto outros indicam a preservação deste mecanismo cardioprotetor em modelos com diabetes (39,40,43,52,53) .…”

“…Ainda que alguns trabalhos experimentais demonstrem que o diabetes pode alterar algumas vias intracelulares do PI, como as vias da quinase 3 do fosfatidil-inositol (37) ou a função dos canais de potássio dependentes de ATP (38) , prejudicando a expressão do PI, o conjunto destes estudos experimentais tem demonstrado resultados conflitantes (39) . Mesmo que alguns trabalhos demonstrem que o diabetes não interfere substancialmente no PI (40,41) , muitos sugerem influência negativa (42)(43)(44) . (17,18,45) .…”