Department of Pharmacology

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Myocardial reperfusion is a common clinical event and occurs during the management of acute coronary syndrome or acute myocardial infarction when coronary perfusion of the affected region is re-established using drug, non-surgical, or surgical interventions. While reperfusion usually results in excellent recovery of LV contractile function, clinical outcomes are less than optimal in patients with hearts stressed by previous ischemia or other risk factors (smoking, diabetes, obesity, advanced age), or where reperfusion is delayed. We investigate mechanisms of reperfusion injury and aim to identify novel drug targets to improve recovery and limit longer-term adverse outcomes of ischemic injury.

Our unique experimental approach uses model systems to examine key mechanisms that 1) affect recovery of LV mechanical and metabolic function, 2) regulate Na⁺ and Ca²⁺ homeostasis, and 3) influence infarct size. Drug-effects on mechanical function (LV work, O₂ consumption, cardiac efficiency), metabolic function (rates of energy substrate metabolism), intracellular Ca²⁺ overload, and infarct size are measured along with cell signaling events that regulate pathways of glycogen and glucose utilization (GSK-3β, PFK, AMPK, NOS, p38MAPK, and PKB).

Current Projects:
Cardioprotection by adenosine: We are investigating the molecular mechanisms underlying the regulation of glycogen and glucose metabolism by adenosine receptors in normal hearts and in hearts altered by acute ischemic stress or by impaired insulin signaling. We also examine how attenuation of acidosis arising from excessive rates of glycolysis limits intracellular Ca2+ overload and thereby improves LV function.
Cardioprotection by late INa inhibition: An additional mechanism that leads to intracellular Ca²⁺ overload is delayed inactivation of the voltage-gated Na⁺ channel that generates a persistent inward current (termed late I_Na) that leads to Na⁺ accumulation and activation of reverse mode Na⁺-Ca²⁺ exchange. We are investigating 1) metabolic and other mechanisms that augment late I_Na and, 2) the cardioprotective effectiveness of inhibitors of late I_Na.

Soliman, D., Wang, L., Hamming, KS., Yang, W., Fatehi, M., Carter, CC., Clanachan, AS., Light, PE. (2012) Late sodium current inhibition alone with ranolazine is sufficient to reduce ischemia and cardiac glycoside-induced calcium overload and contractile dysfunction mediated by reverse-mode sodium/calcium exchange. J. Pharmacol. Exp. Ther. 343(2), 325-332.

Omar, MA, Verma, S., Clanachan, AS. (2012) Adenosine-mediated inhibition of 5'-AMP-activated protein kinase and p38 mitogen-activated protein kinase during reperfusion enhances recovery of left ventricular mechanical function. J. Mol. Cell Cardiol. 52(6), 1308-1318.

Ussher, JR., Wang, W., Gandhi, M., Keung, W., Samokhvalov, V., Oka, T., Waggs, CS., Jaswal, JS., Harris, RA., Clanachan, AS., Dyck, JR., Lopaschuk, GD. (2012) Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury. Cardiovasc. Res. 94(2), 359-369.

Zaugg, M., Wang, L., Zhang, L., Lou, PH., Lucchinetti, E., Clanachan, AS. (2012) Choice of anesthetic combination determines Ca2+ leak after ischemia-reperfusion injury in the working rat heart: favorable versus adverse combinations. Anesthesiology. 116(3), 648-657.

Lucchinetti, E., Bestmann, L., Feng, J., Freidank, H., Clanachan, AS., Finegan, BA., Zaugg, M. (2012) Remote ischemic preconditioning applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass graft surgery: lack of synergy or evidence of antagonism in cardioprotection? Anesthesiology. 116(2), 296-310.

Lucchinetti, E., Wang, L., Ko, K.W., Troxler, H., Hersberger, M., Zhang, L., Omar, M.A., Lopaschuk, G.D., Clanachan, A.S. & Zaugg, M. (2011) Enhanced glucose uptake via GLUT4 fuels recovery from calcium overload after ischaemia-reperfusion injury in sevoflurane- but not propofol-treated hearts. Br. J. Anaesth. 106(6), 792-800. PMID: 21474475.

Wang, L., Ko, K.W., Lucchinetti, E., Zhang, L., Troxler, H., Hersberger, M., Omar, M.A., Posse de Chaves, E.I., Lopaschuk, G.D., Clanachan, A.S. & Zaugg, M. (2010) Metabolic profiling of hearts exposed to sevoflurane and propofol reveals distinct regulation of fatty acid and glucose oxidation: CD36 and pyruvate dehydrogenase as key regulators in anesthetic-induced fuel shift. Anesthesiology 113, 541-551. PMID: 20683255.

Omar, M.A., Wang, L. & Clanachan A.S. (2010) Cardioprotection by GSK-3 inhibition: role of enhanced glycogen synthesis and attenuation of calcium overload. Cardiovasc. Res. 86, 478-486. PMID: 20053658.

Folmes, C.D., Wagg, C.S., Shen, M., Clanachan, A.S., Tian, R. & Lopaschuk, G.D. (2009) Suppression of 5'-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts. Am. J. Physiol. 297, H313-H321. PMID: 19429810

Wang, L., Lopaschuk, G.D. & Clanachan, A.S. (2008) H2O2-induced left ventricular dysfunction in isolated working rat hearts is independent of calcium accumulation. J. Mol. Cell. Cardiol. 45, 787-795. PMID: 18817782.

Omar, M.A., Fraser, H. & Clanachan, A.S. (2008) Ischemia-induced activation of AMPK does not increase glucose uptake in glycogen-replete isolated working rat hearts. Am. J. Physiol. 294, H1266-H1273. PMID: 18178721.