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Ischemic heart disease. hypoxia and reoxygenation. metabolic control of coronary circulationThe major objective of our research is to determine the roles of physiologically important regulators in the control of coronary circulation and ventricular rhythmicity. Our main focus has been on the role of the adenine nucleoside. adenosine. We have also examined regulators such as estrogen. We routinely use hypoxia and ischemia and reperfusion to challenge the heart before and after interventions designed to augment or attenuate the actions of adenosine. estrogen. etc. We have shown that adenosine deaminase (ADA). the enzyme that inactivates adensine by removing an amino group from the purine ring. is a good research tool for investigating the regulatory roles of adenosine. For example. we hypothesized that myocardial release of adenosine contributes significantly to the coronary vasodilation caused by regional hypoxia in the anesthetized. instrumented dog. To test this hypothesis. we pretreated dogs with commercially-available ADA before causing regional myocardial hypoxia. Coronary circulatory responses to hypoxia were significantly attenuated in the presence of administered ADA. In more recent years we hypothesized a role for adenosine in the ventricular arrhythmias caused by systemic hypoxia. Using administered ADA. we saw a significant reduction in the incidence of ventricular arrhythmias caused by hypoxia. Blocking the actions of endogenous ADA with erythro-9-(2-hydroxy. 3-nonyl) adenine (EHNA) significantly increased the incidence of hypoxia-induced ventricular arrhythmias. Most recently. we have found that the acute pretreatment of dogs (both male and female) with estrogen markedly and significantly attenuates the ventricular arrhythmias caused by regional myocardial ischemia and reperfusion. We plan to continue these lines of research in the future. Selected PublicationsHadzimichalis, N.M., Baliga, S.S., Golfetti, R., Jaques, K.M., Firestein, B.L. and Merrill, G.F. (2007) Acetaminophen-mediated cardioprotection via inhibition of the mitochondrial permeability transition pore-induced apoptotic pathway. Am J Physiol Heart Circ Physiol 293: H3348-55. Merrill, G.F., Merrill, J.H., Golfetti, R., Jaques, K.M., Hadzimichalis, N.S., Baliga, S.S. and Rork, T.H. (2007) Antiarrhythmic properties of acetaminophen in the dog., Exp Biol Med (Maywood) 232: 1245-52. Koc A. Mathews CK. Wheeler LJ. Gross MK. Merrill GF. (2006) Thioredoxin is required for deoxyribonucleotide pool maintenance during S phase. J Biol Chem. 281(22):15058-63. Rork TH. Hadzimichalis NM. Kappil MA. Merrill GF. (2006) Acetaminophen attenuates peroxynitrite-activated matrix metalloproteinase-2-mediated troponin I cleavage in the isolated guinea pig myocardium. J Mol Cell Cardiol. 40(4):553-61. Spiler NM. Rork TH. Merrill GF. (2005) An old drug with a new purpose: cardiovascular actions of acetaminophen (paracetamol). Curr Drug Targets Cardiovasc Haematol Disord. 5(5):419-29. Rork TH. Van Dyke K. Spiler NM. Merrill GF. (2004) Acetaminophen in the hypoxic and reoxygenated guinea pig myocardium. Exp Biol Med (Maywood). 229(11):1154-61. Merrill GF. Rork TH. Spiler NM. Golfetti R. (2004) Acetaminophen and myocardial infarction in dogs. Am J Physiol Heart Circ Physiol. 287(5):H1913-20. Golfetti R. Rork T. Merrill G. (2003) Chronically administered acetaminophen and the ischemia/reperfused myocardium.Exp Biol Med (Maywood). 228(6):674-82. Golfetti R. VanDyke K. Rork T. Spiler N. Merrill G. (2002) Acetaminophen in the post-ischemia reperfused myocardium. Exp Biol Med (Maywood). 227(11):1031-7. Merrill GF. (2002) Acetaminophen and low-flow myocardial ischemia: efficacy and antioxidant mechanisms. Am J Physiol Heart Circ Physiol. 282(4):H1341-9. Merrill GF. Goldberg E. (2001) Antioxidant properties of acetaminophen and cardioprotection.Basic Res Cardiol. 96(5):423-30. Merrill G. McConnell P. Vandyke K. Powell S. (2001) Coronary and myocardial effects of acetaminophen: protection during ischemia-reperfusion. Am J Physiol Heart Circ Physiol. 280(6):H2631-8. |
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