Coronary Collateral Angiogenesis: A diseased coronary artery may become occluded over time, but despite total block of antegrade flow, perfusion of myocardium distal to the occlusion still remains. This flow arises from newly developed collaterals from other coronary arteries surrounding the ischemic zone. The pathophysiological mechanisms involved in coronary collateral growth are presently being studied in conscious, chronically-instrumented large animals. Angiogenesis in the ischemic region is induced by repetitive brief coronary artery occlusions (a 2 minute occlusion each hour for 8 hours each day). The degree of coronary collateral development over time is assessed by contractile function (poor in the absence of coronary collaterals and normal in the presence of adequate collateralization), the reactive hyperemic response following each brief coronary occlusion (high in the absence of collaterals and markedly diminished or absent with adequate collateralization) and myocardial blood flow using the radioactive microsphere technique. Pharmacological agents are studied in an effort to enhance or attenuate coronary collateral development. In addition, by means of a microdialysis technique, interstitial fluid can be harvested from the ischemic zone at regular intervals. The mitogenic activity of the dialysate is quantified in vitro by its ability to stimulate isolated vascular smooth muscle cells or endothelial cells grown in tissue culture. The presence of various growth factors can be established by molecular techniques. Thus, this project aims to determine pathophysiological mechanisms involved in coronary collateral angiogenesis within ischemic myocardium, and whether the growth of vessels can be altered to produce beneficial or detrimental effects. The use of growth factors in the diseased coronary circulation may offer a new and unique therapeutic strategy to protect ischemic myocardium from irreversible tissue injury.
Left Ventricular Failure: Systolic and diastolic ventricular function before, during and after development of severe left ventricular failure are studied in chronically-instrumented large animals. Cardiomyopathy is produced by rapid ventricular pacing over a period of 3 weeks. The temporal sequence of alterations in systolic function, left ventricular filling dynamics and ventriculo-arterial coupling are studied. Alterations in coronary artery blood flow produced by pharmacological agents in the absence and presence of failure are assessed. The mechanisms of changes in coronary perfusion early and late during development of left ventricular failure and their relationship to vascular endothelial dysfunction are determined. New positive inotropic agents with unique mechanisms to enhance left ventricular contraction and relaxation are presently being studied.
Mechanisms of Cardioprotective Actions of Volatile Anesthetics: Commonly used volatile anesthetic agents have been found to have marked cardioprotective properties against myocardial stunning and infarction. The protective effects of these drugs are only partially related to changes in myocardial oxygen supply and demand relationships. Volatile anesthetics appear to pharmacologically precondition myocardium against ischemic and reperfusion injury. The mechanisms of enhanced recovery of contractile function following a brief coronary artery occlusion, and reduction of myocardial infarct size following prolonged occlusion by volatile anesthetics are presently being studied. The interactions of volatile anesthetics with adenosine receptors, ATP-dependent potassium, intracellular kinases and reactive oxygen species are active areas of investigation.
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Wang, C., Weihrauch, D., Schwabe, D.A., Bienengraeber, M., Warltier, D.C., Kersten, J.R., Pratt, P.F. and Pagel, P.S.: Extracellular signal related kinases trigger isoflurane preconditioning concomitant with upregulation of hypoxia-inducible factor-1α and vascular endothelial growth factor expression in rats. Anesth. Analg. 103:281-288, 2006.
Venkatapuram, S., Wang, C., Krolikowski, J.G., Weihrauch, D., Kersten, J.R., Warltier, D.C., Pratt, P.F. and Pagel, P.S.: Inhibition of apoptotic protein p53 lowers the threshold of isoflurane-induced cardioprotection during early reperfusion in rabbits. Anesth. Analg. 103:1400-1405, 2006.
Ljubkovic, M., Mio, Y., Marinovic, J., Stadnicka, A., Warltier, D.C., Bosnjak, Z.J. and Bienengraeber, M.: Isoflurane preconditioning uncouples mitochondria and protects from hypoxia reoxygenation. Am. J. Physiol. 292:C1583-C1590, 2007.
Amour, J., Brzezinska, A.K., Weihrauch, D., Zielonka, J., Warltier, D.C., Pratt, P.F. and Kersten, J.R.: Role of heat shock protein 90 and endothelial nitric oxide synthase during anesthetic and ischemic preconditioning. Anesthesiology 110:317-325, 2008.
Zhang, R., Mio, Y., Pratt, P.F., Lohr, N., Warltier, D.C., Whelan, H.T., Zhu, D., Jacobs, E.R., Medhora, M. and Bienengraeber, M.: Near infrared light protects cardiomyocytes from hypoxia and reoxygenation injury by a nitric oxide dependent mechanism. J. Mol. Cell. Cardiol. 46:4-14, 2009.