Date of Award
1995
Degree Type
Dissertation
Degree Name
Doctor of Philosophy
Abstract
Protein kinase C has been implicated as a mediator of myocardial function following both physiological and pathophysiological stimuli. The purpose of the present study was to examine the functional effects of PKC in mediating phorbol esters as well as receptor-induced effects in myocardial tissues. Additionally, the possible role of PKC in mediating cardiac pathophysiology was assessed under conditions which mimicked aspects of myocardial ischemia/reperfusion. The effects of phorbol esters on cardiac function were assessed in isolated perfused guinea pig hearts. The effects of phorbol esters, acidosis/realkalinization and hydrogen peroxide were assessed in isolated guinea pig ventricular myocytes to determine PKC-dependent changes of intracellular Ca{dollar}\sp{lcub}2+{rcub}{dollar} and unloaded cell shortening in single cells by the technique of fluorescence microscopy. The effects of receptor-mediated PKC activation by phenylephrine and endothelin-1 (ET-1) on intracellular Ca{dollar}\sp{lcub}2+{rcub}{dollar} and cell shortening were examined in isolated rabbit ventricular myocytes.;The results of this study demonstrate that in whole hearts, phorbol esters exert concentration-dependent positive and negative inotropic effects. These concentration-dependent effects are paralleled by both increases and decreases in intracellular Ca{dollar}\sp{lcub}2+{rcub}{dollar}, respectively, in isolated guinea pig myocytes. Additionally it was shown that although both phenylephrine and ET-1 increase intracellular Ca{dollar}\sp{lcub}2+{rcub}{dollar} and cell shortening, different cellular PKC-dependent pathways are involved. Studies examining the effects of acidosis and realkalinization have shown that inhibition of the N{dollar}\sp+{dollar}/H{dollar}\sp+{dollar}-exchanger, during both acidosis and realkalinization, enhances functional recovery of isolated guinea pig myocytes. Additionally, this study demonstrates that H{dollar}\sb2{dollar}O{dollar}\sb2{dollar}-induced increases of intracellular Ca{dollar}\sp{lcub}2+{rcub}{dollar} and cell shortening can be attenuated by PKC inhibitors suggesting a PKC-dependent component of the effects of H{dollar}\sb2{dollar}O{dollar}\sb2{dollar} exposure.;The results of this study demonstrate that the role of PKC on myocardial function are complex. Furthermore, the PKC-dependence of observed effects varies significantly by the activating stimulus. From this study, it can be concluded that PKC is involved in mediating the physiological responses of receptor-mediated agonists as well as pathophysiological stimuli associated with myocardial ischemia and reperfusion.
Recommended Citation
Ward, Christopher Andrew, "Role Of Protein Kinase C In Mediating The Effects Of Physiological And Pathophysiological Interventions In The Heart" (1995). Digitized Theses. 2516.
https://ir.lib.uwo.ca/digitizedtheses/2516