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Note to Users NOTE TO USERS Page(s) not included in the original manuscript and are unavailable from the author or university. The manuscript was microfilmed as received. This reproduction is the best copy available. EFFECT OF COMBINATION POT.-i\SSIL'bI CHANNEL BLOCKERS ON CARDIAC REFEb$.CTORINESS IN ISOLXÎED RABBIT HEARTS AND NTACT GUI'IE.4 PIG HE.4RTS A thssis submitted in conformit>.with the requiremrnts for the degres of hlastrr of Science Graduate Depanment of Medical Science Universit). of Toronto O Copyright by Nikolaos Marnalias 200 1 National Libraiy Bibliothèque nationale du Canada Acquisitions and Acquisitions et Bibliogrâphic Senrices services bibliographiques The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distntbute or sell reproduire, prêter, distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/film, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts from it Ni la thèse ni des extraits substantiels may be printed or otherwise de ceiieîi ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. EFFECT OF COMBINATION POTASSIUM CHANNEL BLOCKERS ON CARDIAC REFRACTORiNESS IN ISOLATED RABBIT HEARTS AND iNTACT GUiNEA PIG HEARTS NIKOLAOS MAM.4LIAS MASTER OF SCIENCE 200 1 GRADUATE DEPARTMENT OF MEDICAL SCIENCE LJNIVERSITY OF TORONTO ABSTRACT Dofetilide and sotaiol prolong ventricular refractorinrss by blocking the rapidly açtivating delayrd rectitier potassium channel (Ikr). In vitro studies suggest that dofetilide blocks the Ikr channel in the open state. whereas sotalol may block the closed state. We tested whethrr this potential dittrrential statr-dependent blockade could br pharmacologically distinguishrd bu altering Ikl currrnt density. Sotalol (4 PM) and dofetilide (8 nM) were given alone and in combination with 3 pM barium (Ikl blocker) to isolated perfused Langendorff rabbit hearts (n=8 per group). Ventricular effective refractory penod (VERP). action potential duration. vèntricular tibrillation cycle length. and defibrillation threshold were measured pre and post drug'vehicle treatment. The VERP was prolonged with dofetilide. sotalol. barium. combination dofetilide plus barium. and sotaloi plus barium by 10?6%. 8e%. 7+3%. I-l+j0'o. and 824%. resprctively (~~0.01 ). The cffect of dofetilide plus barium on VERP was additive. whereas sotalol plus barium was no different than each drug alone: this interaction was qualitatively the same for al1 other variables measured. This is the fint study to show that different Ikr blockers have differîng effects when combined with another potassium channel blocker. ACKNOWLEDGEMENTS The completion of rhis thesis is my grearest scholastic accomplishmenr to dore. and I ivould like to ocknowledge the conrribirtions of severul indiricfurrls to rhis research. It is wirh sincere gratitlrde rhat I rhank Dr. Paul Dorian for providing an environment conducive [O learning and scientifc inquiry. His scientific reachings und kind, genuine. strong moral support isill never be forgotfen. He rvas not only o mentor, but also a role mode1 thut exposed me [O the medical world oitfside the specificity of'my research. Throughout my gradirate rraining he helped me develop criricul thinking und problem solving skills. ivhich I ivillfind inwliruble horh in a crrreer in medicine. und rvhile encounrering chrrllrnges txprrirncrtl in lifè. I would dso like tu rhonk Drs. David Yrwman anJ Perer Buck fur fheir gui~krnce as Program Advisory Cumrnitter membrrs for the diirariun ofhy reseurch. Their inqtrisitive nature und consrnrcrive !kedbock grearly broadened rhe scope ofrny knoivledge. It was rheir conrinuoirs encourugemenr thut hrlprd nie upprouch nerv chullenp wirh conjidence. The help of Dr. .Yiungqinn Qi rvill rrhvcrjs h rememhered. us he sirpentsed tny rrork in rhe rinimui luborurory. He rvas u greur terrcher nor only of'rirrgicaf mrrhods, hirt rrlso of anest iesia. ctrrdiology, unJ concepts in rlr~*trophy.siolo p. Hi.s cissis~rin~~fi~rnied rht. groirndrivrk of'rstuhlishing the jirsr elecrrophysiologic infacfgttineu pig hrurr rnocirl. The ncrrurr o#:hispedtrgo~~ iius wirh good hrrrnoiir und enthir.sirrsm. ivhich helped me rnzhrace my rwrk dzrri>~prhe musi diffictrfr rimes. I um very graiejirljor the bcisic science rmhings in cdiac e1ectrophysiulog-y uf' Ur. Rafid Rumirez (Ph.D. ctrndiciurr) mdfor rhe crssistunce in rhe oninial lcihoruroq. of !W.Cumeron Smirh (,Cf.Sc.cuntlidure~ over rhe l~isrycrr oj'mv resrcirch. I.fC.rl privilrpd ro itoiw collrburared ri+i!lithese two j~tniorrcicntisrs who gwdy wlire rhr tool 91' research us a meuns of-de fermining the ~rzrrh. I thank Drs. Gil Gross. Perer Pennefirther, Robert Tsirshirnu. and Sirsan Belo /or rhe ir r ivocio us prrrt icipu ion in my M.Sc. Oral Ermninarion. Their us.sis~unceut rr rnornenr 's no rice. und rheir inrerest in my resecrrch lefi rin impression !rit il1 not soon forger. The rrajj'of 'SI. Mchd S Hospital Reseurch CÏwrirrm >vusrhe sole pro vider of' onimul cure and laborutory safety. The experinrenis presented in this thesis woitld not have been possible ivirhout their splendid dedicution to proper luborutory practices. Finally, I rioirld iike ro express my grorirzrde roivords the Grathrare Depurzmenr 01' rhe Insrirzrre of Medicol Science nt rhe Lniversih*of' Torontojbr proiiding me with the opporrunihfro ohtuin my .\laster of'Scirnce degrre. and to shme the knoii.ledge g~rinrd over rhe coirrse of my research ivirh scientisrs across the continent. As a new grahrire. I will enduringiy ucr as an advocate ojthe Deparmenr and rhe University. TABLE OF CONTENTS .. Abstract ..................................................................................................................................il Ac knowledgements ........................................................................................................... iii List of Tables ..................................................................................................................... xi List of Figures .................................................................................................................. xiv... List of Abbreviations ..................................................................................................... xvrii Dedication ....................................................................................................................... 'cxi 1.1 The Cardiac Action Potential ................................................................................1 1.1.1. The Resting Membrane Potential .................................................................... 2 1.1.2. Phases of the Action Potential .................................................................. 2 Il3. The Delayed Rectifier Potassium Current ......................................................5 1 .1. 4. The Inward Rectifier Potassium Current ..................................................... II 1 1 Determinanis of Impulse Propagation (Conduction) ............................. ....... 1 1 1 .l.6. Detenninants of Ventricular Refractoriness ................................................. 1-3 1 .l. 7. Measures or' Ventricular Refractoriness ........................................................ 14 1.2. Mechanisms of Arrhythmias ............................................................................. 13 1 .2. 1 . Abnomal Automaticity ................................................................................ 16 1.2.1. Triggered Activity ......................................................................................... 16 1.23. Rrrntry ..........................................................................................................17 1.3. Modulating Cardiac Refractoriness ...................................................................... 19 1 3.1 . Antiarrhythmic Drugs ................................................................................... 19 1.3.2. The Effect of .4 ntiarrhythmic Dnigs on Cardiac Refractoriness .................. 21 1.3.3. The Effrct of Class 1 Antiarrhythmic Drugs on Cardiac Refractoriness ...... 23 1.4. The Effect of Class II Antiarrhythmic Drugs on Cardiac Rrfractorinrss ..... 24 1.3.5. The Effect of Class III Antiarrhythrnic Drugs on Cardiac Refractoriness .... 3 1 6.The Effect of Class IV Antiarrhythmic Dnigs on Cardiac Refractonness ... 38 1 .4. Ventricular Fibrillation - A Reeatrant Arrhythmia ........................................... 29 1.4.1. Initiation of Ventricular Fibrillation ............................................................. 29 1.4.2. Maintenance of Ventricular Fibrillation ....................................................... 31 - . 1A.3. Ventricular Detibnllation .............................................................................. 32 1.4.3.1. The Critical Mass Hypothesis .................................................................. 33 I .4.3.2. The Upper Limit of Vulnerability Hypothesis ......................................... 34 1.4.3.3. The Refiactory Penod Extension Hypothesis ........................................ 34 1.4.3.4. The Threshold of Synchronous Response Hypothesis ............................
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