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In Partial- Fu1fílnent of the Requirenents for the Degree Of EFFECT8 OF CHRONIC VERÀPÀ¡,ITIJ ÃDMINISTRÀTION ON EIIE BIOCHE¡,ÍICAL CIIÀRACTERISTICS OF TTÍE IJ-TYPE CAIJCIUM CHÄNNEI.¡ BY BIJAIR BURTON IJONSBERRY A Thesis Subnitted to the Facul-ty of Graduate Studies in Partial- Fu1fílnent of the Requirenents for the Degree of Masters of science Departnent of Physiol-ogy Faculty of Medicine University of Manitoba Winnipeg, Manitoba Septenber, 1993 Bibl¡othèque nationale K*& |,*lå!';o^o du Canada Acquisitions and Direction des acquisitions et Bibliographic Services Branch des services bibliographiques 395 Wellinoton St¡eet 395, rue Wellinglon onawa, oñtario Onawa (Onlarjo) KlA ON4 K1A ON4 Out l¡le No¡rc ftlè¡e.ce The author has granted an L'auteur a accordé une licence írrevocable non-exclusive licence irrévocable et non exclusive allowing the National Library of permettant à la Bibliothèque Canada to reproduce, loan, nationale du Canada de distribute or sell copíes of reproduire, prêter, distribuer ou his/her thesis by any means and vendre des copies de sa thèse in any form or format, making de quelque manière et sous this thesis available to interested quelque forme que ce soit pour persons. mettre des exemplaires de cette thèse à la disposition des personnes intéressées. The author retains ownership of L'auteur conserve la propriété du the copyright in his/her thesís. droit d'auteur qui protège sa Neither the thesis nor substantial thèse. NÍ la thèse ni des extraits extracts from it may be printed or substantiels de celle.ci ne otherwise reproduced without doivent être imprimés ou his/her permission. autrement reproduits sans son autorisation. ISBN 0-315-85935-0 C¿nadä Nt^-- Disserlolion Abstrqcls lnlernolionolis orronged by brood, g{nerol subiect cotegories. Pleose select the one subject which most neorly describes lhe conlent of your disserlolion. Enter lhe cdrresponding four-digit code in lhe spoces provided. \)h¡r¡ìur .;#i+* ffi UN/Í.I Ancien|.............. ................0579 Medievoj ............................0581 Modern ..............................0582 81ock....... ..........................0328 Africon ............................,..0331 Asio. Ausl¡olio oñd Ocenio 0332 Conódion .... .. .. .. .. 033¿ Eurooeon............................0335 1orin Americon.................... 033ó Middie Eostern....................0333 unired-srores....................... QqlZ Hrllôry ôl s.ren.e ()5¡15 Low..l. .... .. .. 0398 PoliricolScience Genero|..............................0ó15 ìnternolionol Low ond Re|orions..........................0óló Public Adminislrolion...........0ól 7 Recreorion ................................081 4 sociol wôrk ............................. 0¿52 Geni¡ol .............................. oó2ó C¡iminolw ond Penoløv 0ó27 Demooroôlív................"..1....0ç¡e Ethnic-onil Éociol Studies.....0ó31 lnd iduolond Fomilv súdies ...............:............0ó28 lnduslriolond Lobo¡ Relotìons..........................0ó29 Puhlic ond Sociol Welfqre....0ó30 SocìolStruclure ond Devêloornent................... 0700 Thmru ¡ld Marhod< 0-3ÀÀ TronsDod¿:rion ..........................O7O9 UrboÄ ond Roionol Plonnino . 0999 women's Studres ...............1..... o¿s¡ ÎI{E SGIEN€Eg ANÞ E}¡@¡NEER¡hIG 0t0GtGt sc t(r5 " cenero|..............................0¿23 Ao¡onomv..... ...... .............0285 añ¡molcilture ond Nukilion..........................0¿25 ,Animol Potlol(w. ........ O47ó ræd science oñâ Tshnoløv ...................... 0359 Fo,erry onðwldli{€ ........... 0¿78 Plont Cultu¡e .......................0479 flont lothology ................... Q!8Q Plônl Phv3iôlôov ..................O8 I / Ro¡n¡ únnnn-pncnr 0777 woãd Te<hnå|osy ............... 07¿ó Biol(w dámrcl o30ó Anoromv ........... ................0287 Eioslori!íics .. .....0308 8o1ony................................0309 cel| ..1.............. ...... ...........0379 Ecolæv O329 Entomi|oov........................ 0353 Genêr;.s:1....... ......... .... .03ó9 timnoløv 0793 Mic¡obiðfocv ...................... oal o Mol<ulor ll .. .......0307 Neu¡oscience...................... 031 7 ocænæ¡oohv. .............041ó phvsioloìóv :...1..................... 0433 Rdiiiôrio;' .... ............0821 Vêlêrinôñ S.iencê 0778 Bioohvsìcí' (Jenerô1.._...._...._........._.......u/ðô Medicol..............................0Zó0 tÂRTH SCttN([S Biôoêô<hemislry........ .. .. 0¿25 ce&hemisr¡/ .i......................... 099ó EFFECTS OF CERONIC VERAPAHIL ADMINISTRATION ON TEE BIOCEEMICAL CEARACTERISTICS OF THN L-TYPE CÂ],CIUI'Í CEÄNNEL BY BLAIR BTIRTON LONSBERRT A Thesis submitted to the Faculfy of G¡aduate Studies of the University of Manitoba in partial fuUillment of the requirene-nts for the degree of ÈIASTER OF SCIENCE @ 1993 Pen¡rission has been granted to the IIBRÄRY OF TI{E TINTyERSITY OF MA\TTOBA to lend or seII copies of ii.ís thesis, to the NAIONAL LIBRåRY OF OINADÄ to microfilm this thesis ¡nd to lend or sell copies of the 61m,. and LINTT¡ERSITY MIG'OEIL¡VS to publish ar ÂbsEact of ihis thesis. The autåor ¡ese¡r¡es other publications rights, and neithe¡ the thesis nor ertensive exbacts Êom it may be printed o¡ otherwise rtproduced without the autho/s pe¡srjssíon rÀBLE OF CONTENTS Page Acknowfedgements. i Abstract. ii List of Tabl-es. lv List of Figures. v I. INTRODUCTION. II. REVIEI{ OF I.IItrER.ATURE A. EXCÏTATION-CONTRACTION COUPLING. 7 l-. Cardiac muscle. 7 2, SkêIeta] muscLe. 15 3. Smooth muscle. 2e B. CAIJCIUM AND THE CALCTUM CHÀNNEI.,. 26 1. Calciun (i) Rol-e of calcium. 26 2. Calcium Channels (i) Types and Location. 29 (a) T-type caLciu¡n channels. 29 (b) N-type calciun channels. 30 (c) P-type caLciu¡n channels. 31 (d) L,-type cafciun channels. 32 (e) Skel-etal nuscle. JJ (f) cardiac nuscle. 36 (S) Snooth muscLe. 38 (ii) Ion movement through cafcium channels.... 39 (iii) Regulation of cal-cj-urn channel activity.,. 4L (iv) Rêgulat.ion of calciurn channel density.... 45 (a) Circulating drugs/hornones. (b) Disease states. 50 c. CALCIIIM CHANNEI-J ANTAGONTSTS 1. History. bl- 2. Classification. , . 53 3. Mêchanism of action. 56 4. Clinícal- application 64 XII. I'ÍATERIÀI.,S Àì¡D METITODS A. Methods l-. Drug treatnent protocol..... 70 2. Radioligand binding. 7L 3. Verapamil quantitation. 4. Statistical anaLysis. 73 B. Materj-als. 73 IV. RESULTS 1. Plasma verapamil and metaboLite quantitation and mortality data for the various drug adrninstratj-on protocols. 75 t Analysis of t3HlPN 2oo-11o binding characterj-stics in cardiac and brain tissues fron 2-week veraparnil implanted and injected rats (17.9 n.g/kg/day) ...,.. a7 3. Anafysis of [3H]PN 2oo-110 binding characteristics ín cardiac, brain and skeletal nuscle tissues and plasna veraparnil concentrations after a constant s.c. vêrapamíI injection from 2-16 $reeks. 90 Analysis of [3H]PN 2oo-110 binding characteristics in cardiac, braín and skeletaL muscl-e tissues and plasna veraparnil concentrat.ions after varying s.c. veraparnil injections (2.5 to 30 ng/kg/day)... 90 .Analysis of [3H]PN 2oo-l-10 binding characteristics in cardiac tissue and pLasna veraparnil ::::::::::l:::. :::::. ::::. ::il:.i:::?::. il.rîilfiT";^ 6. Influence of veraparnil treatÌnent on al-losteric interactions between the dihydropyrídine and phenylalkyla¡nine binding sites. 99 vr. DrscussroN. ... 106 VII. REFERENCES. ".. 1.18 ACKNOWIJEDGE¡'ÍENTS The years that went into the completion of this thesis vras not an indívidual- effort, but a col-l-aboration of several peoples hard \^rork and tal-ents. There are severaL individuals r¡/ho have helped me enornously in the last several- years. I r^rould like to extend my gratitude to Deborah Dubo, Mike Czubryt, James Gilchrj-st, John Docherty, Shoba Thomas and Thane Maddaford for their help and friendship. To my committee rnernbers Dr. Parvan Singal, Dr. Paul Ganguly and Dr. Angel Zarain-Herzberg r I hrould like to thank the¡n for their encouragement and acade¡nic expertise throughout ny years here. .Forenost, I would like to thank rny advisor and friend, Dr. Grant Pierce. crant allowed ne the opportunity to start, continue and finish the years necessary to put together rny thesis, He took a chance on ne that others might not have, and he was afways there, providing support and encouragement. Final-1y, I v¿ould like to thank ny parents, farnily and friends who have always encouraged me to continue and strive for something better. Thanks for being there. ABSTRACT The Ca2+ channef antagonists are an inportant group of drugs used in the treat¡nent of a variety of clinicaf diseases. Patients are often on long-term treatment regimens in order to treat their particular disorder. The purpose of this study was to determine if chronic adrninistration of verapamil 1a ca2+ channel antaqonist) could ålter the biochemical characteristícs of the L-type Ca2+ channêl- as deternined ly ¡3H1rN 200-110 binding. Various modes of drug administration such as inplantable sl-ot¡-release pellets, s.c. injection and oral dosages vtere tested as means of raising plasma veraparnil l-evels. Circulating pl-asna verapamil fêvêls obtained from rats irnplanted with slo\^r-release verapanil pellets often reached levels l-0 fofd higher than s.c. injections and oraL dosages. In addítion, large quantities of the drug lvere rel-eased within the first 24 hours post-irnplantation, resulting in a high rnortality rate in these animals. It was concluded that inpfantable slol^r-release pellets are an unreliabÌe means of veraparnil ad¡ninistration. The bioche¡nicaI characteristics of cardiac, brain and skeletal muscle tissue all appear to be very resistant to al-teration by chronic veraparnil treatment. Variations in drug dosage
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