van Amsterdam, Franciscus Theodorus Maria

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   University of GroningenMolecular pharmacology of calcium antagonists in the normal and ischaemic heartvan Amsterdam, Franciscus Theodorus MariaIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1988Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):van Amsterdam, F. T. M. (1988). Molecular pharmacology of calcium antagonists in the normal andischaemic heart. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 13-02-2023S U M I - í A R YThe disturbance of the normal coronary Derfusion of the heart as a result ofthrombosis, atherosclerosts and coronary yascular spasms is one of the maJondirect causes of cardiac tschaemtc diseases l ike angtna pectorls and cardtacin fa rc t ions ,  Ca lqum antagon is ts ,  wh ich  pr rmar i l y  inh ib i t  the  so  cê l ied  s lowcalcium channels in the plasma membrane, are a relat iyely new group of drugsused in the treatment of cardlac and coronary drseases. They not only tmprovethe supDly of blood to the myocardium (due to therr vasodrlat ing effects), butl imit the energy need of the heart through a negative inotropic effect ênd theyshow some anttarrhythmtc activi ty as well .In this thesis the effects of the prrncipal classes of calcium antagonrsts(v{i th nrfedigine, verapamii,  di l t iazem and bepridi l  ês representatives) on thecoronary vasculature (vasodilatat ion) and the myocardaum (negatiye inotroprsm)are studied in the normal and ischaemtc rat heart,  A coronary Derfusron moclelof the heart was chosen, as described original ly in 1897 by oscar Langendorff ,in which the changes in coronary f low as well  as in myocarcl ial  contracti l r tycan be measured stmultaneously, lschaemia was induced by a comDlete cessattonof the coronary f low,Large dif ferences in yasoselectivi ty were found among the vartous calctumantagonrsts, For several compounds i t  was observed that the enantiomers showeda dif ferent stereoselectiyi ty tovíards the coronary vasculature and the myocar-dium, Furthermore, the Krnetrcs of the effects of these drugg on the coronaryvasculature (f low rncrease) appeared to be much faster than on the heart muscle(negat ive  ino t rop ism) ;  moreoyer ,  w i th  the  ( - ) -enant iomers  o f  some yerapamr lcongeners i t  tYas found that the wash-out kinetics of the negative inotroprce f fec t  were  subs tan t ra l l y  s lower  than fo r  the i r  op t rca l  an t rpodes ,  Theseresults indicate that imDortant dif ferences exist between the va$cular andmyocardial isochannels. The posit ive inotroDtc effect, which was observed atlow, vasodtlat ing concentrattons of calcrum antagontsts yít th perfusron underconstant pressure condations wês shown not to be a direct (calcium agonistrc)ac t iv i t y  o f  the  drugs ,  bu t  a  consequence o f  the  Fran | (  S tar l ing  pr inc ip le ,induced by the vasodtlatat ion rtself  (chapters 2, 3 and 4).In ischaemic condit ions (no coronary f low) the deplet ion of hrgh energyphosphates (ATP, CP) incluces a ventr icular drastol ic contracture, which couldbe selectivel),  and concentrat ion dependently dela!,ed and inhrbited at energysaying (negative inotroprc) concentrat lons of al l  calcium antagonrsts studred.Furthermore, a new, protectiye mechanism was found at the lower, vasodilat ingconcentrat ions of the drugs, result ing In an ,mproved recovery clurtng thereperfusion phase, f ' loreover, the protective actryrt ies of the calcium antago-nists cl isplayed a stereoselectivi ty whrch clurrng ischaemia (delay and decreaseof  the  d ias tohc  cont rac turê)  l vas  s imi la r  to  the  s te reose lec t iv i t y  o f  thenormal  negat rye  Ino t rop tc  ac t iv t ty ,  whereas  dur ing  the  reper fusron  phaSe(accelerat ion of the recovery from the diastol ic contracture) a cloge Daral lelí57was obsefved w i th  the  s te reose lec t rv i ty  o f  the  vasodr la t tng  e f fec t  o f  thedrugs  (chapters  5  and 6) .  In  add i t ion  we have found tha t  the  ca lqum agonrs tBAY K 8644,  and especra l l y  the  laevoro ta to ry  enant . iomer ,  aggravated  thed ias to l tc  cont rac ture  and de layed the  recovery i  these e í fec ts  were  shown rnpar t i cu la r  a t  vasoconst r rc t ing  ( reduced oxygen and subs t ra te  avar labr l t y )  andpos i t i ve  lno t foDrc  ( rncreased enerqy  expend i tu re)  concent ra t rons  (chapter  7 ) ,A l though ca lc ium antagonrs ts  un t i l  now were  cons idered to  be  ac t iye  agarns t  thedet r imenta l  consequences  o f  i schaemta  on ly  when grven Drophy lac t ica l l y ,  thenesu l ts  on  the  pro tec t iye  e f fec ts  dur tng  reper fus ion  o f  the  (s te reo tsomers  o f )vasose lec t iye  comDounds t rong ly  suggest  d t rec t  therapeut rc  e f fec ts  o f  th tsc lass  o f  d rugs  as  we l l .Bes ides  s tudres  w i th  the  In tac t  hear t ,  the  second lead in  th rs  thesrsconcerns  b iochemrca l  s tud ies ,  A t  the  membrane leve l .  ca lc rum t ransDor t  acrossthe  myocard ia l  p lasma membrane (sarco lemma)  was s tudred,  in  par t rcu la r  ATP-cleDendent Ca2+-transport and Na+/Ca2+-exchange In sarcolemma vesrcles. Atphysiological condittons these processes serve to extrude from the heart theca lc ium tha t  has  en tered  dur ing  the  cont rac t ion  cyc le .  A  d i f fe ren t ia i  cen t r r fu -ga t ton  techn lque was used to  ob tarn  pur i f ted  sarco lemma f rom ra t  hear tyent r i c les .  Inh ib t t ion  o f  these two Drocesses  by  ca lc rum antagonts ts  was no tfound to  be  s te reose lec t ive ,  However ,  c lear  d i f fe rences  rn  d rug  sensr t rv t ty  andin the slope of the concentrat ion-inhibit ion curves between the ATP-dependentCaz+-transport and the Na+/Ca2+-exchanger were found. The resuits indrcate thatthe  drugs  ac t  no t  on iy  a t  the  leve i  o f  the  s low ca lc rum channe l  bu t  may a lsoin te r fe re  w i th  o ther  (possrb ly  ca lmodu l in -med ia ted)  p rocesses  (chapter  8 ) .lschaemic sttuations af e usually accompanted by a drop rn DH, whtch altersthe degree of protonation and possrbly the activrty of drugs, However, forbeDrict i l ,  which at pH 7 is Drotonated f or 11'/ . ,  the inhrbit ion of the ATP-de-pendent Caa+-extrusion and the Na+/Cae+-exchanger appeared to be independent ofthe degree of Drotonation. In contrast, the two calcrum transport processesthemse lves  were  s t rong ly  sensr t rve  to  ex terna l l y  aDphect  pH changes (chaD-ter 9), suggesttng that in tschaemtc condit ions the extnuston of accumulatedCa2+ may be imparred. ïhis was conftrmed by the observation that membranesder ived  f rom ischaemtca l l y  DreDer fused ra t  hear ts  indeed showed a  decreasedAïP-dependent  ca lc rum pumping ac t iv i t y ,  Pre t rea tment  w i th  verapamr l  a t  arelat iyely low concentrat ion wês found to enhance marl(edly the activrty of this6u2+-pumD before the onset of ischaemia and during the reperfusron Dhase( c h a p t e r . l 0 ) .In view of these results, i t  was considered of interest to investigate tfthe modulat ion of the yascular and myocardial rsochannels in the heart,  both innormoxic and ischaemic condtt ions, could be confirmed at the receptor level.Thus, calcium antagonist binding sites were $tudied rn membrane fractrons fromnormal and ischaemrc rat heaf ts usrng [3H]-(+)-PN 2Oo-110, a dihyclropyr"rdrnecalcium antagonrst selecttve fof the vascular rsochannel, and [3H]-(-)-devapa-mil,  a calcium antagonrst from the verapamrl group, which is more selectrve forthe myocardium. l t  was found that at negative Inotroprc (energy saving)concentrat ions verapamil affords pfotection against ischaemia-induced chanqesr58in the number of btndrng sites (Bmax) of t3Hl-(+)-PN a0o-110, Furthermore, atl o w e r , v a s o d i l a t i n g c o n c e n t r a t i o n s n t f e d i p l n e e x e r t e d a p r o t e c t i v e a c t i v i t yselective for the reperfuston phase (chapter 11)'T h e r e s u I t s f r o n e x - v i v o a n d i n - | l t r o s t u d i e s s h o w a c l e a r p r o t e c -t i v e r o I e o f c a l c i u m a n t a g o n i s t s i n i g c h a e m i a a n d s u p p o r t t h e v i e w t h a t t h e s ed r u g s | m p r o v e t n e e n e | g y b a l a n c e , t h e i o n i c h o m e o s t a s i s a n d t h e r e m o v a l o fde t r imentó l  agents  whrch  are  In t imate ly  connected  to  myocard ia l  i schaemtc0 r s e a 5  e  s .tEq

Molecular pharmacology of calcium antagonists in the normal and ischaemic heart

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Molecular pharmacology of calcium antagonists in the normal and ischaemic heart

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