15

Myocardial Protective Effec ts of Lidoflazine During Isch emi a and Rep erfusion I•. Guoendik, J. /lgnd. A . Drake-Holland. and D. J. Parker Depertmem ofCa rdiolho racic Surgery. St. George 's lIospia l. London. Greal Britain

The myocardial protective elTect c rt r urev enous Ii. v.llidoflazjne with pota ssium ca rd ioplegia a nd hypothermia (28 OCI wa s investigated in 21 grey hounds. Animals were injected a singl e dose of cardioplegia (30 mllkg body weight) and subjected to 120 minutes of ischa emia an d 60 minutes of re perfusion. Ten dogs SI1 I"Vcd as controls (Group Cl a nd 11 dogs received i . v. lidoflazine (1.2 5 mg/kg b.wl (Group Ll. Myoca rdial drill biopsies for the edcnoslne triphosphate {AT? ) and the crea tine ph osphate (e p) levels were obta ined. Hemodyna mic measureme nts were made at interv als. In Group C. no dog could be weaned from bypass. whereas all II dogs In Group L ca me ofT bypass an d mefntalned th eir circulation for 15 min utes . After a 120 minute ische mic period. the ATP a nd CP contents diminished significa ntly in bot h grou ps. Following repe rfusion. the ATP level was 28 % of th e controllevel in Group C Ip < 0 .005 1 a nd 38 % in Group L Ip < 0 .01). Th e CP levels showed an overshoo t in bot h grou ps. There was no significa nt dilTtrence be tween th e grou ps. In Group L a nima ls. ca rd iac ou tput (COl a nd mea n aortic pressure IMAP) were significantly reduced a jter bypa ss . from 5 ± IIm in to 3.2. ± 1. fro m 156 ± 26mmllg to 82 ± 11 mmllg respectively Ip < 0 .(05). Len vent ricular minute work ILVMW) also deterior ated ma rkedly from 9 .7 ± 2 kg-m to 3.2 ± I (p < 0 .(05). The use of hdoflazine ac hieved cons idera ble pro tection in terms of su rvival. but did not pre ven t (he seve re loss of highenergy pho sphates in thi s experi menta l model .

Introdu clion Despite vast Improvements in myocar dial preservation over the last decade. sea rch for better and simpler methods for use in cardiac surgery continues . Hypothermia (5) and hyper kalemic cardioplegia (4. to . t t. 20. 30) are well established methods which have been shown to minimize the myocard ial damage during ischemic periods. Homogenous distribution of car dioplegia solution can be impai red by the presecence of severe coronary artery disease 04 .1 5) and changes in the collateral circulation (21 ). In recent years. beta -adr enorecept or blocking agents (9.23) and calcium antagonists (1. 3. 22,29. 34) have been demonstr ated to have protective effect on the ischemic myocardium . In contrast. these agents also have a varying degree of myocard ial depressant action which may have an adverse effect on the recovery of myoca rdium after an ischemic period.

Thorae. ea rdiovasc. Surgeon 38 (1990) 15- 19 CI OoorgThieme Verlag Stuttgart- NewYork

~I)'oka rd pro trk t h'e wtekun gen des U do n ali ns wihr rn d Ischa m te un d Re pl'rfuslon

F.swird uber 21 Experi rnente a n Wind hu nde n miteinem du rchschnntnche n cewtcm von 28 .5kg be richte t. Zeh n lI unde die nten als Kontrollgru ppe (Gruppe C) und elf (Gruppe I.) erhielten 1.25 mglkg Kcrpergewlcht des Kalziuma ntagonisten Lidnflalin. Nach Narkoseeinleitung wu rde via rechrssetttgcr Thorakotomic da s Ilerz Irelgelogt und Druckkathcter in Iinken Vcnt rikcl und Aort a sowle em Swe n-Oan z-Ket heter in die Pulmonala rte ric plaziert. Nach lnstallierung des extra korpora len Krelslaufs wurden Biopsic n aus dcm hnken Vcntrikcl cntnommen und dann der ka rd ioplcgische Herz stlllstand minds der 51. Tho mas-Losu ng ejngelenet. Nach t 20 min tscha mte und nach wei te re n 60 mi n Reperfu sion wueden wiederu m Myokardbiops ien e ninc mme n. in denen ATP und Kreat inphosphat bes ummt wurd en . Von den Kontroll tieren konote kem es vom kard iopu lmoneten Bypass abko mme n, von der Uoters uchungsgru ppe L a ne. Nach t20 min tschamte fiel der ATP·Gf.halt in bei den Gru ppen stark ab o in Gruppe C a uf 28 % u nd in Gruppe L a uf 38 %. Oil' uberlebenden Tiere der Gruppc L zeigten na ch der extrakorpora len Zirku lation e ine erhebliche Heduzlerung des IfZV un d des Aortenmineld ruc kes. Aus den Experi me men cotnebme n die Auto re n. da BUd oOaz in zwa r e in Bbe rleben ermoglir ht , ebe r den erhe blfchen Verlust der energie re jche n Phosphat e nkhl verhute n Ka nn o Kf>ywords Myoca rdi al protection - Calcium a nta gonis ts

Lidoflazine 414.4-bis(4,fluorophenyl) butyl ll-N- (2.6dtmethylphenylj-Lptperazm e acetamide. is generally classified as a calcium-channel blocking agent. Its exact site of action in the myocardial cells is not entire lyclear. The membra ne-stabilizing and coro nary -ert ery -dnat or effects of IidoOazine have been shown by other work ers (6. 31. 33). Lidoflazine neithe r has a beta ed renorecepto r-blocktng activity nor an y documented dep ressant effect on the myocardium in clinical studies. It has been successfully used for the treatment of angin a pectoris with significant impr ovement in exercise toleran ce (2. 8. 16.28.32). The cardtoprotect ive effects of Iidoflazine during normothermic ischemia (6. 7. 24) and in combination with potassium cardioplegia ( t 9) have also been clearly document ed . In this stud y we investigated the myocard ial prot ective effects of lidoflazine in combination with systemic hypother-

Received for Publication : Novem ber 17, 1988

Downloaded by: National University of Singapore. Copyrighted material.

Su mma ry

Thvr uc. cardin/'us c. Su rgeon 38 (199m

1•. GUl·endi k. J. llgn d. A. Drake -l toliand. an d D. J. Parker

rnia (28 OC) a nd cold potassium ca rd ioplegia in greyhounds. All a nima ls we re subjec ted to 120 minutes of globa l ische mia a nd 60 mi nutes of re pe rfus ion. ~I ethods

Greyhounds with a n aver age weight of 28.5 kg 122.5- 32 kg) were a nesthe uzcd with thiopentone 15 mglkg b. w .) a nd sodium chlorose 1100 mR!kg b.w.L The an imals were paralysed with panc ronium bromide 10.2 mglkg b. w.) a nd ventila ted with room air. The hea rt was exposed through a right tho racotomy. A microtip cat heter IGal'ltl'C 571 was msened into the len ventricle through the left a trium a nd a nother pressure-monitoring cathete r was placed in the asce nding aorta via the fero mal a rtery. A 7 FG Swa n-Ganz thermodilution cat heter was passed into the pulmonary a rtery through the right jugula r vein for dete rmination of ca rdiac output using a ca rdiac output computer (Edwar ds I.a b. Model 9520Al. Aortic a nd pulmonary artery press ures a nd lead 2 of the electroca rdiogra m were recorded on the multichannel chart recorder . Cllrdiupulmonary bypass circuit was primed with one litre of Dextra n 70 and one litre of Hartmann's solution. Bubble oxygcnators IOxybell a nd rolle r pumps were used lAmerican Optical lnc.l. Hcmatocrit remained greater tha n 2 1% in allthe experiments using this hemodilution technique .

Outline o/Experiments The experimenta l pro toco l is outline d in Fig. t . Ane r ca nnula tion oft he he art . he modynamic as se ss ment was made and

,......

,.-

,-- I...... ::0.: -··----1 --- ,~ _ ,,--

Fie. 1 OutIJle of

expermental protocol

F-

, , ,.

b. _1ft

/'_M _ ~ ----''j---

--

,,,.

,--

left vent ricula r biopsies we re tak en. Udo Oazine 11 .2 5 mglkg b.w.l was injected intravenously ove r a pe riod of 10 minut es . In ad d ition. 5 mg of lidofiaz ine was a dde d into 2 litres of pump prime . Hemodynamic measure ments and myocardial biopsies were re peat ed 20 minut es a fter the completion of lidoOazine injectio n. After establishing cardiopu lmonary bypass. th e a nim al was cooled to 28 OC and the ascending aorta was cross clamped . Th e St. Thoma s' Ilospita l ca rdioplegia solutio n (30 mVkg b. w.l was de livere d at 4 °C into the a ortic root through a FG 8 ca n nula . Aorticroot pressu re wa s ma intain ed at 100 mmHg d uring cardio plegia injection. Cardiac a rrest was usu ally obta ined within two minu tes . Thermistor prob es we re positioned in the inte rventricula r septum a nd the posterior wall of the left

ve ntricle . Systemic perfusion flow ra te was red uced to hair of the ca lculated f low rate (lOOmllkglm inl ma intaining mean a ortic pre ssu re of 60-80 mmH g d uri ng the ische mic peri od. After 120 mi nu tes of ischemia myoca rdial biopsies were ta ken and then. ao rtic cross clam p was rem oved . The heart was reperfused for 60 minutes . while the an ima l wa s being re wa rm ed w ith the left vent ricle vented th rou gh the left a triu m. In the prese nce of ventricular fib rillation at 3 1 "C. regular sinus rhyth m .....as restored by d irect-curren t defibrillat ion . After 60 mi nutes of re pe rfusion third biopsies were obta ined and ca rdiop ulmo nary bypass was gradually d iscontinued. The he arts were left to sta bilize for 15 minutes before th e final hem odyn amic ass ess ment.

Myocardial Biopsies Full-thickness myocardial biopsies wer e obt ained from the left ventricular wall by usi ng a tu bula r oscillating biopsy d rill at four differe nt times . The first a nd second set of biopsies we re collected shortly befor e, a nd 20 mi nut es aft er, the comp letio n orJido l1az ine injection . The third biopsies were obta ine d at the end of th e two ho ur isch em ic period a nd th e fourth set after one hou r of perfusion. Biopsy specimens were immed iately im me rse d into hexane a nd ca rbondioxide snow ba th for th e ATP and the CP level est ima tions.

lIemodynamic Assessment Hemodynamic measu remen ts were ca rried out before a nd aft er the injection of lidollazine and 15 minu tes followi ng th e termina tion of ca rd iopulmona ry bypass. Hea rt rate . mean ao rtic a nd pulmonary artery pr essure s we re monitored contin uously. Ca rdia c out put (CO) and th e firs t deri va tive of leR ventric ula r pre ssu re dPtdT max w ere measu red a t a fixed LVEDP of 10 mmH g. Fixed filling pressu res wer e a chieved by appropriate volume loading from the extra co rpore a l circ uit. Left ve ntri cular minute work (LVMW) in kg-m was calculated from the formul a : LVMW = COIMAPLVEDP) ·0.0136.

Experimental Groups 2 1 gr eyhoun ds of eithe r sex were used. Ten a nim a ls se rved as the con trol grou p an d 11 received t.v. Jtdonezfne a nd add itiona l lidoOazine in the pu mp prime . After cross-cla mping the as cending aorta . all the a nima ls had a si ngle injectio n of St. Th omas ' Hospital ca rd ioplegia (30 mVkg b.w .1at 4 OC. The ca rdioplegia solution wa s composed of: KCL. 16 mmol/L: MgC1 2 • 16 mmol/L: pr oca ine hyd rochloride . 1 mm ol/L: in 20 mls of wa ter. This .....a s added into a litre of Ringer's lactate soluti on . (NaCI. 147 _13 mmol/L KCL. 4.0 2 mmol/L . CaCll • 2.25 mmol/Lj. The data a re presen ted as plus a nd minu s of th e standard devia tion (SDI of the mean. Statistica l a nalyses .....ere ma de with th e Stu dent .1' test be twee n the gro ups an d th e pal re d ,']" test for comparison of p re - a nd post-byp ass va lues in th e sa me gro up . Results

Myocardial Content 0/ Adenosine Triphosphate and Creatine Phosp hate The cha nges in the ATP an d CP content of the myoca rd ium a re shown in Fig. 2. There was no significant difference in

Downloaded by: National University of Singapore. Copyrighted material.

16

Myocardial I'rotective Effects o/U dojlazine {Juring Ischemia and Reperfuste n

-

.,.

."""0 1 I;doll. , ..... -

__

'"

00

00

~, 50

00

~Q

00

P" < zo

'"