al., 1980; Millard et al., 1982). In anaesthetized dogs only verapamil has been identified as being a negative

Transcription

1 Br. J. Phrmc. (1985), 86, Importnce of myocrdil blood flow chnges in the protective ction of diltizem in new model of myocrdil ischemi L. Szekeres, Ev Udvry & Agnes Vegh Deprtment of Phrmcology, University Medicl School Szeged, Szeged, Hungry 1 The effect ofdiltizem ws studied in new model of myocrdil ischemi in which in ddition to criticl constriction of the left circumflex brnch (LCX), the left nterior descending coronry rtery (LAD) ws suddenly occluded. This model is probbly more relevnt to the clinicl sitution in which multivessel coronry rtery disese is common. 2 In this model diltizem exerted beneficil effect, mnifested by n increse in myocrdil blood flow (MBF) within the stenosed re of the LCX; by mrked reduction of the enhnced prelod (LVEDP); by diminution of the inhomogeneity of electricl ctivtion nd by decrese in STsegment elevtion. Diltizem lso cused significnt reduction both in the number of extrsystoles nd in the incidence of ventriculr fibrilltion. 3 Incresed MBF within the stenosed re ws ssocited with enhnced blood flow to the ischemic myocrdium, i.e. diltizem directed flow to the ischemic zone by improvement of the collterl circultion. 4 The beneficil electrophysiologicl chnges cused by diltizem re probbly t lest prtly due to the drug-induced improvement of myocrdil blood supply to the ischemic re. Introduction The phrmcologicl ctions of diltizem, potent coronry vsodiltor, were first described by Sto et l. (1971) nd by Nkjim et l. (1975, 1976). Evidence hs been provided tht the drug belongs to the group of 'clcium ntgonists' (Fleckenstein, 1977). Diltizem hs been successfully used in the therpy of ngin pectoris (Ellrodt et l., 198; Schroeder et l., 198, Bertrnd et l., 1982) s hve other clcium chnnel blocking gents such s nifedipine nd verpmil (Ellrodt et l., 198). As is well known, the clinicl ppliction of this group of gents extends to wide rnge ofindictions. These include ngin pectoris, hypertension nd suprventriculr rrhythmis. Experimentlly, the three most widely studied clcium ntgonists re verpmil, nifedipine nd diltizem. All three drugs possess more or less expressed coronry diltory effect (Henry et l., 1978; Wrltier et l., 1981; Millrd et l., 1982) nd t higher concentrtions cn to vrying degrees reduce contrctile force in isolted tri nd ventricles. However, in the conscious niml, nifedipine increses, verpmil decreses nd diltizem hs little effect on the inotropic stte (Stone et l., 198; Millrd et l., 1982). In nesthetized dogs only verpmil hs been identified s being negtive inotropic gent (Wrltier et l., 1981). Among the three mjor clcium ntgonists, verpmil hs been the most extensively investigted with regrd to rrhythmi. In ptients, verpmil ws shown to be effective prticulrly ginst suprventriculr rrhythmis (Antmn et l., 198; Brunwld, 1982). 'It hs been reported tht both verpmil nd diltizem (Nky et l.; 198; Peter et l., 1982) reduce the ischemi-induced conduction dely in nesthetized dogs. Ribeiro et l. (1981) hve found tht verpmil, in contrst to nifedipine, lso decreses reperfusion ventriculr rrhythmis in nesthetized dogs. However, nifedipine ppers to hve no direct ntirrhythmic effect (Ellrodt et l., 198; Ribeiro et l., 1981) but does protect the myocrdium from ischemi nd reduces infrct extension (Henry et l., 1978; Bruckner et l., 198). In contrst to the bove gents, diltizem is more potent vsodiltor nd lcks significnt negtive inotropic ction (Frnklin et l., 198; Millrd, 198; Ngo et l., 198; Nkmur et l., 198). It hs been t) The Mcmilln Press Ltd 1985

2 342 L. SZEKERES et l. found highly effective in the relief of nginl pin relted to coronry rteril spsm (Stone et l., 198; Bertrnd et l., 1982). In niml experiments diltizem hs slutry effect on the ischemic myocrdium both through n increse in collterl circultion (Frnklin et l., 198; Nkmur et l., 198) nd lso by direct ctions on the myocrdium (Millrd, 198; Ngo et l., 198; Bush et l., 1981). Diltizem cn reduce or moderte the hrmful effects of reperfusion on the severely ischemic myocrdium (Wrltier et l., 1981) nd decreses the occurrence of erly postocclusion rrhythmis (Nkmur et l., 198; Peter et l., 1982). The present study ws undertken to study the effect of diltizem in new model of myocrdil ischemi in which, in ddition to criticl constriction of one of the mjor coronry rteries (left circumflex brnch, LCX), the other min brnch (left nterior descending coronry rtery, LAD) ws suddenly occluded. Methods Generl preprtion Adult mongrel dogs of either sex, weighing kg were nesthetized with sodium pentobrbitone (Nembutl, Serv, 3 mg kg-' i.v.) nd ventilted (respirtor, RO-5, SU) with room ir t 1-15 strokes per min. Arteril blood ph nd Po2 were monitored t selected intervls by mens of blood gs nlyser (Astrup, OP-212), nd mintined t 7.4 ±.2 nd between 79-9 mmhg respectively. Body temperture ws monitored from temperture probe in the oesophgus nd mintined t 37 ±.5 C by heting pd. Hemodynmics Men rteril blood pressure (MABP) ws recorded by mens of ctheter inserted into the right femorl rtery ttched to pressure trnsducer (Stthm P23Db) nd registered on Hellige pressure recorder, while left ventriculr systolic (LVSP) nd end-distolic (LVEDP) pressures were mesured by mens of ctheter introduced through the left crotid rtery into the left ventricle nd ttched to pressure trnsducer (Stthm P23Db) nd n electromnometer. These prmeters were recorded (together with the first derivtive of LVSP) on Wtnbe recorder t pper speed of Imms'1. Coronry flow, stenosis nd occlusion Thorcotomy ws performed in the fifth intercostl spce, the LAD nd LCX coronry rteries were dissected free nd silk threds loosely plced round them. Left circumflex coronry flow (coronry blood flow, CBF) ws mesured by mens of flow probe (AS Nycotron 376, Type 1613, size: mm). Distl to the flow probe constrictor screw ws plced round the LCX in order to produce criticl stenosis of the LCX. In the re supplied by the LAD, peripherl coronry perfusion pressure (PCPP) ws mesured in smll brnch of the LAD distl to the site of occlusion by mens of ctheter filled with heprinized sline. This ctheter ws ttched to pressure trnsducer (Gould-Stthm P23Db). Men PCPP ws registered on NEK4-six chnnel recorder. ST-segment nd electricl inhomogeneity In order to follow the ischemi-induced inhomogeneity in electricl ctivtion, composite electrode contining 3 bipolr electrodes connected with ech other to give one single led (Willims et l., 1974) ws sutured on the epicrdil surfce in both regions supplied by the LAD nd LCX respectively. In this wy it becme possible to obtin summrized picture of the R wves from 3 epicrdil mesuring points. The records so obtined were filtered in the rnge between 4-2 Hz. In the dequtely perfused nd oxygented myocrdium ll sites were ctivted simultneously, resulting in single lrge spike. However, widening nd frctiontion ofthis summrized picture of R wves following occlusion indicted tht djcent fibres were not simultneously ctivted becuse of n inhomogeneous conduction of impulses. Inhomogeneity of ctivtion ws expressed s the gretest dely in ctivtion in ms between the first nd lst burst. Chnges in the epicrdil ST-segment were recorded by unipolr electrode built seprtely in the composite electrode. Chnges in the endocrdil ECG were registered from two sites in the re supplied by LAD. Both epicrdil nd endocrdil ECGs were registered on 6NEK4-six chnnel recorder. Locl myocrdil contrctility nd bloodflow Locl myocrdil contrctility ws mesured by strin-guge rches plced on res supplied by the LAD nd LCX respectively nd on the border zone. The rches were clibrted by mens of 2, 5, 1 nd 2 g weights t the beginning nd t the end of the experiment. The deflections were registered on Wtnbe recorder. In ddition left ventriculr contrctility ws estimted s dp/dt. Myocrdil tissue blood flow ws mesured by mens of the het clernce technique (Juhsz-Ngy et l., 1974). Flexible copper-constntn thermocouples were inserted trumticlly in two different lyers of the ischemic re nd in one lyer ofthe re supplied

3 PROTECTIVE EFFECT OF DILTIAZEM IN MYOCARDIAL ISCHAEMIA 343 -E E _. _,-- _4 z o m. Wo.-q ': vt:i I < 1. m z + r^ so o) + C'n z _ * -, U O W P6 * *- * + * s2 I * ~ * * -L Li M WL, o% IZ ii Cud? U,IC tl ' r- T.en v:q w r o * C4 eni CA e4 Z +ln (A + U li O N Z r-: U evi IFF1 o.l + J= _r * +l N U _ W +I oo W en U ON S 'n % U e.t 'g *. 'g.,, +l-n +I CK I Rt I im - * o'c' S Cd 11 wbu + + U> +l. + Yi o CuY _ m o'* en Cur - u 6 u ṬE (1.,t W) U + +l- U -4 * t * * % $ - ON I u - = ci.q oq I * o go e W) +I I =,, o; + _*, u r- I I- +l <, :., r- N co 1 C-. _~ o Nc z 1+ --I -~~~~~~r No _ 4 4 en _ t- wi "i Cu eni O W: z u Q ue <-o 'ct >% -=r,, U)o FX Cu Cu) el Oi* 11 =EC l U m 1 l1 > 11 > 11 <ZI 11 i1

4 344 L. SZEKERES et l. by LCX. The probes were fixed by epicrdil sutures. Seprte ECG leds were ttched to ech probe to loclize the site of probes. One thermojunction recorded the temperture of the tissue, while the other junction ws heted continuously by stbilized d.c. current through seprte thin constntn wire. An initil temperture difference of 1.5 C ws estblished between the two junctions of the probe nd the intensity of the heting current ws mintined constnt throughout the experiment. The temperture difference (AT) between the heted nd the reference junction, which is inversely proportionl to the rte of blood flow perfusing the locl tissue, ws continuously registered on Kipp-Zonen BD6 recorder. The mgnitude of the blood flow chnges ws expressed s percentge (the flow vlue t the beginning of experiment ws rbitrrily tken s 1% nd the vlue t deth s %). Experimentl design We exmined the effect of diltizem in severe myocrdil ischemi produced by occlusion of LAD in the presence of criticl stenosis of the LCX. After control recordings, repeted 5 min LAD occlusions were performed t 3 min intervls. Therefter the LCX rtery ws subjected to criticl constriction (i.e. until the disppernce of the postocclusion hyperemic rection). The LAD occlusion ws then repeted. After relese of the occlusion diltizem infusion 1 Fig kg- min-' ws given for 3 min. This ws followed by further occlusion of the LAD. After the relese of this occlusion the infusion ws stopped; 5 min lter the constriction of LCX ws removed. Results Hemodynmics After occlusion of the LAD lone, MABP, LVSP, PCPP nd left ventriculr dp/dt decresed slightly. These chnges were more pronounced in the presence of the LCX constriction. Hert rte did not chnge significntly. During the diltizem infusion HR, MABP, LVSP, dp/dt nd PCPP were essentilly unchnged, except t the beginning of the infusion (Tble 1). LAD occlusion lone cused significnt increse in the LVEDP which ws more pronounced in the presence of the criticl constriction of LCX. During diltizem infusion the LVEDP ws significntly reduced lmost to the control level in spite of simultneous LCX constriction; following dditionl occlusion of the LAD, there ws only moderte decline in LVEDP. LCX inflow ws mrkedly incresed following LAD occlusion lone, prcticlly compensting 4- Ce._ CU._ Cd C.) C. ) CU C. Cd C) ) ) N CU u.) CU C.) uec j r- co r. U. o * - ; * E * W[Jso N en IS9 To + U E Qv -t It l U I.- t m i I, t ( czem+ b -. %o + e ~j Q - m oo + t +U +I +l m,i +m 1- - U + <.+ +* + en * oi* w * 6 Z + C en II ~o * u + I Ci X r o~~~~~~~~- 6 ~~~~~~~~~. CU~~~+ U C-~~ C 4~~~ CU CU )C ~~~~~~ N~~~~ CAU ~~ fl oil C.)fl~~.. ZW = + CU W

5 PROTECTIVE EFFECT OF DILTIAZEM IN MYOCARDIAL ISCHAEMIA 345 for the lck of circultion within the occluded re. However, this compenstion ws bolished when the LAD occlusion ws repeted in the presence of the LCX criticl constriction. Diltizem infusion ugmented the blood flow to the re supplied by the LCX rtery. Locl myocrdil contrctility In the hert with intct coronry circultion, control occlusion of the LAD cused compenstory increse in contrctility of the re supplied by the LCX (Tble 2). This increse becme more nd more ccentuted s the ischemic re ws pproched nd ws mximl round the border zone. At the sme time contrctility in the centre of the ischemic re decresed considerbly. In the presence of stenosed LCX, repeted LAD occlusions resulted in reduced compenstion in the border zone. In the re supplied by the LCX the compenstion ws bolished nd in the centre of the ischemic re, contrctility ws lmost completely bolished. During diltizem infusion, locl myocrdil contrctility ws slightly, but significntly incresed both in the re supplied by the LCX rtery nd in the border zone, but not in the re supplied by the LAD. Repeted LAD occlusions evoked more intensive compenstion both in the border zone nd in the re supplied by the LCX rtery. Even in the ischemic re the fll in contrctility ws less mrked thn before diltizem. Locl myocrdil bloodflow After occluding the LAD lone, MBF in the region supplied by this vessel suddenly nd mrkedly declined (Figure 1.). The decline ws somewht more pronounced in the subendocrdium thn in the subepicrdium. During LCX criticl constriction, MBF lso decresed in the region supplied by the LAD occlusion D LAD occlusion CX criticl constriction I Diltizem 1 Ig kg-1 mini,1 1 LA U- ] endo/epi =.96 5 H B endo/epi =.75 Cendo/epi = 1.15 C4 endo/epi = Time (min) Figure 1 Chnges in regionl myocrdil blood flow (MBF) of subendocrdil (*) nd subepicrdil () lyers of ischemic re nd lso in the re served by left circumflex brnch (LCX) (A) fter left nterior descending coronry rtery (LAD) occlusion, LCX constriction nd diltizem tretment. Absciss scle: time (min). Ordinte scle: myocrdil blood flow (% chnge). Vlues re men with s.e.men shown by verticl lines. n = 6. B-C-D-, B1 -CI -D1 etc. Indicte the sites of MBF chnges where significnce of differences between vlues ws clculted. Level of significnce: * P<.5; ** P<.l; ***P<.l; NS = not significnt. Differences were s follows: A-B***; A-C***; A-D***; B-C***; A-Bi***; A-Ci***; A-DI***; B-B2 NS; C-C2**; D-D2**; Bj-B3**; C,-C3**; DI-D3**; B2-B4**; C2-C4**; D2-D4**.

6 346 L. SZEKERES et l. _ E~.2 ei S v 'o 4i, +l C14 C + * m 4l * o LL o z m *er _. Z +I w o.4 * 4. Ci - % + *-.C :.Q h. C- S *.E i g o+ +- go +u z z z ul UN UN ( I.. C) Il C) +n * e--n N- * * * bi - C > l +I1 I C'i + O O m C4nm '4 g c = e. I r- _ oo+< +l +, C ) + < n UO C- V) " CUt oz oz oz u u 1 < (l1< <. ) C4 + <t en <~ o _ C 4 - o - Q o It,. qi C) E (swi) B3JB ollr3bsi (Atu)~~~~~ - UO!WLAtLI)B (A m) Jo AI!OuSouIoquI C C CIO UO!lBA. )ulos-is.~~~.

7 LAD, especilly in the sub-epicrdium nd the endo/ epi rtio ws incresed to 1.8. In the presence of criticl stenosis, the ischemi produced by subsequent LAD occlusion becme more severe; MBF in the ischemic re decresed further, minly in the subepicrdium. We ssume tht during control occlusions of the LAD, the subendocrdil circultion 25 PROTECTIVE EFFECT OF DILTIAZEM IN MYOCARDIAL ISCHAEMIA 347 hs lredy mximlly decresed nd further ugmenttion is unlikely. At the sme time the subepicrdium is less ffected by the occlusion, in such cse criticl constriction of LCX exhusts the epicrdil reserve of the ischemic re. In this model of severe ischemi using LAD occlusion in the presence of LCX constriction, dil- LCX criticl constriction Diltizem 1,ug log- min-r LAD occlusion n 2 E 15 U- 1 5 b (min) B1 E L- I) (n w B A A2 B2 i,, "'' VF: /16 1/16 /15 2/15 3/13 /1 /1 /1 Figure 2 () Chnges in the ST-segment elevtion of the epicrdil () nd endocrdil (-) ECG leds of the ischemic re. Absciss scle: time (min). Ordinte scle: ST-segment elevtion (mv). Vlues re: men with s.e.men shown by verticl lines. A, B; AB, nd A2B2 men mximl vlues of ST-segment elevtion used for comprison nd clcultion of sttisticl significnce. Level of significnce s in Figure 1. Differences were s follows: A-B**; A,-B, ***; A2-B2***; A-A, ***; B-B, ***; B,-B2***; A,-A2***. (b) Number of extrsystoles (ES) nd the incidence of ventriculr fibrilltion (VF) in the presence of left nterior descending coronry rtery (LAD) occlusion lone, left circumflex brnch (LCX) constriction lone nd combined with LAD occlusion, finlly fter diltizem tretment. Ordinte scle = ES per 5 min. Time scle nd intervention s indicted in (). Htched columns number of ESs during LAD occlusion (A, A,, A2) stippled column number of ESs during reperfusion (B, B,, B2) open columns number of ESs during criticl LCX constriction (C, C,, C2). Vlues re men with s.e.men shown by verticl lines. Level of significnce s in Figure 1. Differences were s follows: A-A, ***; B-B, ***; C-C, ***; A, -A2 ***; B-B2 *** VF below horizontl line = number of nimls developing ventriculr fibrilltion following different interventions (s indicted by the columns).

8 348 L. SZEKERES et l. tizem incresed the MBF both in res served by LCX nd LAD. This enhnced blood supply moderted the diminution of MBF following LAD occlusion both in the LCX nd in the LAD regions but ws not ble to lter the flow distribution s compred with the sitution in the bsence of diltizem. The rbitrry endo/epi rtio thus remined t Electrophysiologicl prmeters nd extrsystolic ctivity Tble 3 shows the chnges t the unipolr nd multipolr electrode sites recorded from both res served by LAD nd LCX. Inhomogeneity of electricl ctivtion incresed following LAD occlusion, i.e. there ws n increse in the dely of ctivtion between the first nd lst deflection ppering in the composite electrogrm nd t the sme time there ws ST-segment elevtion of 11 mv (epicrdium) nd 14 mv (endocrdium). In the presence of criticl stenosis of the LCX, the inhomogeneity of electricl ctivtion ws more mrked both in the res supplied by the LAD nd LCX. Additionl occlusion of the LAD incresed ventriculr inhomogeneity nd STsegment elevtion in the ischemic re, especilly in the epicrdium. Diltizem significntly reduced this inhomogeneity s well s the ST-segment elevtion (Tble 3). Figure 2 shows the effect of the bove interventions on the development of ST-segment elevtion compred with the extrsystolic ctivity (clculted over 5min intervls) nd the incidence of VF. In the presence of n intct coronry circultion, LAD occlusion cused moderte myocrdil ischemi with no or only slight extrsystolic ctivity but significnt increse in the ST-segment elevtion. In the presence of stenosed LCX, LAD occlusion led to more mrked myocrdil ischemi nd n enhnced elevtion of the ST-segment. The incidence nd severity of rrhythmis incresed significntly; in one third of the nimls (5/15) ventriculr fibrilltion occurred either during the occlusion (2/15) or fter its relese (3/13). Diltizem mrkedly reduced ST-segment elevtion, especilly in the endocrdium nd reduced the number of extrsystoles. No ventriculr fibrilltion occurred fter LAD occlusion or during reperfusion. Discussion This study describes the effects of diltizem in new model of myocrdil ischemi in which, in ddition to criticl constriction of one of the mjor coronry rteries (LCX), the other min brnch (LAD) ws suddenly occluded. This model my pproximte the rel clinicl sitution, where multivessel coronry rtery disese is common. This fct hs not been tken ccount of in previous experimentl infrction models. We hve found tht the hrmful consequences of myocrdil ischemi due to LAD occlusion were ggrvted by simultneous constriction of the LCX. In the re served by the LCX, the compenstory increse in bloood flow ws bsent; in the re supplied by the LAD the perfusion decresed minly in the subepicrdium nd ccordingly, ST-segment elevtion ws more mrked in the epicrdium. Ventriculr fibrilltion occurred in one third of the nimls either during LAD occlusion or fter relese of occlusion. This study ws performed, in order to ssess the effects of diltizem on hemodynmics, myocrdil blood flow nd on the incidence of rrhythmis in n experimentl model in which more thn one coronry rtery ws involved. Diltizem tretment mitigted the detrimentl ischemic chnges mentioned before. The explntion for this beneficil effect is probbly complex (Weishr et l., 1979; Ssym et l., 1981; Ptterson et l., 1983). Severl investigtors hve observed (Fleckenstein, 1977; Frnklin et l., 198; Millrd, 198) tht diltizem hs peripherl vsodiltor ction nd thus reduces left ventriculr fterlod (Stone et l., 198; Bush et l., 1981). Furthermore it hs slight negtive inotropic (Millrd 198; Ngo et l., 198; Wrltier et l., 1981) nd chronotropic (Bourss et l., 198; Stone et l., 198; Wrltier et l., 1981) effects, which lso contribute to decrese in myocrdil oxygen consumption. Diltizem could improve crdic pumping function in terms of n increse in crdic output (due to reduced fterlod) despite negtive inotropic ction (Futmur et l., 1982). One of the min effects of clcium ntgonists is the relxtion of the vsculr smooth muscle (Fleckenstein, 1977). This explins their benefit in ngin pectoris (Bourss et l., 198; Bertrnd et l., 1982) nd prticulrly in Prinzmetl's vrint ngin (Schroeder et l., 198; Trtglione et l., 1981). Clcium ntgonists would thus be expected to increse coronry blood flow by mens of direct coronry vsodilttion (Nkjim et l., 1976; Frnklin et l., 198; Nkmur et l., 198; Millrd, 198; Futmur et l., 1982; Millrd et l., 1982). In our experiments diltizem significntly incresed LCX inflow despite the criticl constriction. Following LAD occlusion this enhnced flow (which previously plyed compenstory role) ws bsent. In spite of the stenosis (Futmur et l., 1982) diltizem incresed blood flow to the whole left ventricle including the ischemic myocrdium nd despite reduction in perfusion pressure. This diltizem-induced increse in blood flow within the ischemic zone occurred minly in the subendocrdium nd resulted in further increse in the endo/epi flow rtio. STsegment elevtion ws, s consequence, considerbly reduced both in the epicrdium nd endocrdium.

9 PROTECTIVE EFFECT OF DILTIAZEM IN MYOCARDIAL ISCHAEMIA 349 There is good greement concerning the improvement of collterl circultion in the ischemic re by diltizem (Frnklin et l., 198; Nkmur et l., 198; Millrd et l., 198; Wrltier et l., 1981; Millrd, 1982; Futmur et l., 1982), but views re more controversil s to the mechnism of ction of this enhnced blood flow. Some uthors (Millrd, 198; Nkmur et l., 198; Frnklin et l., 198) found tht diltizem ugmented perfusion in the ischemic zone by improving collterl circultion, while others (Frnklin et l., 198; Wrltier et l., 1981; Zyvoloski et l., 1982) suggested tht diltizem enhnced blood supply in both norml nd the ischemic res. Our finding tht the beneficil effect of diltizem on blood flow ws more mrked in the subendocrdium of the ischemic zone is supported by number of other investigtors (Frnklin et l., 198; Millrd, 198; Wrltier et l., 1981; Bche & Dymek, 1982; Futmur et l., 1982; Zyvoloski et l., 1982); others hve found tht diltizem incresed blood flow to the subepicrdium of the ischemic re (Nkmur et l., 198; Jolly et l., 1981; Hof, 1983). Ischemi produced by LAD occlusion ws very severe in the presence of criticl stenosis. In mny experiments cute coronry occlusion performed before or fter the drug dministrtion hs shown tht the effect of diltizem my depend on the degree of stenosis (Futmur et l., 1982). We observed beneficil effect of diltizem during severe myocrdil ischemi nd tht this effect ws relted to the preferentil increse in blood flow to the subendocrdium (Mrshll & Prrtt, 1974). The mechnism involved in this redistribution of flow within the ischemic zone is unknown; it my be relted to the decrese in LVEDP (Futmur et l., 1982). LAD occlusion in the presence of criticl stenosis cused prticulrly mrked increse in LVEDP nd diltizem decresed this significntly. This would protect ginst the decrese of subendocrdil blood flow (Futmur et l., 1982). On the bsis of the beneficil hemodynmic nd electrophysiologicl effects of diltizem we expected preventive ction ginst ventriculr rrhythmis nd ftl ventriculr fibrilltion due to severe myocrdil ischemi. This expecttion ws relised since diltizem mrkedly decresed the inhomogeneity of electricl ctivtion nd ST-segment elevtion. During LAD occlusion in the presence of criticl stenosis, diltizem significntly reduced the number of extrsystoles nd ventriculr fibrilltion did not occur either during the occlusion or its relese. Diltizem thus decresed ventriculr rrhythmis to the level observed during control LAD occlusion in the bsence of criticl stenosis. There re some reports indicting, tht diltizem reduces ischemi-induced conduction dely (Bush et l., 1981; Nky et l., 1981; Peter et l., 1982). This effect is ssumed to ply protective role ginst ventriculr fibrilltion in dogs subjected to coronry occlusion. In contrst, Ptterson et l. (1983) nd Sheehn & Epstein (1982) hve found tht the development of ventriculr fibrilltion ws not prevented by diltizem either during myocrdil ischemi (Ptterson et l., 1983) or during subsequent reperfusion (Sheehn & Epstein, 1982). Sheehn & Epstein (1982) found tht ventriculr fibrilltion rrely occurred on reperfusion in dogs with high collterl blood flow or when the region perfused by the occluded rtery is smll. In our experiments ischemi ws very severe since the ischemic zone ws surrounded by n re in which the perfusion ws restricted by criticl constriction. Under such circumstnces the incidence nd severity of rrhythmis incresed nd ventriculr fibrilltion commonly occurred. Diltizem, by its vsodiltor effect incresed blood flow within this restricted re nd directed flow to the ischemic zone by improvement of the collterl circultion (Frnklin et l., 198; Millrd, 198; Ngo et l., 198). We re grteful to Professor J.R. Prrtt (Glsgow) for his vluble suggestions s well s for criticl comments concerning our mnuscript. We lso wish to thnk G. Grosz for his vluble technicl dvices. References ANTMAN, E.M., STONE, P.H., MULLER, J.E. & BRAUN- WALD, E. (198). Clcium chnnel blocking gents in the tretment of crdiovsculr disorders. Prt I.: Bsic nd clinicl electrophysiologic effects. Ann. Intern. Med., 93, BACHE, R.J. & DYMEK, D.J. (1982). Effect of diltizem on myocrdil blood flow. Circultion, 65, BERTRAND, M.E., DUPUIS, B.A., LABLANCHE, J.M., TIL- MANT, P.Y. & THIEULEUX, F.A. (1982). Coronry hemodynmics following intrvenous or intrcoronry injection of diltizem in mn. J. Crdiovsc. Phrmc., 4, BOURASSA, M.G., COTE, P., THEROUX, P., TUBAU, J.F., GENAIN, C. & WATERS, D.D. (198). Hemodynmics nd coronry flow following diltizem dministrtion in nesthetized dogs nd humns. Chest, (Suppl.) 78, BRAUNWALD, E. (1982). Mechnism of ction of clcium chnnel blocking gents. New Engl. J. Med., 37, BRUCKNER, U.B., KELLER, H.E., MITTMANN, U. & WIRTH, R.H. (198). Influence of nifedipine on myocrdil blood flow in dogs with cute coronry rtery stenosis. Arzneim.-Forsch., (Drug Res.), 3,

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