Title

アセチルコリンの冠注で誘発されるブタの主および小冠動脈攣縮モデルの開発とこのモデル動物を用いたニプラジロール, イソソルビド・ジニトレート, ブナゾシンの冠攣縮予防効果に関する研究( Dissertation_全文 )

Author(s) Kawamura, Atsushi

Citation 京都大学

Issue Date 1991-03-23

URL https://doi.org/10.11501/3053050

Right 本文は出版社の公開条件により公開していない部分があります

Type Thesis or Dissertation

Textversion author

Kyoto University

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アセチルコリンの冠注で誘発されるプタの主および小冠動脈管縮モデルの開発と

このモデル動物を用いたニプラジロール、イソソルピド ・ジニトレート、プナゾ

シンの冠峻縮予防効果に関する研究

円| 村淳

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Response of large and snlall coronary arteries of pigs

to intracoronary injection of acetylcholine:

angiographic and histologic analysis

AlSll~h i Kawamura 1. Hi::.ayo::.1竹下UJI、，¥'ara1、Ttlm('yaunndera 1. Der-.Iinn Wu 1

Mitsuo ¥1ablH.la 1、MoriharllIshidu 1， GじnZOllTakemura 1， '{aslloori Fujiwara 1

and Chuichi Kawai I

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Kawamura A.ドiljiwaraH‘()nοdera T. ¥¥iu D・J."v1:tt、mbM、いhidaM. Takcmura G. Fujiwara Y. Kawal

( 代csp(\n~c (.)f largL' and、lTIallL'οrοnaη 辻rtcrie:--llf Pψto In tra~:orl\Oar~ injecti~)n 0r acetykh~)line:

angjographil.' (tnd hi~tol\)g lc analyぉiλ lntJ Can.li(ll 19lN:25:2終9302.

Wilhωronary arleri()記raph)附 ex;量llIinedthe effect (1( aCN~ Ich()line (1¥ぐh)011 lar良eand ~llIall {'ornnaQ

arh:ric草.ACh (l2.奈川 2似}μ日)¥¥'a!> injecled into the righl {'oronar:)o aru.'ric可。f10 pigs during Idl V{'ntrkuhlr

I)adng. The perceOla記世 ofnarrowin父()fIheをpicardialma.Ior coronar:)o artcr~ wa封 lLl¥cda~ 3n indicalorりfthe (.'On草trIl'tiυn (lf Ihe I日rgcl'(1r(.lIlaη.¥rll.'ric払靖則Jthe lil11t.' rNluirl'd for Ihe conlrll刈lIlcdium11'1 readl thc

1M附leriord制 ccndingcoronar下 artcr~ from rhc ostium of the ri良hlcoron"r~' 踊rteη ( bloodイlυw dcla)} w出

U持l'd泊‘ anindkalor of the COIl対Irictionof the災mallcorunar) arlerie丸 Asmall d(l~e of A Ch {12.5 to 1(附 μ同

induced mild narrowing (14 10 41'7(-) of 11)(.' epil'ardial major coronar下山rtl' r~ and持 markedblo(刈・rI()Wdday

of ()、'N 7.0 se{' (ωnlml: $ 1.8 sec) in all 10 pigs. A large do吋 ofAChけ伺 I()2ω 同)c<llL'，ed OH'r 7例

n泊rrowingof thc l'pic<lrdial rnajor coron泊Qart(.'ry and a markcd blood-flow dela~ in 4υf Ihl' 10 pi位、 Wh{'1lIIIl' Illarkcd bl()od-fI()w del的 apl附 arcd.the perf凶 edright、ωllricular1lI~ oc訂正liulI1became ll1acruscωpicalh

aneOlIC (isdlcrnk). ・rhcconslrittion of largl' and ちlIlall(.'oron泊り artcries was n()1 prc¥'l'ntl'd b~ diphl'lI'

h)'dr:unilw (HI blocker: 100 mg i.¥.). but was preu>llled b~ pretrealment with atrol)ine (1.0 mg I.，.). Thc

inlracMonary injl'clion of histaminc (I.S mg) in 5 pi野 ωnstrktedthc cpicardial major coronar~' 泊rtN~ 。、 {' r

75(~ in 2 piJ.ts. 50 to 759; in I pig・and25 In 50~f. in 2 I)i!.:s. bUI thcrc w悩 nol'、idl'nl'Cof blood-nl)\~ dela~ .

Neither lI1ethoλaminc nor norl'l)inむphrinccaUSl'd an) sij!nificilltl coronarう泊rter)narrowin~. Thc histology ()f

thc largl'州 d巧I)lall C()rO削 r)arteries was cxamined qmmtihlti刊行 withlln im油gcanal~ l{'r. Thc C(l roll.lr~

arlery showed no inlimal Ihkkt.'ning・llndth(' endoth-clium was inlact on lighl microscopic examination. Thc

%、arcavf Ih"，川100thlIluscle I川町 (mcdia)to thl' ('akulalt'd 10lal 、'''M.'ulararω‘and Iht' ratio ()f the

calculatcd mcdial thickncss to tht.'(.'akulall'd inncr radius (h / 伏i ) 帆crc か4 土 7~号 (mcan 土 SO) and 0.69士0.16.

n.'刈x'l.tin'I~'. in ttll' small coronary artcries Icss than 1似}μ111in extcrnal diameter. 47 士 ~~ and 0..19:!: 0.12

in Ihc small coron油ry泊rtcril'S10() 10 2000μm in l'xtc.:rnal dianll'tl'r. and 34土41耳、誼nd0.24 :!: 0.0.¥ in tlw lar)~l' righl (，.りr(lnaηartericso¥'(.'r 2倒防 μmin cxtt>rnal di ~似4

nむ只ati~、\'(' corrl'la泊liりnwi“th Ihc s幻izeοf Ih昔 corのnar~ ar刊tcr“ies.Thcs叫(.' f“indings ind“Il'ale tlu泊H ..¥、(ぐ、hα刊川B刊吋悦t付ricむts%

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Protective effects of nipradilol， isosorbide dinitrate" and bunazosin on coronary artery cons凶ction 也.duced~yin町a:coron~injection of acetylcholine in pigs

AωuぬiKawamura， Hisayoshi Fujiwara，. Mo.出制Is脳血，G包 zouTakemura，附句碍U京地，Tは&lhiUeg&Ito，.Muahiio Tailaka， ch叫ぬiKawai

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occuttea;"dii"~rijhtventitiUtU-riiJoWaium became ~Peall7 anaemic O.c:haemlc). Over 75% swrowb;IC of the. major epicardial c:OroD&r7 artery wu bulucecllu air of the 1S pip, ud over 50% ~wiq la 12, with maibcl·bloocl flOW de1a.r ~ lOO to lOO ,_,.. of acetJlCiaoU...! Ro......v, afte, Jntracof'ODU7 '1DfualoD of 10 J.l.& Of Diptadllol, ace­tylcholine lDducec! ~Win& m the.~ major coroJWJ artery wu ai.P,ffieantly red,ucecl from 44-79%in control to 19-37%detpite lOO J.L&of ae&tJI~o­line, thouch the time delay la co.toiWJ blood flow cUd not c:baup e.Jinifl.cutlJ •. By pretreatment 'With intrac:ardlae tao.Orbide dinltlate (l.S N), die per­cent narrowin& of the larp coronary 'UW1 and the time delay in c:orou.uy bloOd flOw were aipificandy .reduced' (n.afto:Wbac' from 32-84% to' lO.l7%; tiine delay &om 7.6-41.6 • to 1.1-1:1..1 •>· Pretreatment with liiti&eardiac baaazoaln; u a 1 aetrenoC:eptor utact»niat, (100 #A-C) ahoweclno protective effeCt oa narrowinc cl the qticarc:Ual'majo« c:orOnarr ~or blood flow delay. · · · ·

CottcUuitnu-&o.orbldedinltrate prnenm ccil'Oil­arr artery eoutdction induced by atet:jlc:holine in aw,iDe. NlpndDo1 prneDb lup, but DOt IIDil1, c:,o.ronary artery C?OJlatri~n, pro))ab)1 throup a

·~et a,ltrate' lib ~tiq ac:tlOil.

/

Q10010· Kawamura DiJc: 7 I •

Galley 1

The effectivcneaa of~ adrenooeptor antagoniJtJ on effort ~ and h~on hu been wdl c:stabliahCcl. ~ Howoever, treatment witb p ~ ceptor antagOniata ia ·pot alwaya beneficial, becauae they induce c:o.r:ooary_aitery ~· 5 and IOme cases of effort angina and/or hypertenalon are _accompanied by vuoaputic angina. Nipradilol, 3,4-dihydro-8(2-hydrozy-3-ilopropyl.amino) · propoxy-3-Ditnuy-2H-l­be:ozopyran (fia 1), hu been :oewly-l)'ntheaieed at the Tokyo R~ Laboratories of Kowa. Co, Japan. N"lpl'lldilol poiiCIICI llOD_-alec:t:ive ~ adrenoceptor blocking ~n~ a weak ~ adren~tor blocking action, and nitroeater' aroup activity~ NipradilOl di­lates coronary arteries in vitro.7 However', i~ preven­-tive efl'ect:a on the c:aoatriction of coronary arte1jea hav~· not beenc::umincclin viw, ainceno aoodanimal~el of large~ amal1 coronary_artery CODIUictionhu been found. ne raponae of h;uman ~ coroo.uy ~ to acetylcholine ia var;iabie, _rangi.Da &am dDatation to c:onatriction in the normal 1atgc cotOD&r)' f.1'te:tY. a. t However, _acetylcholioc senerally conatricta an .abnor­mal' large coronaiy artir:y' 10 and inducea 'lpum in most PJ~tl with vuiant angina.11 In vitt:o, acetyl­c:boline ~porcine 1arse coronary Uteries, u •lJ

and we rc:ccotly reported an aqiosraphic: atudy ahow· ins that it ~tricta porcine Jarae and IZDill .COI'ODI.ry arteries in vivo. 14 In the present atudy, uaina the a,.me pia model, ~ examined augiopaphically whether nipradllol prevented the CODI~OD of the iarJe and amall cOronary arteria induced by aceiyb:holioe. The effects of iaolorbide dinitrate and bno•Ullio, anal antagooiat, 15 w~ a1ao examined for .oompe.rison..

Meth~ ~ PRBP.GAnON . ·p-J.fteen farm pip, ~ ·ao to .90 q were anaesthetised with 'intramQICU.lar · ketamloe hy~oride(12.S mi·ks'"1)~follo,wed byintr&veoo:ua aod.i~ pentobarbitone (20 ma·kt*1), and ventilated with a vol~ limited ventilator. To aclude coronary artery a_pum cauaed · by hypc:nentilatioo, 16 the veotilatory nte and ioap1red oxyp:n coocenuation were controlled to maintain artcPa1 pH~ 7 .3S and 7.4S, putial arterial~ preaure.~ 10.6 and 16.0 kPa (~120 .mm Ha), ~ partial arterial carbon dioxide preaaure between 4.7 and 6.0 kPa (3S~S ~.Ha). ~b leads oftbC ~ograu1 and arterial' blOod praaure 'WC!EC moaitorccl continuously durh;\1 the ·exP.erlment. · 'EXPDIMBNTAL PJtoroc:oL The pip· were divided into nipr:adilol, ilosorbidc dinitrate, and bnn•'mlin arouP'.· Bacli aroup ,.. compoted of five pip. The heart waa eKpoaed by median ate.rnotomy 'and pacina wlra were implailtcd in the1eftwn~·&eewall Mtu.~of 20 000 Ubita heparin intra~, adective c:orooary arteriop'aphy wu pa:f~ by ~ manually about 10 -ml of warmed. {36-3rc) CODtrut medtum (lopamiron• 370, Nlhon Sc:heriD& KK) ihrou&h ao IF Sonea catheter. AcetylcholiDe diuolved in 5 .ml of

. wuined 0.9% ailioe .O.ution wu inj~tecfaiiD~ dosea of 12.5, 25, so. 100 and 200 p.g into ·me ri&ht c::oron.uy artery ~ 10 min. "l!Jght coronary aneri<>PJpby WU performed within 3 I after each

• acetylcholine inj~. When the dearee of narrowjng of the major epi.c:ardial riabt coronary artery wu over 75%~ the adminiatration of acetylcholine wu stopped. JrlfteeQ minutes later, wbai the effec:ta of myocardial iacbaeml•. induced bY acetylcholine infulion, ~ u anaemic coloUr and dya)dnetic movement m the right ventricular wall, had ·disappeared completeiy, the ~were then liven into the.rlgbtcoroziary iitery.In the rupndilol JIOUp, 10 J.LI of nipra~ol (Kowa Co, Tokyo), and in the buD.azoain sroup, 100· p.g of bnnameJU ~ Co, Tokyo), dillolved in S .ml of warmed 0.9% la1ine solution, were liven into the rliht c::oronuy artery. In the iao.orbid.e diniirate sroup, 2.5

0 ma q£ Uoeorbide dinitrate (Bisai eo. Tokyq) · wu injected into the riaht coronary artery. About 30 a later the ame doae of acetylcholine wu injected again into the riabt coronary. artery, and right "coronary arteriography was performed. To a?Oid brady­arrhythmiu and hypoteoaion during intracoronary injection 0£ ~lcboliDe,' co·rooary artc:rlograpbyw_u pet{~ ·while lhe heart ~te wai ~t ph.y_l.iologically conatant by le:ft ventricular pcina.

..

ASSJ!SSMENl' OF LAaGB ANl> SMALL CORONARY .U.'i'DY <::ONSnlCOON BY C!Oa.ONAltY AJtTZIUOGilAPHY . Corooary ~ wue reviewed.~ a video TV screen by ~ iDdepeodem,_ bliDded obtcrvcn. ~ lumiDal diameter of the. epicardial major c:oronary artery was meuured u.dnl iD imqe aiWyaer (AviD excel, MOOd TVIP-4100, Nippon A~ Co) with autpmatcd edge detection at proximal. middle, and diml sites of~ ri&htepic:ardial major coronary artery in marched eud diutoUc fn.mea. The nurowinrof the epicardial major corooary artery 1!'&1 c:akolaJCd u ((diameter before injection of AOl. minoa diameter after~ of ACb) + cHameter before injection of ACh) x 100: The ~um vilue amooa the abOve three aitea wu U8Cd u an iDdicator of laip c:o:ozwy artery c:ooatric:doD. The time required {or the conttut ·medium to ~ tbc pouerior detc:endin& coronary artery frOm the Oltium of the riaht·c:orooary artaywu meuured mcl dallified into three arades: marked delay: >7 .0 lj aliPt dd&y: 1.8-7.0 ··; and normal <1.1 •. Marbcl delay wu dcfiDcd u the time delay when m~ iacbaemia, auch u anae;mic colour chanp iDd dyakiuctic wall motion in the right vmtriclc,. appcu:ed. Blood flow delay wai uaed u an Jndex of aiDall conmaiy lrter1 c:cmatdctiaa, wbeD the ~ ofnarrowiDI of the major~ artery wu UDder 90% SICC tbe accdco ol animll model in Dilcullioo). 1 To deu:tmJDe Jnte(Oblerver variability, me radiDp were performed blind by the obterven coo.dUctiDI tbla study, UliDa the ~ a~ cUtferent timea.: 'J'be variability between~ tw.o oblenen wu ±5" tor thJ . JW'1"'WiDa' of me epicu:dW major CIOr'OD&l'Y uU:ty, &net ±0.3 • f'or the time of blood flow delay.

STATISTICAL ANALDD • lhc:mod)'DaliUc data . for · control and after ad­

miniatration of acctykbollne with or Without each qmt were com~ by Qll!C way ana1yaia of vUiance wi~ multiple c:om~IODI uaq & Bonferonni ~.Jn ~ poup (p<O.OS; aipifi<:tnt). The data Oil the coroaary artery DaaO'triD& and OD the time ofblood'Oow delay Jn ach &rOuP-= analyaccl by the pired t cat (p<O.OS.aipiflc:a'?t). Data were~ 11:1. ~ ftl~ (SD) •.

lleAb IWIMODDIAMIC OIANOBS ~ IJIU)lk and diutoUc ~and heart Uta did DOt c:baDae aipificantly .after the .injection of .acetylcbo1iD.e with or w.itbout Dipradttol; ~bide ~ or ~mamcbi (table 1).

---~-- --· ---·--- -- ·-EIJ'J!Cl'S 0'1 Nll"JtADlLLL, DOSODIDE DINrl'RATE AND BUNAZOSIN ON LARGE AND sMAu C010NAJlY AllTD.Y CONSTaicttON INDUCED BY ACETYLCHOUNB In. all pip; a delay in coroiwY blood flow .&Dd a narrowina of the. epicardial' major Coronary artery occurred dole ~tly ifter injections of acetyldlolinc raJllini from 12.S to lOO 14 (fip 2 A,B; tablca II-IV), and they aublldcd a.Pooimcoully within ·S min. Howevu, a marked· delay in c:oroxwy blood flow WU DOted in each pia when the DID'OWins of the .epicardial majQr coronary artery wu ~ (34% or less). . .

.Maaolc:opicall, the myocardium (riaht 1'tDtri.cular wall) auppUcd by the riaht coronary arterY became anaemic (ilchtemic) md wu clearly demarkated from the area IUpplicd by the 1c:ft coronary artery, when a IDarUd delay. (the time delay of blood ~ow > 7.0 a) in npt coronary .arterialfiow wu noted (fia 3). After the ad.m1Distntiol1 ollO H of nipradilol into the riaht cuco.uy artery. DUrOWina of die epLc:ardia1 major rlaht cbroDary artery IDduccd by 200,.... ~ reduced from 44.79%, before .the adminiatrition of nipndilOJ., to 19-37% (p<0.01, fia 1 C). 'I:bt ratio of percent DI.ITO'flrin&' fo11owins pretrta~t with Dipradllol to that of control without nipradilol'at a maimiun. dole of 200 1'1 ICCitylcholiDc pcrcent CODttrlc:tioD of the- Iarse coronary UU:ry with nipndllol) wu 49(8)% (38-S6%) (p<O.Ol). However, there. wu no aignificant difference in the time delay in c:oroouy blood 'f10w with oc without nipradilol; the ntio of the time delay in coronary bloocfflow follo'Wing pi;'Ctrelt:mcDt with nlpndilol tO that 'of conuol

· ~tioo of accty~ without Di~ol (percent c:eoatricdoD of the a;nall corooary artery with nipnd.ilol) wu95(9)%.(86-108%).

After 'the; ........ ........_ • ..., adminiatration of2.S of --~~ . Dll, iaorbidc dinltrate, the DmOWing in the m&Jor epiCardial. c:oronary artery at the same dole of ac:etykhoUDe (100 p.&ln one pia &Dd 200 14 in the other four pip) changed from 32-14% in the: contt01 to 10-,27% (p<O.Ol); the percent c:oDsu;iction 9f.the 1qe COl'ODU)' artery with ~rbide ·dinitrate wu 28(4)% (21-32%) (p<O.Ol). With iaolocblde dinitrate

. ~tmeot .. the time ~in~ blood fiow wu -tsniflC.Dfly rec~W:ect io S3(21)% {26-76%) or the CQDti:ol value when acetylcbolme wu ail'tD without iiQsor~ dlnitrue; the ~t ·.colllt:ric:tion of the small c:orooal'1. artery with iiosorbide dinitrate was S3(ll)% (p<O.OS). . ·

ln each pis · of the btm•znsin group, despite pretreatmcllt withintracardiac bim•zoain (lOO p.g), the iame d~ of .intriCUdiac acetylc:holine (200 p.g) induced a ~ narrowing of the major epk:ardial coionary artery and aiml1ar blood ilow delay u the COil~ without bnnaroti.n ~tment (fig 4).

I>iac:uuioD ANIMAL MODEL Injection of acetylcholine in~ the left coronary artery alm,o.t alwaya ind~Jc:ed ventl;icular fibrillation and death in pip. Tberdotc, acietylchoUne W.. aclcctivcly liven into the zi&ht COl"'OarY artme.. To avoid bradyarrhythmiu and hypotenalon after the intnle:OrOoary injection, • pecem•ker wu implanted in the left :ventricular wan. ha a rault, the baemodynamJca were DOt alta'ed aJ.Inificantly by the ad.miniltndOn Of acetY.lc:bolioe, 'with ~ wi~o.Ut Dipndilol, ~ diDltraie,. or bnnazoain. We do not ·know whether the praent data frOJD the ri&ht corona'ry artery can apply dii:ectly to the left Coronary artery. . . .

In the present study, wc used a.ngiogllpbic: narrowing of the major epicardial coronary artery u aJi indicator of~ oflqecorooary arteries, and delay in the coroouy blood 1low :without aignific:ant (mqrc than 90%) narrowing .of the ~JOt cpicard.ia1 corouary artery u an iadialtor of C0D1triction of ama1l corouary arteries. The tin;le ~ u an index of smaU coronary artery CODitrlction 11 influenc:ed ·by 1ai:ge coroiwy artery reapoD~a, when teVcte Darrowins occun in a IUP, c:orooary artery. In our previous atndy, intriC:Ol'OIW'J injection of h.immiae did oot induce any time delay in coronary blood flow despite 7S-90% ~,.of tJJc epicardial major caroiwy aruzy.l4 In the prc.lellt itudy, ID)I1J. d~ of ac:etylcbolinc induced • marked del.aY in coronary blood flow despite D1ild nairowina (~~)in the epicardial major c:orooary artery, and: C'ftn at large doaes of~ (lOO. or lOO. #Jt&)~ a marked delay :in COl"'JW'y bloOd flow waa aeeo with lea than 84% cpic:uWal· major COl"'JW'y artery n.irrowina. The time

• delay in COl"'JW'y bloOd flow in the pfeaent atudy therefore ~ amall coron.ary artery c:onattiction. Althoqgh tbcreprocluc:ibllity"ofthca~timcail aood, the metboda m the pmau study arc Dot quaoti~tive with rcpid to the relatiooahip betweeil COI'OG.UY·artcrill preaure·aod blood~. However, nriDc c:oronary artery wu irritable ·to nwh•nieal .amu1i and induced spurn and ventric:ular fihdUation were cui1y induced. 'I'bereforc, wc did DOt uae any deric::ea. to IDCai\1R coronary b&ood flow. .

The CODtrut mediUm (1~•370_, NJhon Sc:heriDa KK) uaed in the preaeDt lllJdy ia DOD·ionic, and hu b~od)'J;WDlc c::ft'eet» auch u vuodilata,don. altbougti the dearee of 'ftiOdllatation ia ~ than that ciUICd by ionic CODtrut media.17 However, it wU impouible to oblene this pbeoomeoon with the ~ctbod Of~ art.cposnphy ~: IDdicatara 'of 1arse and amall COI'OIW)' artery CODitrictioD "'= theidorc.Wl}oscd to,ie.ther with conttol artcrioaraina, which wae pcrfoaDed uaiDa infulion ·of .cootraat mediUD:l·alone, and 'with ~ uaiq coi,ttrut medium with or 'Without CIC)lipllt aftei • · • • of ~· ·· ·~ t':n .. 9&._T.,..._1' ,.... - - ·

OOMPAJUSON OF EPl'1ICTS OF ~RADn.oL, ISOSOJtBm:a DINlTL\'tZ AND BUNAZOSIN ON CxmsnuCI'lON OF LAllOZ AND SMALt,. . OORONAllY AllTDID .· . In previo.ua htiman and animalatudiea, the dOitl of ~ve drup which were given inlo the right .c;oronary ~in~ Jli'CICDt study were aufficlent to produce rapoDICS in the C!OrotWY arteries without ayatemic eff'cc:ta.• 10 1'-» The ptesent data reveal that pretreatment of Dipradil'ol reducea 1irge · coronary ~ COliatriCtion 'induced by acetY.lchOline. It .hu been rePorted that Dipradilol poncaaca a J).yceryl

· trinitrate like 'VUOdilating action and weak a adr:enoceptor. blocldni action, ~ . ad.dition to a non-eelective P adrcnoceptor ~action.~ It is known that ~ admlOCieP.tor qoniau relax. porCine c:orozwy arterlea and ~ adrenoceptor antaaoDhta constrict them in 'ritro.• 1 At~, the effects of u adrenOceplQr ~ta and antagoDiatS on the coronary artery are controvenial. ~ The pre~ent study revealcCI· that bun•MCJn, u an eel adrenoceptor antaganjst, u did DOt s)tevent poicine C\Ot01W'Y artery c:onst;rictiOD induced bY acetylcholine. ~ data are conailtcnt with ihe view that methoxamine (al .ac:lrenoceptor aaoniat) hu.n6 effect on re1axi,ns ~ coronary · ~ in vitro. 2S It ia ~ell kno~ that 1&9aorb.ide dinitrate, a long dng nitrate, prevenu the coMtricti.on of coronary artery in.humana.11 19 In the present in vivo 'atwly, l:ioth iaolorbide dinitrate and Dipradilol prevented the c:Onairlction of porcine large c:oroo&ry ~ induced by ~tylcholinc. This aug8esu ~the sm-=ti~ etfec.ta. of Dipndilol on large coronary artery CODitriction in swine are oot due

· to .a adreDocep~ or p adrenocepror blocltin& iction.a, hu~ to nitrate like vuodiktina i.Ction.a. However the pco~ve dfccta of i:UP.fldilol-.M iaolorbide dini'trate were different; .iaolorbide dinitrate prevented the constriction' of large and ana1l c:oronlry ·arteries induced. by acetylcholine', but Dipradllol prevented onlJ the c:onatriction of the large c:Oro.nary arterY·

. Ni~ hu DOt only a Di~tc ~ vuodilatiog ~ b~t el8o an ~cct aa a DOD-:td~ p adrenoceptot: antqOnlat. 6 p AcUenoceptor antqoniltl conatrkt po[ciDe ~ and ana1l corooaxy arterlca,31

but the nitratt like 1uodiluing ~n appears more a,ttOng1y ·in the lar&e than in' the &mall corooary ~.6 & a. result, nipradil~ may .not have proteCtive ef{ccu on ana1l coronary · ~ ~cti9D. .. ·.

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