Vol. 244, No. 3Prirz2ed in U.S.A.

ABSTRACT

ABBREVIATIONS: ESPVR, end-systolic pressure-volume relationship; PEG, polyethylene glycol 400.

1000

0022-3565/88/2443-1000$02.OO/O

THE JOURNAL 0? PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

Copyright © 1988 by The American Society for Pharmacology and Experimental Therapeutics

Effect of Nisoldipine on Coronary Resistance, Contractility andOxygen Consumption of the Isolated Blood-PerfusedCanine Left Ventricle

JOCHEN D. SCHIPKE,1 DANIEL BURKHOFF, JOE ALEXANDER JR., JOCHEN SCHAEFER and KIICHI SAGAWA

Department of Biomedical Engineering, School of Medicine, The Johns Hopkins University, Baltimore, Maryland

Accepted for publication December 1 6, 1987

Nisoldipine reportedly has little direct myocardial effect. How-ever, because of interactions between the heart and vascularload, the effects on myocardial contractility and left ventricularoxygen consumption (LVO2) have not been established. Theauthors performed experiments on six isolated, blood-perfusedcanine left ventrides that were isovolumically contracting andpaced at constant rate. Coronary arterial pressure (CAP) andcoronary blood flow were measured for evaluation of coronaryvascular resistance, and coronary arteriovenous oxygen differ-ence was measured for determination of LVO2. lntracoronary

injection of 1 and 10 �g of nisoldipine decreased coronaryvascular resistance by 1 6.9 and 36.8% (CAP 40 mm Hg),respectively, and by 21 .5 and 47.7% (CAP 80 mm Hg). Atboth doses, nmsoldipmne caused no decrease in peak systolicpressure as long as CAP was kept constant at 80 mm Hg.

However, when CAP was decreased to 40 mm Hg, peak systolicpressure was significantly decreased even without nisoldipine.This impaired contractile state was associated with a decreasedcoronary blood flow and a slight decrease in LVO2, whereas 10IL9 of nisoldipine at CAP 80 mm Hg increased LVO2 signifi-cantly. Using the end-systolic pressure-volume relationship asan index of contractility, the authors found nisoldipine not tochange the contractile state at CAP 80 mm Hg. They concludethat nisoldipine decreases coronary vascular resistance over awide range of CAP. It neither depresses the contractile state nordecreases LVO2 in the canine left ventricle. Nisoldipmne mighteffectively counteract anginal attacks by dilating the coronaryvessels without depressing myocardial contractility as found inthis study on normal ventricle.

The pharmacologic properties of nisoldipine, a calcium an-

tagonist of the dihydropyridine class, have been investigated

for about 10 years. It has consistently been reported to have

marked vasodilator effects on peripheral vascular smooth mus-

cle both in anesthetized dogs (Kazda et at., 1980; Knorr, 1982;

Maxwell et at., 1982; Hess et aL, 1984) and in humans (Pasanisi

et at., 1985; Rosendorff and Goodman, 1985; Debbas et at.,

1986). Thus, like other slow Ca�-channel blocking agents, its

use has been proposed for the treatment of hypertension

(Knorr, 1982; Maxwell et at., 1982; Wanibach et at., 1984;

Pasanisi et at., 1985; Laederach et at., 1986).

In addition, nisoldipine drastically reduces the coronary vas-

cular resistance (Maxwell et aL, 1982; Rousseau et at., 1984;

Lopez et at., 1985; Serruys et aL, 1985), and, because of its

spasmolytic properties (Perez et at., 1983), it could be used for

the treatment of variant anginal attacks. There is also consen-

Received for publication September 8, 1987.

1 Supported in part by a postdoctoral fellowship from the American Heart

Association, Maryland Affiliate, and by the German Research Foundation (DFG;Schi 201/1-1). The study was supported in part by National Institutes of HealthResearch Grant HL 18912.

sus that calcium blocking drugs are useful in treating stable

angina (Moskowitz et at., 1979; Hossack and Bruce, 1981; Silke

etat., 1985).

Nisoldipine has been reported to improve the oxygen balance

of aerobic metabolism in ischemic myocardium (Rousseau et

at., 1984). This beneficial effect could be due to three different

mechanisms. Nisoldipine, like other calcium antagonists, may

increase the myocardial oxygen supply via an augmentation of

collateral blood flow to the ischemic area (Henry et at., 1978;

Warltier et aL, 1981; Crottogini et at., 1985). However, these

findings have been challenged (Weintraub et at., 1984; Sjoequist

et at., 1985; Tumas et at., 1985). Second, nisoldipine could limit

the consequences of decreased myocardial blood flow by de-

creasing the oxygen demand through reduced ventricular after-

load (Vogt and Kreuzer, 1983; Lopez et at., 1985; Tumas et aL,

1985). A third possibility is that nisoldipine also has direct

suppressive effects on the myocardial contractile state and,

consequently, on myocardial oxygen demand.

As to the direct effect on myocardium, some investigators

report positive inotropic effects (Debbas et at., 1986; Sakanashi

et at., 1986) and some report negative inotropic effects (Rosen-

76.0 ± 10.3701 ± 112

79.3 ± 13.0

21.1 ±9.220.8 ± 07200±0.4

006 ± 38.194.5 ± 198

1083 ± 386

661 ± 271741 ± 322’

103.8 ± 40.2’

60 ± 3.10.7 ± 2.36.0±3.2

61 ± 378 ± 4.4

42 ± 47

46 ± 1.060 ± 1.26.7 ± 0.9’

1 �g10 �g

, P < .05 control vs. I “0 an#{248}control vs. 10 � el CAP � 60 mm Hg.tP< .05CAI�00ve. CAP�.

loAn

dorff �n4 Uoodmtsn, 1U85; Tt�k�h4�hl tind Tt�iri�, 1986), wher�othors do not find �ignlflc�nt changes in th� ecintr�ti1ta stiitt�

(Sorruys ef a!,, 19$5; Supr�sn�t..� � � W85; Tumiis et a!,,1D$�), The� t�ontroverst�1 fln4ing� could be rhw to th� compl�

IntOMctIon$ betwt�n th� ctrug�ln4uc�d decrease �n met*n �rte�

r1�l pr�Mur�, b�rt�r��ptor r�flox�ln4uc�d tt*chycar4its �nd r�losse of e�t�cho1�min�s unthar th� in i.ilvo experinwntal �ondl�

tion,w� w�lnt�d to �nvo�tlg4to thsa dir�et offet�t� of nlsotdipino on

left v�ntrieu1�*r �ontr�tUity �n4 oxygon �onbumptlon inde�pondontly of the � effo�t.a �ia � v�s�ulnr n�tlons,Thoroforo, wo �nve�tignted the offo�ts of nisoldiplnt� in on

Isolot�d, bloo4�porfubed �onine hoort proporotion tho� ho� beenusod in our loborotory for etudylng the 1�SPVR os on index of

�ontro�tl1ity ($ogowo1 1U7$) nod the energetfre of ventriculor�ontro�tIon (Buga et a!. 1981),

Msthodi

Oenor*1 pr�pai�n�Iou. The supported i�otete4 �onine heort prepe-r4L100 ho� previon�ly lwen 4e�ribe4 in 4e�oiI �8ts�o ond Me�ewe, 1974).In brief, two 4ogs (20-25 kg) were one�the�e4 with eo4ium pentobor-htt4l (30 mg/kg lv) The heort wo� removed from the 4onur 4o� endperCu�e4 with blood from the ��pport dog with the aid of e �ons�entpre�ure perfusion pump (fig 1) The perfus#{232}onwee retrogm4e through�he eorti� or�h i4p e eennqle ineerted in the left Mulwlevien erterv�oronory orteriel pre�sure we� moniU�red from the cennule in the

brRehkwephelle ertery After opening the left etrillrn end �,tt)ng thevhnr4ee tendineee, e lete� hellon wes pliwed in the left ventriculareavity, An adapter was sutured tn the mitral ring to aid connection of

the ventrieular halloo �n u the ventricular volume servopump The �pecebetween the balloon and the ventricuter welt wee vented Arterial PCO�

pos and pH of the eupport ring were maintained within the normalranp (�eigl and P’Alecy. 1972)? Arterial PQ� was raiaecl if neceeaary,

by anriehing the in�pired air with o�ygenThe coronary venous blood flow wea meaaured by 4rainin� the

Pig, 1. 0ehorn�tie d$�gr�m of the IsolMed o�nine howl prepereflonCoronery peritmion w�e meinteined with blood from a support do� Theleft vontriouler oovlty wee filled with e belloon that wee oonner�ted to apiston pump The i�ovolumioelly oontreoting venirsouler aevity volumewos *ot �nd aentrolled by e servomotor oonneoted with the pieton pump.AVO� ertoriovenoue ditferenoe in oxygen content

Nlaoldlpino and tha laolated Heart 1001

unloaded right ventricle and by uaage of an electroma�netiv flowmet4rlilT 400k Narco B�o�8y�tema, l-Ioustcan, TX. The t�rnperature of theperfu�ate we� kept cloae to � To mtn1mi�e any effet’te of nl�oldIpineon the aupport 4#{176}Lthe coronary venou� line was eRposed to light and,e�cept for the infusion line, only silicone ruhher tubing wa� usedhecauae of its high affinity to niaoldipine (4� Jong et 4!� 1984)

Ventricular volume control system. The servosysteni (see fig. 1)

baa been previously deacribed in detail ($unagawa at a!, 1982) Briefly,the poaltion of a piston within a cylin4er (SM-4�F�8M; Bellofram,Burlington MM was controlled by a linear motor (4l1� 1..ing l�lectron�ice, Royaton, GB) The intraventricular latex balloon, the connectingtube and the cylinder were filled with water Thue, a change in ventric�ular volume woe accompanied by a displacement of the piston A signal

derived from a piston-attached linear displacement transducer (Trans-

Tel� 244-000) was compared with a volume-command signal Thedifference was used as the error signal to be supplied to a poweramplifier (DC�iO0� Crown glkhart, IN) to drive the linear motor.Thus, we gave a constant volume command for isovolumic contraction

and changed this command value when we wanted to have isovolumlc

contraction at several different volumes for determination of theVII

il�perImental prifiocol, II�periments were performed on si� iso-

lated canine hearts (149!�1 ± 3$. I g). The hearts were made to contract

isovolumically at a volume of about �0 ml, at which the average peaksystolic pressure was 90 to lOt) mm Hg They were paced at a rate �0%

above their sponteneous rate throughout the eRperiment After thepreparation was stahiliaed coronary erterlal pressure was stepwisechanged over a wide range (�fI-1�O mm Hg) to obtain the coronaryarterial pressure-flow relationship at the same ventricular volume! Toevaluate the effect of nisoldlpine on the left ventricular contractileatate the IISPVII was determined by changing left ventricular volumesat several values while coronary arterial pressure was first kept constantat ahout $0 mm 1-Ig and then at about 40 mm Hg (table I)

Because nisoldipine was to he dissolved in PIIG, we administered a

TAft� 1

IUeot of atrocoronary nl�oldlplne at coronary artarlal pre.auria ofsbout 40 (left) end ebout $0 (rl�ht) mm HgCAP, coronary arleiial presaure; LVV left ventricular volume; i�V�P left ventflo�ular en�1�syetotc pressure; ChFI coronary blood flow; �,. elope oftiw �8PVFi; V5

volume intercept of ttie �fl�Vft LVQa l&t ventricular osypen consumption

GAP (mm Hg)control

I �g

10��gLVV (ml)

control1 �g

10 �gLV�BP (mm Hg)control

I �10 �g

CRF (mI/mm/IOU g)control

I �g10 �

�.‘ (mm Hg/mI)control

I �10 �g

VP (ml)control

I �g10 �g

�-vos (mi/i c�o � and beat)control

43.2 ± 674�.9 ± fil445 ± 64

206 ± 100190±9.8

64.3 ± 144t614 ± 20�t663 ± 214t

�EL5 ± 17.6t4�.7 ± 18.2t’fiU!2 ± 26.8t5

flU ±4.� ± 1.ot3.9 ± I 7t

4.8 ± 416.0±3.846 ± 4.3

3.7 ± 1.13.7 ± 1 441 ± 1.flt

us

180

0

0

C

E

! 120

‘a.a0

80

0

1 ug

control

0 40 80 120

CAP ImmH#{243}I

leo

-. leo

I

us

0

0 20 40

Lv� (ml)

1002 Schipice.tai Vol.244

bolus of 1 ml of PEG into the perfusion line to see whether it causedany response in coronary flow and ventricular pressure. After a newsteady state was reached, we repeated the measurement of the coronaryarterial pressure-flow relationship and the ESPVRS at both coronaryarterial pressures about 3 mm after bolus injection of 1 �&gofniso1dipine.It took about 50 mm to complete these measurements. The effect ofcomparable doses of nisoldipine has been reported to last for 60 mmby Maxwell et aL (1982) and 120 mm by Kazda et aL (1980). Themeasurements ofcoronary preseure-flow relationship and ESPVR werethen repeated after administration of 10 gzg of nisoldipine. Administra-tion of nisoldipine did not necessitate the readjustment of the ventric-ulei volume to maintain the same peak systolic ventricular pressure.For normalizing coronary blood flow to 100 g and for calculation of theleft ventricular oxygen consumption, both the right and left ventricleswere weighed at the end of each experiment.

Data acquisition. Left ventricular pressure (PC-380; Millar, Hous-ton, TX), ventH�t.il� �rb1tthi�, ait�riov�ki�us &fF#{233}i�h#{241}c#{235}in #{244}*�vgh#{241}con

tent (4�k� S�74thii1; �#{225}ftAiI)#{243}hio,‘ti), coiOh#{225}� �renoti� bioo�i ��iiai� #{225}fthH#{225}l�si�tsuie (t�3b�; S�#{225}flithiI,U*#{241}thi,CA) dud Rf+�H#{233}J

pressure of’ the sup�oF� dog (Smtham p23Db) weFe t�dhtin#{252}#{243}u*i�r�corded (i�et,ordhr �RO0 t3otild, t�ih�#{235}land tili) All variables *�res�.&�!43it th*�ii htik� di*k a�ei dig1�ii1iig a�a �ath�lihg mth of 2t10 tia�te� #{225}h#{225}1�s1s(LSt ii/34; bEC, Ma�#{241}#{225}i�d,MA).. . �i��iIa&i8fii �iit� i1;aH�th�aI #{225}i�rM� A�oi�ding to Pi�’s �m-cip’1e�t�e myot#{225}rk�1�lo�rg#{235}nconS#{252}m�iott was c#{225}ktilaled as l�ie �fot�iil�to�c�ron�rjv vhti�3U* f’lo* dstd �i+hrio�hno#{252}s �ifterence in oxyg�n �biittht

T#{176}�#{231}ulat;e the left �‘hiitFi#{235}til#{225}io�eki cd#{241}suiiiptibn, we �Iist �3lk�thdthe myoc#{225}rdi�l o*yg�h �,otIsuthpt1oii ag�inst pth5sure �rolIim#{235}area(�ig#{225}��fat., 1981) #{225}iidIheli flfi� 1�I� d#{225})#{225}1o a regrasalon line. the

�!��8iOh lbha�Iii� � ti2 �#{243}fl$#{220}th�UOflal aeio pf�ssuib-*�o1#{252}thh #{225}ih#{225})is co�sI4�fbd th f�f�a�kit a �uth of�h� baa�1 and #{225}�tFtr�tkthIdthJkth�iif.e� ��aidiai o�rgh#{241}C#{243}iimii*�H#{243}nof the unl#{243}fldedilRht thid l�t

�en�c�*. We t�1�Tl�� �j5 coiii�tthaiil lit p�o�oHion th t�1e right andje4 s.i�zitfit�iila� *alghli aiid, I%i#{225}#{220}�atha fight v�ntHc1C *asunloa4ed �tibtrac�ed th� ttnload�d right �renlncular oijrg�n t�onsttinp

t�! � � �Tah1�s o� th�i*ai*li#{225}i ot�g�h eohsuthp�io#{241}th obtain left

venti�cuIar d*3rgeii b#{243}n*tii#{241}pti#{243}h., ��jg of �r1Haii�e tbi� re�ated theasui�es (�Mb�2V) *as �th-plo�4 �OF �tat1�tik�a1 tests to leblate the eff�t ot the tfhatmerit amultiple cdtii�l#{225}risb#{241}Prd�%dUr� #{225}c�ordingto �onterroni *aeperfbfmhd�or c�ijiaHklg I�bFtth#{225}f.�Tih*latan k�CS 1*Ibi4 iiid aftef adthlnietmtlbn b�

t:�; �pai� t teat *o� �mae&i.A t� �iue lees than .05 *as �oiIaid�ed�#{243}�ir�di�;e smt1st1�al sightheai�e. bata a�e ke�oi�ted as theati �lti#{235}e±� .,,

�j!c1;�bn of the s#{244}l*�nt (t�EW ��#{252}s�d brief d�teaSes liicor#{224}nazyf�R1�t#{225}h�C arid l� *r�kitH�#{252}1at ehd�std1l� �F�8S#{252}F#{235}

�a�r � ei�as� o!��% arid itt nith ti�� �Q�3 s�t� after the lktj�tloh. tile �t �om�l�te!� t�la�i-peare4 in R2 ± 38 se� We t�ie�f’�i�e #{225}st±�ib�all th� e�f�t.a�cr�.Ib�#{225} beld* to hi�oId1�lkie����dfdh#{225}� itij�t�tidh o� iiiaotiIij�iiie d�tea�d the tesist-ai� O�111� l�bfbft#{225}ij7 i�%l:� lb a�#{243}s�#{128}�leii dtht th#{225}ii#{241}�f(� 2).

� exanipl#{233}, at a �o�tiii#{225}� aft�Flfl.l �essure o�80 i#{241}th�g, iaj.�4 i� � ti�kilsbldl�i1ki� d�kif�as�kI th� theaii cbr#{244}h#{227}�f�1st�ht%

�rom149±O76to117±b57anItdIi7B±040thth#4g/thi/th� � g; F�5�%t�tirC1y; th�s� de�ieases ate 215 and 47.7% ofco1�ro� (t.able 1) As e�ltIeht iii f1�ir� 2 autoregti!ation of

c�ronary tlb* *#{225}sg�at!y f�dU�ed itt adlitlon e*ren belb* t�1e

� ssiire �iig�; i amid iO �g of nis�1dl�ii#{241}� stillre4uced �he t�kii�tift#{225}fj7 F�sistaiit�e At a cotonary arterial �,f�ssttr�o�abou� 40 #{241}imtig; the Fealatahee *�e �e�easad froth L36 �hcj�7� �;: j�j� ± t�j� ahd i.s� ± o.� mni tig/ml/mi� . j��tj g; �

� � L4liti � F�s�et�tire!�r. A� C�ridtht in fig�ite � the

�. 2. R�aae�a�e �&�tIoiishlp #{243}bt&�dIn a tie#{225}i1b�*aari corOna�#{225}F[�H#{225}l�Ui�a #{225}�dl�#{243}�b�yb�dd ft�* b�t� (0) #{225}�aft� b�tusI�j8#{233}fI�i�at � (*) �i�d io (*) 0g o� nI�i�lh� l1�1#{224}�oi�oi�� �ttma�E�AP.�o�aiy a�1�riai pi8�st#{224};bBF, cored a� �

h� � R�fr��iitafI�e E�PVR b�#{243}i’e(0) and aft8� b�IUS l�J�h#{243}�i d� I(*) �k�d Id (*) j� �3l ril�l�Ifi� frito .i.*�hiaf� ��Sl&i Illid. L�i’� �&t�htft�i�a� �U�; E�/, l&� �fitf$#{234}tiI� v#{243}�uh*.

thf#{235}e�ofonaf� afteflal �fess#{252}Fe-b1ood flow t�#{252}�s�#{244}h�f�d ata �oiiithoii poitit on the p�suFe a*ls. ‘this pF�ssufe iht�F�j�t

a�eFa�d ie�8 ± B.8 ftth� �4g�W�i�i1 �#{243}roiiai�r #{225}it#{233}rl#{225}!�ssure *a�ke�it constant at about

so ifith }�g; iluj�t�t1Oft b� 1 �ht� 1t� � of ii1soldl�1h� c#{225}liS�tilib

�hah�e lii left veritrlcuiaf end systolic #{216}essu.te(table 1) S1uIilati� 1fij�tioh o� iieitiie� i nor 10 � of riiaok�lj3lhe slgiiitl��aiiti� �1aiiged thC slO�3e Oi the volume 1iit#{233}t��ptof the EIS!�Tti

(fig� � tabie 13. 1hje�tion of th ,i� of hls#{246}ikli�ilh#{235}llirfeaaed l�f1�efitfl�ulaf o*�gem� t�oiistithptioh sl1�ht!� but at#{225}tistit�#{225}.ii�aig.fi1f1k,aht!�r (table �

th.if tesuith ifidirate th�ee &ffefeut �fre�ts of lkitfa�oFdiiaf�hlsbit�1�lft� on th� isoiated, blood-�ie�flised �anhii� left �kitFic!e�

bi�us�iou of ea�h of th�se efle�t� fblio*s.E�f�h� oh �bf*�*#{252}t�f�iM#{228}hbt� the eff�ts of iiitrat�oto.

� uisokIi�1he on the �sistat�e of the &�o�oiiai� bei� o� theicolated heait are ih good agreei±iekit *ith C#{225}tlICtfiuid1i1�S iiiakieet!letlaed dbgs (Lath�bj� � a!.,i98� M#{225}x*�lI st #{225}t�i9R��e�auae t�ie cofonai� �SlSt#{225}ht� hi the lfit#{225}�tcotoha� b�d is

10031988

predominantly determined by the small resistive vessels (Famand McGregor, 1968; Winbury et aL, 1969), our results clearlyshow that nisoldipine dilates these vessels and thus tends toabolish coronary autoregulation. This effect is due to the direct

action of nisoldipine on smooth muscle cells (Kazda et at.,

1980). Below the autoregulatory pressure range, this direct

action is not effective anymore. However, circulating catechol-amines supplied by the support dog in our preparation are

additionally involved in determining the tone (i.e., steady stateof constriction) of the resistive vessels through atpha-2 adre-

noceptors (Heusch et aL, 1984). This remaining component of

vasoconstrictive tone can still be eliminated after the metabolicautoregulatory component is exhausted. It has been shown that

the influx of extracellular calcium is essential for linking theactivation of the vascular a�pha-2 adrenoceptors to vasocon-

striction (van Zwieten et aL, 1983) and that calcium antagonistssuch as nifedipine can reduce constriction of coronary resist-ance vessels (Vatner and Hintze, 1982; Heusch and Deussen,

1984). Thus, nisoldipine is expected to reduce a�pha-2 adreno-ceptor-mediated vasoconstriction in our preparation by block-mg Ca� influx. Our results clearly indicated that nisoldipineindeed antagonized alpha-2 adrenoceptor-mediated vasocon-

striction because it decreased coronary resistance even belowthe autoregulatory range. This property of nisoldipine (andother calcium antagonists) becomes particularly importantwhen coronary arterial pressure falls below the physiologic limitdue to stenoses and when the coronary autoregulatory reserve

of the regional arterioles is already exhausted (Gould et aL,1975). However, this property may also “steal” blood flow fromthe ischemic region.

Nisoldipine has been reported to have beneficial effects in

the treatment of anginal attacks (Silke et at., 1985; Takahashi

and Taira, 1986) and even to relieve coronary spasms (Perez et

aL, 1983). We can, therefore, consider that it dilates largecoronary arteries as well.

Effect on myocardium. The effect of nisoldipine on heartcells has not been as clear as its effect on vascular smoothmuscle. Kazda et aL (1980) report that nisoldipine reduced thecontractility of guinea pig papillary muscle, and Takahashi andTaira (1986) describe similar effects on canine papillary muscle.

In addition, de Jong et aL (1984) report a significant negativemotropic action on rat hearts; Rosendorffand Goodman (1985)purport that nisoldipine is a negative inotropic agent. On thecontrary, Sakanashi et aL (1986) and Debbas et aL (1986) report

positive inotropic responses of the heart to this drug in dog and

man, respectively. Finally, a third group of authors found no

effect of nisoldipine on the myocardial contractile state in both

dog (Warltier et a!., 1981; Tumas et at., 1985; Hess et at., 1984)

and man (Vogt and Kreuzer, 1983; Rousseau et at., 1984;

Suryapranata et aL, 1985).

In fact, it is difficult to estimate the in vivo effects of any

cardiac drug from in vitro studies because the in vivo effect willresult from complex summation of direct myocardial effect,interactions between the heart and vasculature altered by the

drug and reflexwise altered neurogenic drive to the heart. The

interpretation will be further compounded if changes in con-

tractility are measured in terms of changes in the maximal rateof pressure rise (dP/dt,,,j, as in almost all studies cited above,

because this parameter is reported to change with heart rate

(Siegel et at., 1964) and pre- and afterload (Reeves et aL, 1960;

Wallace et aL, 1963), as well as contractility.

Our experimental data were obtained in isolated hearts in

order to eliminate compounding influence of the interactionsbetween the heart and the vascular load. For determination of

Nisoldipine and the Isolated Heart

the left ventricular contractility, we measured the ESPVR

originally proposed by Jacob and Weigand (1966) and shown

to be linear in the physiologic range of pressure, volume and

the contractile state (Suga et aL, 1973), and we used its slope

as a pre- and afterload-insensitive index of contractility

(Maughan et at., 1984). Because we studied isovolumic contrac-

tions, the slope index is free from loading effect. At a constant

volume and heart rate, we did not find any change in the left

ventricular end-systolic pressure, nor did we find any signifi-cant change in the slope of the ESPVR after either dose of

nisoldipine. These results clearly indicate that nisoldipine hadno inotropic effect at the dosages used.

Effect on myocardial oxygen consumption. Reports on

the direct effect of nisoldipine on myocardial oxygen consump-

tion have also been inconsistent. Some investigators report adecrease (Kazda et at., 1980; Hess et at., 1984), whereas othersdo not observe a change in myocardial oxygen consumption

(Rousseau et aL, 1984; Serruys et aL, 1985; Suryapranata et at.,

1985). It is generally accepted, however, that nisoldipine de-creases myocardial oxygen demand through reduction of after-

load (Vogt and Kreuzer, 1983; Lopez et at., 1985; Tumas et at.,

1985).

In our experiments performed under a constant loading con-dition and constant coronary arterial pressure, we observed a

slight increase in myocardial oxygen consumption after admin-

istration of 10 �ig of nisoldipine (table 1). This increase was

borderline significant at a 5% level. This result might beexplained by the increases in contractility and oxygen con-

sumption described by Gregg (1963) in the presence of approx-

imately constant physiologic perfusion pressure but augmented

coronary blood flow. Gregg’s observation, however, has been

challenged (Ross et at., 1963; Sarnoff et at., 1963). A recent

review by Feigl (1983) concludes the effect to be rather modest,

which seems consistent with the present observation.Effect of decreased coronary arterial pressure. Nisol-

dipine at a dose of 10 �g reduced the coronary vascular resist-

ance by about 50%. If nisoldipine was systemically adminis-

tered at such a dose that would reduce the total peripheral

resistance also by 50%, then coronary arterial pressure might

fail from 80 to 40 mm Hg. To estimate the effect of such an

overdose of nisoldipine on ventricular systolic function, wedetermined the ESPVRS at a coronary arterial pressure of about

40 mm Hg with and without dilation of the coronary bed by

nisoldipine. Without nisoldipine, this lowering of coronaryarterial pressure significantly depressed the end-systolic pres-

sure and decreased the slope of the ESPVR without a change

in the volume intercept (table 1). The impaired ventricular

function was associated with a decreased coronary flow and aslightly reduced oxygen consumption (table 1). With 10-pg

nisoldipine administration, coronary flow was maintained sim-ilarly to the preinjection level despite the lowered coronaryarterial pressure (�40 mm Hg). The Eec value, however, mark-

edly decreased to 3.9 from the control value of 6.9 mm Hg/ml

at normal coronary arterial pressure before nisoldipine. This

depression of contractility was probably owing to transmural

redistribution of coronary flow and consequent subendocardial

ischemia (Forman et at., 1973), rather than a direct negativeinotropic effect of nisoldipine per se. When coronary arterial

pressure was maintained at about 80 mm Hg, 10-gig nisoldipine

injection caused no change in Eec (table 1).

We conclude that nisoldipine dilates coronary vasculature

but has no direct negative inotropic effect or significant directeffect on the oxygen consumption of the isolated canine yen-

1004 Schipke et al.

tricle. It selectively acts on smooth muscle rather than cardiac

muscle and, thus, does not further impair ischemic ventricular

function. The beneficial effect of nisoldipine on aerobic metab-

olism of ischemic myocardium is amplified in vivo through its

dilator action on the total peripheral resistance, which de-creases myocardial oxygen demand.

Acknowledgments

We thank Mr. Kenneth Rent for his excellent technical assistance. Theauthors are indebted to Miles Pharmaceutical (New Haven, CT) for generousdonation of nisoldipine.

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