Nitroglycerin and Heterogeneity of Myocardial Blood Flow

REDUCEDSUBENDOCARDIALBLOODFLOWAND

VENTRICULARCONTRACTILEFORCE

ROBERTFORMAN,EDWARDS. KIRK, JAMESM. DowNEY, andEDMUNDH. SONNENBLICK

From Peter Bent Brigham Hospital and Harvard Medical School,Boston, Massachusetts 02115

AB STRAC T The effects of both intracoronary andintravenous administration of nitroglycerin on trans-mural distribution of blood flow in the left ventricleafter partial coronary artery occlusion was investigatedusing two independent methods. In 16 open chest, anes-thetized dogs, tubing supplying the cannulated left coro-nary artery was partially occluded. Strain gauges su-tured parallel to superficial and deep fibers of the myo-cardium separately recorded the contractile force ofeach layer. With occlusion set so that depression of thedeep contractile force was imminent, 12 Ag intracoro-nary nitroglycerin in seven dogs depressed only thedeep contractile force without changing systemic hemo-dynamics. Intravenous administration of 180 Ag nitro-glycerin in nine dogs resulted in a decrease of deepcontractile force and aortic pressure often associatedwith an increase in superficial contractile force. Dis-tribution of myocardial blood flow during peak coronaryflow after intracoronary administration of nitroglycerinor during a decrease in aortic pressure after intravenousnitroglycerin administration was determined by thetissue uptake of an intracoronary bolus of rubidium-8.This was compared with the uptake of potassium-'2injected before nitroglycerin. Intravenous or intracoro-nary administration of nitroglycerin caused a significantreduction in subendocardial blood flow with a decreasein the subendocardial/subepicardial ratio of isotope.

An. abstract of a preliminary report of this study, whichwas presented to the American College of Cardiology 3March 1972 in Chicago, Ill., appears in Am. J. Cardiol. 1972.29: 262.

Dr. Forman is an awardee of the Lilly InternationalFellowship Program. His current address is the CardiacLaboratory, Groote Schuur Hospital, Cape Town, SouthAfrica.

Received for publication 3 April 1972 and in revised form13 December 1972.

These experiments suggest that under conditions ofacute partial coronary occlusion, the autoregulatoryresponse results in more fully dilated subendocardialvessels causing them to be less responsive to nitro-glycerin. Nitroglycerin may then reduce the vascularresistance in the subepicardial more than the subendo-cardial vessels, resulting in a "steal" of blood flow fromdeep to superficial myocardium.

INTRODUCTION

The mechanism whereby nitroglycerin relieves the painof angina pectoris in obstructive coronary artery dis-ease is unknown. In the past it was generally believedthat nitroglycerin produced this therapeutic effect byincreasing myocardial blood flow through dilation ofthe coronary vessels (1). However, in the presence ofcritical obstruction of coronary arteries, the resistancevessels are probably dilated already and thus have losttheir responsiveness to vasodilating drugs (2, 3). Alter-natively it has been postulated that nitroglycerin actsby lowering the oxygen requirements of the heartthrough the reduction of arterial pressure by decreas-ing peripheral resistance (4) and reduction of heartsize by decreasing venous return (5). Others havesuggested that nitroglycerin may have its action by in-creasing flow through collateral channels, leading to achronically ischemic area of myocardium without sig-nificantly altering total flow (6). To date there is in-sufficient evidence to confirm any of the above hy-potheses.

Most recently evidence has been presented that nitro-glycerin alters the transmural distribution of the coro-nary blood flow promoting flow selectively to the suben-

The Journal of Clinical Investigation Volume 52 April 1973 905

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FIGURE 1 A diagram of the preparation used for all experiments. The common left coronaryartery was cannulated and perfused with blood from a peripheral artery. The system, madeof plastic tubing, included an extracorporeal electromagnetic flowmeter, a screw clamp whichconstricted the tubing, and a side arm attached to a pressure transducer. Intracoronary nitro-glycerin was administered by injection through the tubing as shown. The force gauge recordingsuperficial contractile force was orientated parallel to the epicardial fibers and attached withshallow sutures while the other was attached with deep sutures and orientated perpendicularto the epicardial fibers.

docardium (7, 8). These investigators have suggestedthat nitroglycerin causes a preferential dilation of thedeep coronary arteries and thus increases blood flow tothe ischemic subendocardium of the angina patient.

To test this hypothesis we have evaluated the effectof nitroglycerin on blood flow and/or function in thesubendocardium after it was placed on the verge ofischemia by partial occlusion of the left coronary artery.By administering nitroglycerin selectively into the coro-nary system, the direct effects of the drug on the coro-nary vessels have been studied in the absence of sys-temic hypotension. Experiments have also been per-formed with systemic administration of nitroglycerin.To measure changes in transmural coronary blood flow,contractile forces have been recorded simultaneouslyfrom both superficial and deep layers of the left ven-

tricle using a technique employing strain-gauge arches(9, 10). Additionally, the distribution of the myocardialblood flow across the heart wall has been measured bythe tissue uptake of 'Rb or 'K ( 11).

METHODSPreparation of dogs. The experiments were performed

on 16 mongrel dogs weighing between 18 and 32 kg. Theanimals were anesthetized with intravenous sodium pento-barbital (12.5 mg/lb) and ventilated with 100% oxygenby endotracheal tube using a positive pressure respirator.

After thoracotomy in the fifth left intercostal space, theleft main coronary artery was isolated. The model em-ployed is shown diagrammatically in Fig. 1. A Greggcannula was inserted through the left subclavian artery intothe left main coronary artery and firmly ligated in thisposition. The left coronary artery received its blood supplyfrom a peripheral artery via plastic tubing. Coronary flowwas measured with an electromagnetic flow meter using anextracorporeal flow transducer' in series with the cannula.Partial occlusion of the tubing was obtained with a screwclamp.

Separation of the contractile forces of the superficialfrom deep fibers was obtained by taking advantage of thefiber orientation of the anterior wall of the left ventriclewhich rotates 120° from the most superficial to the deepestlayers (12). Two isometric strain-gauge arches 2 were su-tured to the anterior wall of the left ventricle in each ex-periment. One was oriented parallel to the subepicardialfibers and attached with shallow sutures and the other wasattached to the inner fibers with deep sutures and orientedperpendicular to the epicardial fibers. The gauges weretested to verify their responsiveness. If the gauges werefunctioning properly only the gauge attached to the super-ficial fibers responded to local cooling of the epicardial fiberscaused by topical cold saline whereas both gauges respondedto systemically administered inotropic stimulus (e.g., iso-proterenol infusion) (9, 10).

1Biotronex Laboratory, Inc., Silver Spring, Md.2Walton-Brodie types, from John Warren, Department of

Pharmacology, University of South Carolina, Charlestown,S.C.

906 R. Forman, E. S. Kirk, J. M. Downey, and E. H. Sonnenblick

Procedure. 'As the perfusion tubing was gradually oc-cluded, contractile force in the "deep" gauge declined beforethat in the "superficial" gauge. In all experiments the per-fusion tubing was narrowed to a point just before thatwhere depression of contractile force of the "deep" gaugeoccurred. In seven dogs a bolus of 5 1ACi of 'K in salinewas then injected into the perfusion tubing. Within 2 min,12 /Ag of nitroglycerin in 20 ul saline was administered intothe perfusion tubing followed by 5 1ACi of TMRb at approxi-mately the time of peak increase in coronary flow. In asecond group of nine dogs, 180 /&g nitroglycerin was in-jected intravenously within 2 min of an intracoronary in-jection of 'K. An intracoronary bolus of 'Rb was subse-quently injected during the resultant maximum fall in sys-temic pressure. The two isotopes were interchanged inalternate experiments.

1 min after the last injection of isotope the hearts wereexcised, frozen, and four separate full thickness segmentsof the left ventricle removed. Each segment was sliced intofour approximately equal layers, from outer to inner wall,weighed to the nearest milligram, and dissolved in 3 mlnitric acid. The samples were placed in a well counter andcounts corresponding to two different ranges of gammaray energies were recorded. The radioactivity of each iso-tope was calculated, taking into account the decay of 'Kduring the counting procedure.

In six dogs who received intravenous nitroglycerin, asegment of myocardium under the "deep" gauge was re-moved and analyzed similarly.

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FIGURE 2 Representative recording of the decrease in deepcontractile force caused by intracoronary nitroglycerin.Partial occlusion of the coronary artery before this recordhas reduced coronary pressure from a mean of 112 to 58mmHg. Nitroglycerin caused a small increase in coronaryflow (8 ml/min) which increased the pressure drop acrossthe occlusion resulting in a drop in coronary pressure to 47mmHg. Systemic blood pressure was unaffected.

RESULTS

Partial occlusion of the left main coronary artery to alevel where a fall in contractile force of the "deep"gauge was imminent, reduced mean coronary perfusionpressure from a control average of 105 mmHg (range,87-125 mmHg) to an average of 70 mmHg (range,57-83mm Hg).

This amounted to a 33% (range, 1949%) reductionin perfusion relative to the control state while the meancoronary flow was decreased by only 10% (range, 6-35%) indicating autoregulation of the coronary bloodflow was occurring.

Intracoronary nitroglycerin. After administration ofintracoronary nitroglycerin at this level of partial oc-clusion, the contractile force of the "deep" gauge dimin-ished in every case which averaged a 21% decreasewhile only small and inconsistent changes in "super-ficial" contractility occurred. "Deep" force was restoredto normal levels when the coronary flow returned to itspreinjection level (Fig. 2). After the administration ofintracoronary nitroglycerin, the mean coronary flow

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FIGURE 4 Normalized uptake of 'Rb and '2K at four levelsof myocardial depth from a single representative experi-ment in which intracoronary nitroglycerin was administered.16 samples were analyzed for each isotope, four at eachlevel. The uptake of the isotope was uniform across thewall in the presence of the occlusion but before nitroglycerin.Nitroglycerin caused a gradient across the wall which indi-cated that myocardial blood flow steadily decreased fromepicardium to endocardium.

Intravenous nitroglycerin. A representative exampleof the results obtained after intravenous nitroglycerinon the contractile force in the presence of critical coro-nary obstruction is shown in Fig. 5. The force recordedfrom the "deep" gauge fell an average of 32% with thefall in aortic pressure. In contrast, contractile force ofthe superficial gauge commonly increased. Coronaryflow increased briefly and then fell as systemic hypo-tension occurred. In the absence of any restriction tocoronary flow systemic administration of nitroglycerindid not lead to any reduction in either deep or super-ficial contractile force.

The inner/outer ratios of isotope in the presence ofcritical coronary obstruction before and after intra-venous administration of nitroglycerin are shown inFig. 6. After nitroglycerin the inner/outer ratio wasreduced in seven dogs and unaltered in one dog. Sta-tistical analysis as described above show that the reduc-tion in the mean inner/outer ratio from 0.82±0.07 (SE)to 0.62+0.09 (SE) after intravenous injection was sig-nificant (P < 0.01). In six hearts segments of ven-tricle excised from under the "deep" gauge all showeda decrease (P < 0.01) in the inner/outer ratio afterintravenous nitroglycerin administration (Fig. 7).

increased by 5% (range, 3-7%), and coronary per-fusion pressure decreased by a mean of 10 mmHg(range, 7-16 mm Hg). Systemic pressure was un-affected by the administration of these levels of intra-coronary nitroglycerin.

The results of isotope analysis have been expressedas an inner to outer ratio before and after nitroglyce-rin administration (Fig. 3). The ratios represent theactivity of the inner half of the myocardial segment(in counts/gram for each isotope) divided by theactivity of the outer half. The mean of the four sepa-rate inner/outer ratios of each segment from individualdogs was obtained by meaning the logarithm of theirratios. Before nitroglycerin, the inner/outer ratio ofactivity averaged 1.07±0.15 (SE). After intracoronaryinjection of nitroglycerin, this ratio decreased in all ofthe seven dogs (P < 0.01) to an average of 0.68±0.18(SE). This significance of differences was obtainedusing analysis of variance of the logarithm of mean

differences in each heart (13).A more detailed analysis of the four slices from four

different segments of one heart obtained from a repre-sentative single experiment is shown in Fig. 4. Theactivity of each slice has been divided by the activityof the full thickness segments. A uniform activity isdemonstrated across the heart wall before administra-tion of nitroglycerin, whereas after nitroglycerin theactivity decreased progressively from outer to inner slicesfor each segment.

DISCUSSIONThis study has shown that nitroglycerin did not restoreblood flow to myocardium limited by a critical obstruc-

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FIGURE 5 Representative recording of the decrease in deepcontractile force caused by intravenous nitroglycerin. Thisrecord was obtained from the same animal as Fig. 2. withthe same degree of partial occlusion of the coronary artery.Nitroglycerin caused a decrease in systemic pressure'.whichis reflected in a 11 mmHg decrease in coronary pressure.Coronary flow fell concomitantly.

908 R. Forman, E. S. Kirk, J. M. Downey, and E. H. Sonnenblick

tion of a coronary artery. On the contrary, the directeffect of nitroglycerin was a redistribution of coronaryblood flow away from the subendocardium, as evidencedlby both the myocardial redistribution of the radioiso-tope as well as a diminution of the contractile force ofdeep layers in the ventricular wall. Even when thedrug was administered systemically, the net effect wasa redistribution of blood flow away from the subendo-cardium.

Several methods are available for determining thedistribution of blood flow within the myocardium. Be-cause of their relatively rapid washout, freely diffusabletracers, such as labeled antipyrine (14), do not allowenough time for multiple measurements as were donein this experiment. Whereas labeled microspheres mayovercome the problems associated with rapid washoutof diffusable tracers, the intramyocardial distribution ofmicrospheres appears to be dependent upon the particlesize as well as the distribution of blood flow (15). Forthese reasons the potassium uptake technique (11) wasconsidered the most suitable for this study. The majordisadvantage of this technique is that the tissue clearance

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FIGURE 7 The inner half to outer half ratio of 'Rb and42K uptake in the tissue directly beneath the "deep" forcegauge before and after intravenous nitroglycerin. The simi-larity between the results under the gauge and that of theremaining ventricle (Fig. 6) indicates that the tissue underthe gauge was representative of the ventricle.

is limited by diffusion as well as blood flow rate (16).However, any error introduced by diffusion limitationswould only result in an under estimation of differencesin blood flow. The reduced uptake of isotope in the sub-endocardium may to a small extent also reflect the netpotassium efflux from ischemic myocardium.

The present results have been explained as follows.With narrowing of the coronary arterial perfusion sys-tem, pressure distal to the restriction fell. Mean coro-nary flow, however, was only slightly reduced due toan autoregulatory dilation of the distal coronary bed.Several studies have shown that a progressive reductionin coronary arterial pressure will eventually result ina preferential reduction of blood flow in deep layers ofthe heart wall relative to the superficial layers (14, 17,18). Under conditions of the present experiment, thispoint was being approached but, before nitroglycerinadministration, had not been reached. Thus, in the con-trol period, the ratio of deep to superficial activity re-mained normal and "deep" force gauges were mini-mally altered. However, maximal dilation of the deep

Reduced Subendocardial Blood Flow Caused by Nitroglycerin 909

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vasculature was being approached as attested to by thefact that any further restriction to coronary flow leadto reduced contractile forces recorded by "deep" gauges.

It is postulated that administration of intracoronarynitroglycerin resulted in a further dilation of the super-ficial vessels which still had tone, while little or noresponse was possible in the deeper vessels which werealready dilated. The reduction in total coronary re-sistance caused by the dilation of the superficial vesselsresulted in a further fall in the perfusion pressure dis-tal to the occlusion. These changes produced a "steal"phenomenon, reducing flow to the passive deep vesselswhile flow was increased to the superficial vessels. Thereduction of flow to the subendocardial tissue wasindicated by the decrease in the inner to outer ratio ofisotope uptake in response to nitroglycerin as well asa fall in contractile force of the "deep" gauge.

When nitroglycerin was given intravenously, undersimilar conditions of critical obstruction of the coronaryartery, coronary flow fell as systemic hypotension oc-curred. The effect of dilation of vessels which still hadtone was offset by a decrease in perfusion pressure.Thus, in addition to the direct effect of nitroglycerinshown by the intracoronary injections, the decreasedperfusion pressure contributed to a preferential reduc-tion of blood flow in the deep layers ( 14, 17, 18).These effects apparently obscure the effects of hypo-tension to cause a reduction in intramyocardial pres-sure, which would favor subendocardial flow. The ob-servation that intravenous nitroglycerin caused noreduction in the deep layer contractile force in the ab-sence of coronary occlusion shows that changes in thepre- or afterload of the heart do not cause the decreasein deep layer contractile force. The deterioration ofdeep layer function when nitroglycerin was given intra-venously under conditions of critical obstruction ofthe coronary artery appears to be the direct result ofreduced flow to the subendocardial tissue.

It is possible that the tissue under the gauges maynot be representative of the rest of the myocardium.Not only do the fibers beneath the gauge experiencea preload which is different from that of the remainingheart but the sutures which anchor the device maycompromise the local circulation. However, the closecorrelation between the blood flow measurements in thetissue under the gauge and that of the rest of the ven-tricle indicates that the above was not the case.

Recently Mathes and Rival (19) also using the up-take of 86Rb as an indicator of coronary blood flow,have reported that nitroglycerin effected the removal ofa transmural flow differential caused by partial coronaryocclusion. Although this conclusion stands in directconflict with the present results, the model of myocardialischemia used was significantly different from the pres-

ent one. The level of coronary occlusion which wasemployed depressed the mechanical function of the heartso severely that peak systolic pressure fell to less than80 mmHg. In the present experiment, coronary occlu-sion was adjusted so that ischemic depression was notovert but was imminent. Their model is further com-plicated by the simultaneous infusion of norepinephrinewhich by itself has been shown to alter the transmuraldistribution of coronary blood flow (20). Finally, sincenitroglycerin was administered intravenously, their re-sults represent the net effect of systemic hypotension,inotropic stimulation, and severe myocardial ischemiaas well as a coronary arterial response to nitroglycerin.The response of the coronary vessels alone in theirexperiment is therefore unclear.

The results of the present study may be viewed rela-tive to other studies where nitroglycerin was said toalter the transmural distribution of coronary bloodflow. Winbury, Howe, and Weiss (8) interpret in-creases in polarographically recorded oxygen tensionsin the subendocardium after administration of nitro-glycerin as evidence for a redistribution. of myocardialblood flow towards the subendocardium. Although mostof their observations were made in the presence of anormal coronary circulation, similar results are shownwith intravenous injection of nitroglycerin duringpartial occlusion of the left anterior descending coro-nary artery. However, the undefined degree of partialocclusion along with the potential for collateral flowfrom adjacent branches of the left coronary artery makecomparisons with the present experiment difficult. It istempting to associate the results of the present studywith the initial decline in subendocardial oxygen ten-

sion observed by Winbury et al. (8). The measure-

ments of regional flow in the present study were madeduring peak alteration in total coronary flow. It was

presumed that the regional flow returned to its statusbefore nitroglycerin pari passu with the pressureand total coronary flow measurements. Moreover, inthe present study where the partial occlusion was

sufficient to cause some depression of deep layer con-

tractility, nitroglycerin did not cause any increase incontractility corresponding to the late increase in sub-endocardial oxygen tension seen by Winbury et al. (8).However, they employ a model to explain their datawhich requires assumptions that (a) the subendocar-dium is normally ischemic, a concept not supported bystudies of the uptake of various isotopes (14, 20) and(b) nitroglycerin dilates resistance vessels which do

not participate in autoregulation, which is not con-

sistent with our own (unpublished) observations andthat of others (2) that myocardial ischemia abolishesthe fall in vascular resistance following nitroglycerinadministration.

910 R. Forman, E. S. Kirk, J. M. Downey, and E. H. Sonnenblick

Becker, Fortuin, and Pitt (7) using radioactivemicrospheres, chose to examine the distribution of flowwithin a region made ischemic by total occlusion ofits vascular supply. Their preparation in which theischemic region received all of its blood flow via col-lateral channels clearly differs from that used in thepresent experiment.

Though it should be recognized that the present ca-nine model is acute by definition and does not have adeveloped collateral circulation, we believe that theseexperiments represent an experimental model which ismost analogous to the clinical conditions of diffuse myo-cardial ischemia resulting from lesions in the mainstem coronary arteries. The level of occlusion waschosen so that, like in the patient with angina pectoris,the myocardium is on the verge of ischemia. Underthese conditions the direct myocardial effect of nitro-glycerin on the canine heart was to actually divert flowaway from the vulnerable subendocardium. This ob-servation may help to explain the paradoxical clinicalobservation that electrocardiographic evidence of sub-endocardial ischemia may occasionally be induced bythe administration of nitroglycerin (21). We concludethat it is unlikely that the action of nitroglycerin toavert or relieve the pain of angina pectoris is throughselective dilation of the deep coronary vessels.

ACKNOWLEDGMENTSThis work was supported by U. S. Public Health ServiceGrants HE-11306, HE-10788, and HE-05890.

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13. Snedecor, G. W., and W. G. Cochran. 1967. StatisticalMethods. Iowa State University Press, Ames, Iowa.6th edition. 329.

14. Griggs, D. M., Jr., and Y. Nakamura. 1968. Effect ofcoronary constriction on myocardial distribution of iodo-antipyrine-311I. Am. J. Physiol. 129: 370.

15. Domenech, R. J., J. I. E. Hoffman, M. I. Noble, K. B.Saunders, J. R. Henson, and S. Subijanto. 1969. Totaland regional coronary blood flow measured by radio-active microspheres in conscious and anesthetized dogs.Circ. Res. 25: 581.

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