coronary steal by coronary vasoconstriction artery...

REVERSE CORONARY STEAL/Chiariello et al.

7. Stein I, Weinstein J: Unusual reaction to ergonovine maleate in a case ofcoronary insufficiency. NY State J Med 53: 1454, 1953

8. Heupler F, Proudfit W, Siegel W, Shirey E, Razavi M, Sones FM: Theergonovine maleate test for the diagnosis of coronary artery spasm. Cir-culation 51, 52 (suppl II):II-ll, 1975

9. Maseri A, Mimmo R, Chierchia S, Marchesi C, Pesola A, l'Abbate A:Coronary artery spasm as a cause of acute myocardial ischemia in man.Chest 68: 625, 1975

10. Maseri A, Pesola A, Mimmo R, Chierchia S, l'Abbate A: Pathogeneticmechanism of angina at rest. Circulation 51, 52 (suppl II):II-89, 1975

11. Weiner L, Kasparian H, Duca PR, Walinski P, Gottlieb RS, Hanckel F,Brest AN: Spectrum of coronary arterial spasm. Clinical, angiographicand myocardial metabolic experience in 29 cases. Am J Cardiol 38: 945,1976

12. Master AM, Pordey L, Kohler J: Ergotamine tartrate and the two-stepexercise electrocardiogram in functional cardiac disturbances. J Mt SinaiHosp NY 15: 164, 1948

13. Innes IR: Identification of the smooth muscle excitatory receptors forergot alkaloids. Br J Pharmacol 19: 120, 1962

14. Dieckmann WJ, Forman JB, Phillips GW: The effects of intravenous in-jection of ergonovine and solution of posterior pituitary extract on thepostpartum patient. Am J Obstet Gynecol 60: 655, 1950

15. Schade FF: Methergine: A study of its vasomotor properties. Am JObstet Gynecol 61: 188, 1951

16. Friedman EA: Comparative clinical evaluation of postpartum oxytocics.Am J Obstet Gynecol 73: 1306, 1957

17. Baillie TW: Vasopressor activity of ergometrine maleate in anaesthetizedparturient women. Br Med J 5330: 585, 1963

18. Baillie TW: Vasopressor activity of ergometrine. Br Med J 5343: 1477,1963

19. Brooke OG, Robinson BF: Effect of ergotamine and ergometrine onforearm venous compliance in man. Br Med J 1: 139, 1970

20. Crawford JS: Vasopressor activity of ergometrine. Br Med J 5340: 1285,1963

21. Davis ME, Boynton MW: The use of ergonovine in the placental stage oflabor. Am J Obstet Gynecol 43: 775, 1942

22. Wassef MR, Pleuvry BJ: The cardiovascular effects of ergometrine in theexperimental animal in vivo and in vitro. Br J Anaesth 46: 473, 1974

23. Rinzler SH, Travell J, Karp D: Detection of coronary atherosclerosis inthe living animal by the ergonovine stress test. Science 121: 900, 1955

24. Rinzler SH, Travell J, Karp D, Charleson D: Detection of coronaryatherosclerosis in the living rabbit by the ergonovine stress test. Am JPhysiol 184: 605, 1956

25. Karp D, Rinzler SH, Travell J: Effects of ergometrine (ergonovine) onthe isolated atherosclerotic heart of the cholesterol-fed rabbit. Br J Phar-macol 15: 333, 1960

26. Varma DR, Melville KI: Cardiovascular responses to hypoxia and ergo-novine in rabbits and dogs with normal or impaired coronary circulation.Rev Canad Biol 20: 683, 1961

27. Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N: Angina pec-toris: 1. A variant form of angina pectoris: Preliminary report. Am JMed 27: 375, 1959

28. Browning DJ: Serious side effects of ergometrine and its use in routineobstetric practice. Med J Austral 1: 957, 1974

29. Wright EN, Graiewski SJ: Ergonovine sensitivity and/or toxicity; Reportof a case. Obstet Gynecol 6: 347, 1955

30. Baillie TW: Ventricular ectopic activity following intravenousergometrine. Anaesthesia 24: 253, 1969

31. Canning BSJ, Green AT, Mulcahy R: Coronary heart disease in thepuerperium. A case report. J Obstet Gynecol Br Cwlth 76: 1018, 1969

32. Forman JB, Sullivan RL: The effects of intravenous injection of ergo-novine and methergine on the postpartum patient. Am J Obstet Gynecol63: 640, 1952

33. Editorial: Ergometrine - hypertensive drug? Br Med J 5330: 560, 196334. Ringrose CAD: The obstetrical use of ergot: A violation of the doctrine

"Primum non nocere." Canad Med Assoc J 87: 712, 196235. Casady GN, Moore DG, Bridenbaugh LD: Postpartum hypertension.

JAMA 172: 1011, 1960

"Reverse Coronary Steal"Induced by Coronary Vasoconstriction

Following Coronary Artery Occlusion in DogsMASSIMO CHIARIELLO, M.D., LAIR G. T. RIBEIRO, M.D.,MICHAEL A. DAVIS, D.SC., AND PETER R. MAROKO, M.D.

SUMMARY The phenomenon of "coronary steal," i.e., the shunt-ing of blood from ischemic to normally perfused areas of myocar-dium, has been described as an effect of the administration of severalvasodilating agents. This study was performed to ascertain whetherthe reverse situation can be induced, i.e., whether vasoconstriction ofthe vessels supplying the nonischemic zone could increase thecollateral flow to the ischemic area. In 16 open chest dogs, 15 and 30min after occlusion of the left anterior descending coronary artery,epicardial electrograms were recorded and regional myocardial blood

"VASCULAR STEAL" may occur whenever a suddenreduction in the vascular resistance of a given area results inthe shunting of blood to it through collateral channels fromadjacent areas of unchanged resistance. This steal

From the Departments of Medicine and Radiology, Harvard MedicalSchool and Peter Bent Brigham Hospital, Boston, Massachusetts.

Supported in part by contract NO1-HV-53000 under the Cardiac DiseasesBranch, Division of Heart and Vascular Diseases, NHLBI, and USPHSgrant GM-18674.

Address for reprints: Peter R. Maroko, M.D., Harvard Medical School,Bldg. A, 25 Shattuck Street, Boston, Massachusetts 02115.

Received May 30, 1977; revision accepted June 20, 1977.

flow (RMBF) was measured with radiolabeled microspheres.Methoxamine was infused intravenously between 17 and 30 min, themean arterial pressure being kept constant. The results indicate thatwhile the coronary arterial flow to the normal myocardium fell from90.6 ± 4.3 to 77.7 ± 3.2 ml/min/100 g (P < 0.01), the collateralblood flow to the ischemic area increased from 21.4 + 3.5 to41.0 ± 4.2 ml/min/100 g (P < 0.01), and thereby reduced acutemyocardial ischemic injury. This favorable redistribution of bloodflow might be considered a "reverse coronary steal."

phenomenon has been observed in the subclavian,' aor-toiliac,2 mesenteric3 and coronary4 '2 vascular beds. In dogswith coronary artery occlusions or patients with ischemicheart disease, coronary vasodilator agents may increase thetotal coronary blood flow, but they may do this at the ex-pense of reducing the collateral blood flow to the ischemicarea already maximally dilated as a result of metabolicstimuli. This phenomenon has been described with car-bochromen,7 dipyridamole,4 6 8, 10,11 isoproterenoll andminoxidil.'2 Since drugs which cause arterial dilatation innormal myocardium also reduce the arterial flow toischemic areas, interventions which cause arterial constric-

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VOL 56, No 5, NOVEMBER 1977

tion in normal myocardium might be expected to improvethe blood flow to the ischemic areas. Accordingly, this studywas designed to determine whether the administration of a

coronary constrictor that reduced blood flow in the normalmyocardium would increase the flow to the ischemic areas,thus producing a "reverse coronary steal."

Materials and Methods

Sixteen mongrel dogs weighing between 20 and 30 kg wereanesthetized with sodium thiamylal 25 mg/kg intravenouslyand ventilated with a Harvard respirator. A polyethylenecannula was placed in the carotid artery and connected to a

Statham P23Db transducer to monitor arterial pressure.Lead aVF of the electrocardiogram was recorded con-

tinuously. A left thoracotomy was performed in the fifth in-tercostal space and the heart exposed and suspended in a

pericardial cradle. The mid portion of the left anteriordescending coronary artery was isolated from the adjacenttissue and occluded permanently with a silk suture. In eightof the dogs, 17 min after occlusion (control period) methox-amine (20.0 ± 0.5 ,gg/kg/min) was infused intravenously for15 min, while mean arterial pressure (AP) was maintainedconstant by bleeding through a femoral artery catheter intoa constant pressure chamber. This protocol was chosen inorder to render the changes in coronary blood flow indepen-dent of changes in perfusion pressure which would rise withan increase of AP.The regional myocardial blood flow (RMBF) and cardiac

output (CO) were measured at 15 and 30 min after occlusionusing 7-10 u carbonized microspheres labeled with a

gamma-emitting radionuclide (14'Ce or "5Sr) according tothe technique previously described.13 14 Before the injection,a 50 ml vial containing the microspheres suspended in a

solution of 50% sucrose with two drops of Tween 80 addedto avoid aggregation was ultrasonicated for 45 min and thenmechanically agitated for an additional 5 min. For eachmeasurement 1.5 X 10' of one type of labeled microsphere(selected randomly), suspended in an aliquot of 4 ml of thesolution contained in the 50 ml vial, was injected over a

period of 15 sec through a left atrial catheter; during thefollowing 15 sec the catheter was flushed with 5 ml of saline.Random samples were taken from the vial after the injectionfor microscopic examination and these did not showaggregation of the beads. Simultaneously with the atrial in-jection a reference sample was -collected from a femoral

artery catheter using a 50 ml heparinized plastic syringeplaced in a Harvard withdrawal pump operating at a con-stant speed of 15.3 ml/min. The collection of the referenceblood sample lasted one minute, starting 15 sec before thebeginning of the microspheres injection and ending 15 secafter the catheter flushing. No changes in aortic pressure orheart rate were observed during this procedure. Thirty-fiveminutes after the occlusion the heart was excised and 7 to 10transmural biopsies each weighing 3 to 4 g were taken fromthe anterior and posterior ventricular walls. These biopsiescontained all of the ischemic tissue as well as portions of thenormal myocardium. Each biopsy was then divided into en-

docardial, middle and epicardial layers, and the radioac-tivity of each section and that of the reference samplemeasured in a gamma-scintillation well counter (NuclearChicago model 4233). Finally, the RMBF and the cardiacoutput were calculated as described by Utley et al.'5 Sincethe goal of this study was primarily to examine changes inflow, the RMBF of the endocardial, middle and epicardiallayers and the transmural blood flow were calculatedseparately for the ischemic and normal sites, the ischemicsites being defined as those with a blood flow below 50ml/min/100 g. Transmural RMBF for each biopsy was

calculated as a weighted mean of the corresponding endo,mid, and epicardial layer RMBFs.

Total vascular resistance (TVR) (in dyne X sec X cm-,)was calculated according to the formula: TVR = (AP X80)/CO where AP (mean arterial pressure) is in mm Hg andCO (cardiac output) in L/min. Coronary resistance (CorRes) in dyne X sec X cm-,/ I00 g of tissue, was calculated as

follows: Cor Res = (AP X 80)/RMBF where RMBF (inL/min/100 g of tissue) was the mean blood flow of the non-

ischemic sites.Epicardial unipolar electrograms were recorded at 15 min

and at 30 min after occlusion, i.e., just prior to the injectionof microspheres, from 13 to 17 sites on the anterior left ven-tricular wall as previously described.16 The input impedanceof the recorder amplifier was 100 megohms, and the frequen-cy response of the system was ± 0.5 db from 0.14 to 70 Hz.The impedance of the electrode was maintained constant, asreflected in the reproducibility of the tracings. The electrodeemployed was a 15 mm2 copper cylinder with a saline soakedwick connected to the precordial V-lead and held by a cableperpendicular to the electrode, thus minimizing mechanicalstress. Because of the large area of the electrode, smallvariations in location did not change the configuration of the

TABLE 1. Hemodynamic and Electrocardiographic Changes

AP HR CO TVR CR ST AP HR CO TVR CR ST

Treated DogsBefore methoxamine Ajter methoxamine

95.6 150.1 2.432 3,625 9.3 X 104 3.4 95.6 142.2 1.200** 7,928** 10.5 X 104* 2.26.2 9.4 -0.433 = 486 = 0.74 X 104 0. =7.7 ==11.9 0.226 1,374 = 0.82 X 104 - 0.8

Nontreated Dogs15 Minutes 30 Minutes

106.9 155.5 1.621 5,651 10.9 X 104 4.9 110.0 156.4 1.687 5,487 10.7 X 104 4.6=8.4 -4.8 -0.184 -660 1.0 X 104 1.0 -8.2 6.7 -0.176 -525 =1.1 X 104 1.1*P <0.05.**P <0.01.Abbreviations: AP = mean arterial pressure in mm Hg; HR = heart rate in beatsSin; CO = cardiac output in L/min; TVR = total vascular resistance

in dyne x sec/cm5; CR = coronary resistance in dyne x sec/cm5/g of myocardium; ST = average ST-segment elevation in mV.

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125 r

lookAP

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75

4

3

r-n

175r

1501-HR

(bpm)1251-

0o

5

4T

OFTT

( /min ) 2 (mV ) ;h

FIGURE 1. Effect of vasoconstriction and simultaneous bleeding on mean arterial pressure (AP), heart rate (HR), car-

diac output (CO) and average ST-segment elevation (ST). The striped columns represent the control values at 15 min, thedotted columns the values at 30 min during vasoconstriction. All values are mean ± I standard error. * = differentfromcontrol, P < 0.05, ** = different from control, P < 0.01.

recordings.16 The sites, clearly recognizable for their relationwith vascular crossings, were chosen in the area supplied bythe occluded vessels as well as in regions of the left ventriclefar away from this area. For each electrographic map, theaverage ST-segment elevation (ST) was obtained by dividingthe sum of the ST-segment elevations in all sites by thenumber of sites. ST-segment elevations were measured fromthe T-P line to the J point. Nine percent of sites exhibitedfocal intraventricular conduction defect as reflected in QRSduration exceeding 0.065 sec and were excluded from thestudy.'7 The other eight dogs did not receive any drug andserved as controls; all measurements in these dogs weremade at the same times as in the treated dogs.Comparisons between values obtained at 15 and 30 min in

the same dogs were made using Student's paired t-test, andbetween treated and control dogs by Student's t-test forgroup observations.'8

Finally, an additional 12 open chest dogs were in-strumented to evaluate the hemodynamic changes inducedby the same dose of methoxamine. They were instrumentedwith ECG leads and cannulae in the left ventricle, aorta andleft atrium for the recording of pressures.

Results

In the eight treated dogs the infusion of methoxaminewith concomitant bleeding from 15 to 30 min after occlusiondid not change the mean systemic arterial pressure (fig. 1,table 1). Systolic and diastolic pressures did not change(from 126.5 + 9.3 to 125.4 ± 9.8 and from 79.9 + 5.8 to81.0 ± 5.4 mm Hg, respectively). Heart rate fell, but notsignificantly (fig. 1, table 1). Cardiac output decreased by50.7 ± 6.1% (P < 0.01) (fig. I, table 1). The calculated totalperipheral resistance thus incrfased by 122 + 22%(P < 0.01) (fig. 2, table 1). The transmural RMBF in thenonischemic zones, which was 90.6 ± 4.3 ml/min/100 g at

15 min after occlusion, was reduced by the intervention to77.7 ± 3.2 ml/min/100 g (P < 0.01) at 30 minutes (fig. 3and table 2). The analysis by layer is shown in figures 3 and 4and table 2. In the normal myocardium the calculated cor-onary resistance per gram of tissue increased in all threelayers and when calculated for the transmural samples it in-

10.0 r TOTAL VASCULAR RESISTANCE

7.5 -

TVR x 103(dyne x sec/cm 5) 5.0

CR x 104(/c 7.5

(dyne x seckmr 5g

2.5 -

OL

:: - :, .....-...-...C.:...:...

Iee--....:....

12.5r CORONARY ARTERY RESISTANCE

5.01-

2.5 _

O L _

FIGURE 2. Effect ofmethoxamine plus bleeding on total vascularresistance (TVR) and coronary resistance (CR). Note the increaseof both parameters following the intervention. * = different fromcontrol, P < 0.05, ** = different from control, P < 0.01.

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TABLE 2. Alteratioms in Regional Myocardial Blood Flow*Trans Endo Middle Epi Endo/Epi Trans Endo Middle Epi Endo/Epi

Treated DogsBefore methoxamine After methoxamine

Normal 90.6 88.5 79.5 91.1 0.99 77.7** 80.3** 75.2 76.5** 1.10sites *4.3 -4.2 5.7 *5.0 *0.04 *3.2 4.1 *5.5 3.2 *0.06

Ischemic 21.4 15.7 16.5 21.3 0.41 41.0** 23.9** 38.8** 54.9** 0.39sites *3.5 3.4 *3.7 *3.2 *0.09 *4.2 -3.5 *5.8 -6.7 -0.06

Nontreated Dogs15 Minutes 30 Minutes

Normal 81.7 88.0 80.0 78.0 1.08 85.8 90.1 86.6 81.6 1.05sites -3.4 *4.0 *5.0 *3.0 *0.04 *3.6 *4.4 *5.5 *3.7 *0.05

Ischemic 26.5 23.1 25.5 28.8 0.46 26.9 24.8 26.5 29.9 0.49sites *3.0 *2.8 *5.0 *3.6 0.04 *3.0 *3.0 *5.2 *4.0 0.04*Sites with regional myocardial blood flows below 50 ml/min/l00 g, at 15 min after occlusion, were considered to be ischemic.

This applies to the regional myocardial blood flow of any layer as well as when it is calculated transmurally as a weighted mean ofthe flow in three layers. Thus, a transmural ischemic site (i.e., transmural flow <50 ml/min/100 g) could include a normal (i.e., flow>50 ml/min/100 g) epicardial component.**Different from the value before methoxamine, P <0.01.Abbreviations: Trans = transmural regional myocardial blood flow in ml/min/100 g; Endo = endocardial regional myocardai

blood flow in ml/min/100 g; Middle = middle layer regional myocardial blood flow in ml/min/lOO g; Epi epicardial regional myo-cardial blood flow in ml/min/100 g; Endo/Epi = endocardial/epicardial flow ratio.

creased from (9.3 ± 0.74)104 to (10.5 ± 0.82)104 dyneX sec X cm-' (P < 0.05) (fig. 2).While the blood flow following methoxamine infusion was

reduced in the normal myocardium, it increased significantlyin the ischemic sites, thus showing that blood was shuntedfrom the normally perfused to the underperfused areas. Thetransmural blood flow in the ischemic area rose from21.4 ± 3.5 to 41.0 + 4.2 ml/min/100 g (P < 0.01) (fig. 3,table 2) and the endocardial, middle layer and epicardialblood flows increased from 15.7 ± 3.4, 16.5 ± 3.7 and21.3 ± 3.2 ml/min/100 g (P < 0.01), respectively (fig. 5,table 2). The endocardial/epicardial blood flow ratio in theischemic myocardium did not change significantly during

the administration of methoxamine (table 2).As a result of the increase in the collateral blood flow to

the ischemic areas, the average ST-segment elevation, whichwas 3.4 + 0.9 mV 15 min after the occlusion, fellsignificantly during the intervention to 2.2 ± 0.8 mV(P < 0.02) (figs. I and 6, table 1), showing a reduction in themagnitude of the acute myocardial ischemic injury.

In the eight control dogs the AP, HR, CO, ST, RMBF,and total vascular and coronary resistances did not changesignificantly between 15 and 30 min after the occlusion(tables 1 and 2), showing that there is no spontaneouschange in these parameters.

In the 12 dogs evaluated for changes in hemodynamics,

Transmural FlowControl Intervention

110 103

123 104

86 7019 32

131 111

38 46115 109

130 130187 187

3,827 2,1892,154 4,9349.2 x 104 10.9 x 104

FIGURE 3. An example illustrating the changes in regional myocardial bloodflow 15 minfollowing occlusion (Control)and after 15 min of methoxamine + bleeding (Intervention). Left) Schematic representation of the heart, left anteriordescending coronary artery (LAD), sites of the biopsies (squared areas), sites where ECGs were recorded (dots), and siteofLAD occlusion (occl). Right) Transmural bloodflows in each biopsy in the control period and during intervention areindicated, as well as ATP, HR, CO, total vascular resistance (TVR) and coronary resistance (Cor Res). Note the reductionofflow in the nonischemic areas (i.e., with a RMBF over 50 ml/min/J00 g oftissue) (sites 1, 2, 3, 5 and 7) and its increasein the ischemic areas (sites 4 and 6).

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100

90

RMBF 80(ml/min/100g)

70

60

50_

NORMAL MYOCARDIUM

*

S

T*,. ..

...:

,.:M

OL 0W.,.ENDO MID EPI

FIGURE 4. Effects ofcoronary constriction on regional myocardial bloodflows (RMBF) in endocardial (endo), middle(mid) and epicardial (epi) layers ofthe normally perfused sites. ** = differentfrom control, P < 0.01. Note the reductionofflow after vasoconstriction.

methoxamine infusion and simultaneous bleeding resulted inunaltered aortic and left ventricular systolic pressures(127 ± 6 to 125 ± 6 mm Hg), aortic diastolic pressure(107 ± 7 to 108 ± 7 mm Hg), left ventricular end-diastolicand atrial mean pressures (5.3 ± 1.5 to 4.4 ± 1.6 mm Hg)and heart rate (161 ± 6 to 156 ± 6 beats/min). In contrast,max LV dp/dt fell significantly by 20.3% from 2,331 ± 133to 1,857 i 147 mm Hg/sec (P < 0.01).

DiscussionA fundamental aim in the treatment of ischemic heart dis-

ease is to improve the balance between oxygen supply anddemand in the ischemic region of the heart."' 19-22 This maybe achieved either by increasing the heart's oxygen supply(i.e., perfusion) or by reducing its oxygen requirements. Cor-onary artery bypass grafting23 is a typical example of theformer approach and propranolol administration of the lat-ter.24 26 Coronary vasodilators were introduced with thehope that they would increase oxygen supply by dilating thenarrowed vessels; however, their role is controversial

because they may have multiple and complex effects. Theymay, for example, affect the ischemic zone not only throughtheir action on the coronary arteries themselves but alsothrough their peripheral vascular effects. Their ability toreduce systemic arterial pressure and pulmonary vascularresistance may reduce afterload and preload. Drugs such asnitroglycerin may also reduce preload by causing pooling ofblood in the venous system. Such a decrease in afterloadand/or preload reduces myocardial oxygen requirementsand this has been considered important for limiting the ex-tent of ischemia.27 SO Moreover, the effects of the coronaryvasodilators on the coronary bed itself is not uniform.Diverse effects have been shown on the degree of ischemiaindicating that coronary vasodilators are pharmacologicallya heterogeneous group of drugs.3"-33

Vasodilators that act on the proximal conductance vesselsare considered beneficial," 36 while those that act on theperipheral resistance vessels are thought to be detrimental33because they produce a redistribution of flow similar to acoronary steal. We postulated that coronary constrictors

70r ISCHEMIC MYOCARDIUM

60-

50s

40RMBF

(ml/min/100g)30

201

lO1

0'ENDO MID EPI

FIGURE 5. Effects of coronary constriction on regional myocardial bloodflows (RMBF) in endocardial (endo), middle(mid) and epicardial (epi) layers of the ischemic sites. Note the marked increase ofcollateralflow to these ischemic zones

following the vascular constriction of the normal areas. ** = different from control, P < 0.01.

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5CONTROL

METHOXAMINEHEMORRHAGE

4

ST(mV)

3

2

0 -A IV v 20 30 40 50

ISCHEMIC FLOW (ml/min/100g)FIGURE 6. Simultaneous changes in average ST-segment eleva-tion (ST) and ischemic transmural flow. The coronary constrictionproduced an increase in collateralflow and consequently a reductionin ST.

that act on resistance vessels are beneficial while constric-tors that act on conductance vessels are harmful. Accord-ingly, the goal of the present study was to ascertain whetherreverse coronary steal can be induced by coronary constric-tion in the normal part of the myocardium. The constant in-fusion of methoxamine while the systemic pressure was keptconstant resulted in a reduction of regional myocardialblood flow to the normal areas. This reduction in flow can beascribed both to the lowering in myocardial oxygen con-sumption and to the presumed constrictive action of the drugon the coronary arterioles. In contrast, regional myocardialblood flow in the ischemic areas increased (fig. 7). Thefailure of methoxamine to constrict the arteries in theischemic areas may be explained either by a reduced amountof the drug reaching the underperfused zones or, moreprobably, by the more powerful metabolic vasodilation in-duced by the ischemia itself. Collateral vessels may havetheir origin at the level of the arterioles.37 When the pressurein large arteries is maintained constant despite infusion ofvasoconstrictors, the pressure at the level of the arterioles issignificantly increased.38 This increase in perfusion pressureat the origin of the collateral vessels may therefore beresponsible for the reverse coronary steal. This augmenta-tion of collateral flow achieved through the induction of areverse steal phenomenon was accompanied by a significantreduction in acute myocardial ischemic injury as reflected bythe change in the average ST-segment elevation.The possible multifaceted effects of methoxamine on

regional myocardial blood flow in the normal areas and theconsequent reverse coronary steal should be analyzed closelysince they may help to explain the salutary effects of otheragents which have similar general effects. Methoxamine, asa result of alpha receptor stimulation, causes coronary con-striction. However, a reduction in myocardial oxygen con-sumption will also reduce coronary flow in the normalmyocardium. In the hemodynamic experiments performedin this study, heart rate, preload and afterload did notchange following drug administration; however, left ventric-ular dp/dt decreased by 20%, presumably resulting in lowermyocardial oxygen consumption. This fall in dp/dt can beinduced by a beta blocking effect of methoxamine.39 Thus, atleast two factors could have contributed to the coronaryvasoconstriction: the direct effect of alpha receptor stimula-

NORMALMYOCARDIUM

FIGURE 7. Schematic representation of the hypothesis of reversecoronary steal. The left panel illustrates the distribution offlowfollowing coronary artery occlusion. Bloodflow in the nonoccludedvessel is directed mainly to the normal myocardium (larger arrow)which exhibits a normal resistance; less bloodflow (small arrow) isdirected through the collaterals to the ischemic area (diamondshape) where the coronary resistance is low (loose spring). The rightpanel illustrates the alteration due to methoxamine accompanied bybleeding. There is an increase in coronary resistance in the normalmyocardium (tight spring), producing a decrease inflow to the nor-mal myocardium (arrow reduced in size). Consequently there is anincrease in blood supply to the ischemic zone (small arrow in-creases) through the collaterals and the extent ofmyocardial injuryis reduced (smaller diamond).

tion, and the indirect effect of reduction in myocardial oxy-gen consumption caused by a decrease in contractility.The results of this study do not suggest that myocardial

ischemia in patients should be treated with methoxamineplus bleeding, but this demonstration of the feasibility ofproducing a reverse coronary steal phenomenon doessuggest that this principle may provide a useful approach tothe treatment of different forms of regional myocardialischemia. By inducing a reverse coronary steal phenomenonit may be possible to increase collateral blood flow to un-derperfused zones of myocardium in patients with regionalischemia. Moreover, the demonstration of the feasibility ofproducing a reverse coronary steal phenomenon by methox-amine may suggest that the reduction of myocardialischemic injury obtained by several investigators using nitro-glycerin plus methoxamine20 40, 41 could be related at leastpartially to the reverse coronary steal phenomenon due tomethoxamine.

Acknowledgment

The authors gratefully acknowledge the technical assistance of Mr. DanielWhite, Mr. Joseph Gannon and Ms. Alice Carmel as well as the secretarialassistance of Ms. Merrilee Spence.

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4. Fam WM, McGregor M: Effect of coronary vasodilator drugs on

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6. Baker LD, Snow JA, Pomposiello JC, Sharma GVRK, Messer JV:Isoproterenol induced "coronary steal": metabolic observations inhuman coronary artery disease (CAD). (abstr) Clin Res 17: 228, 1969

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vasodilator drug (carbochromen) on blood flow and oxygen extraction inacute myocardial infarction. Cardiovasc Res 7: 401, 1973

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M Chiariello, L G Ribeiro, M A Davis and P R Marokoartery occlusion in dogs.

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