Comparative effects of nitroglycerin and isosorbide dinitrate on coronary collateral vessels and ischemic myocardium in dogs

EXPERIMENTAL

STUDIES

Comparative

Effects of Nitroglycerin

and lsosorbide

Dinitrate on Coronary Collateral Vessels and lschemic

Myocardium

MICHAEL

V. COHEN,

MD,

FACC’

EDMUND

H. SONNENBLICK,

MD,

EDWARD

S. KIRK,

FACC

PhD

Boston, Massachusetts

From the Cardiovascular Division, Department of Medicine, Peter Bent Brigham Hospital and Harvard Medical School, Boston, Mass. This study was supported in part by Grants HL 11306 and 5TOl-HL 05679 from the U. S. Public Health Service. Manuscript accepted June 4, 1975. * Present address and address for reprints: Michael V. Cohen, MD, Cardiology Department, Montefiore Hospital and Medical Center, 111 East 210th St., Bronx, N. Y. 10467.

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To determine the effect of isosorbide dinitrate on ischemic myocardium, this agent was administered to dogs with well developed coronary collateral vessels 8 to 14 weeks after embolization and subsequent occlusion of the left anterior descending coronary artery. After thoracotomy the left coronary artery was cannulated and perfused with blood from the femoral artery. The distal left anterior descending artery was cannulated to monitor peripheral coronary pressure. Regional contractile force in the normal left circumflex and potentially ischemic left anterior descending regions was measured with isometric strain gauge arches sewn to the epicardium. Moderate decreases in coronary perfusion pressure averaging 27 mm Hg produced selective ischemia in the myocardium beyond the site of occlusion of the left anterior descending artery. Under these conditions the average increase in peripheral coronary pressure produced by intracoronary injection of isosorbide dinitrate was 9.0 mm Hg, whereas contractile force in the ischemic region increased by 30 percent. The contractile force was unchanged in the normal regions. Therefore, isosorbide dinitrate can dilate coronary collateral vessels and improve contractile force in ischemit areas. lntracoronary injection of nitroglycerin had similar effects. The durations of responses to isosorbide dinitrate and nitroglycerin were remarkably similar: 8.4 and 8.7 minutes, respectively. Although isosorbide dinitrate can directly dilate coronary collateral vessels, its effects are not longer lasting than those of nitroglycerin.

Since the introduction of nitroglycerin more than 100 years ago, this drug has been recognized as the most efficacious agent in treating attacks of angina pectoris. Although the exact mechanism of its antianginal effect has been disputed, it is now believed that some combination of actions on peripheral vasculature and coronary collateral vessels is responsib1e.l It was reasoned that modification of the nitrate molecule might produce a longer-acting agent that would be effective in the prophylactic therapy of angina pectoris, and numerous compounds were synthesized and tested as antianginal agents. However, conflicting reports based on anima12m5and humansl6 studies have fueled the controversy over the value of these agents. Several investigators15 have been unable to document a prolonged drug effect, whereas others1’-*4J6 have concluded that these agents had no proved clinical efficacy. Furthermore, hepatic degradation of nitrate drugs absorbed from the gutI or administered systemically17*18 has been shown to produce metabolites with weak pharmacologic activity.is Because of the disputed efficacy as well as duration of response of the peripheral vasculature to these organic nitrates, we believed it important to establish whether these agents might have prolonged effects on the coronary vasculature that could account for their beneficial consequences. Accordingly, we studied the action of one long-act-

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NITRATES

ing nitrate, isosorbide dinitrate, on the responsiveness of canine coronary collateral vessels, and contrasted these results with those obtained with nitroglycerin in the same animals. This study documents a comparable effect of nitroglycerin and isosorbide dinitrate on coronary collateral vessels and ischemic myocardium, and does not demonstrate any significant difference in the time course of action of the two agents.

Methods Experimental preparation: Experiments were performed in eight mongrel dogs. By a closed chest technique described previously,20 a gradual occlusion of the left anterior descending coronary artery was produced 8 to 14 weeks before the time of study in all animals. A 3 to 5 mm segment of a red Kifa (U. S. Catheter and Instrument Corp.) catheter (no. 6.6 F) was embolized into the left anterior descending coronary artery with a coaxial cathete; system introduced into a femoral artery. The catheter system consisted of an outer red Kifa catheter and an inner Teflon@ catheter extending beyond the end of the former and carrying a hollow, tapered Kifa plug. Once the catheter system was maneuvered into the left anterior descending artery, the Kifa catheter was anchored while the inner catheter was withdrawn into the outer one, thus releasing the plug into the artery. Prior experience has demonstrated occlusion of the plug within 5 to 10 hours after embolization. Direct. observation at the time of study in all animals confirmed total obstruction of the distal left anterior descending artery at the level of the plug. Careful visual inspection of the myocardium distal to the plug revealed no or only small areas of infarction. Measurement of the cross-sec-

AND

CORONARY

COLLATERAL

VESSELS-COHEN

ET

AL.

tional area of infarcted tissue after serial sectioning of the heart from apex to base confirmed that less than 2 percent of the left ventricle was involved. On the day of study the dogs were anesthetized with sodium pentobarbital (27.5 mg/kg). Additional amounts were administered as required to maintain prolonged anesthesia. A polyvinyl catheter was introduced into the thoracic aorta by way of a femoral artery for measurement of systemic pressure with a Statham transducer. After endotracheal intubation and mechanical ventilation with an intermittent positive pressure respirator with 100 percent oxygen, a left thoracotomy was performed. Anticoagulation was produced by injection of 20,000 units of heparin and maintained by injection of 10,000 units every 1 to 2 hours. The experimental preparation is shown in Figure 1. The main left coronary artery was cannulated with a modified Gregg cannula introduced into the left subclavian artery and perfused with blood from a femoral artery. The perfusion tubing contained a Biotronex 410 flowmeter, a side arm for measurement of coronary perfusion pressure with a Statham transducer, and an area for intracoronary drug injection. The tubing passed through a Sigmamotor pump enabling coronary flow to be adjusted to either higher or lower levels. To maintain constant coronary pressure the blood could be diverted into a reservoir (Fig. 1). The amount of blood in the reservoir was kept constant by adjusting the rate of the Sigmamotor pump, and the coronary perfusion pressure was determined by the reservoir’s height. Autoregulation of coronary blood flow was preserved in these preparations. Measurements of pressure, flow and myocardial contractile force: The left anterior descending artery was isolated at the site of the embolized plug. The plug was extracted and the vessel occlusively cannulated at this level

RESERVOIR

A

\!

low0000l I

1

-

FEMORAL

ARTERY

FIGURE 1. Experimental preparation. The shading of the left ventricle denotes the area supplied by collateral vessels. LAD = area supplied by left anterior descending coronary artery; LCF = area supplied by left circumflex coronary artery.

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ET AL.

with a blunted large bore needle, either 12 or 15 gauge, that enabled continuous measurement of distal coronary pressure. The transducers recording coronary perfusion pressure and pressure in the distal left anterior descending artery were selected to have identical linearity over a range of pressures from 0 to 200 mm Hg. The amplified outputs from these transducers were connected to the input of a differential amplifier. By carefully adjusting the gain of the transducer preamplifiers, the pressure gradient between the left coronary and left anterior descending coronary arteries could be recorded. At frequent intervals throughout an experiment, the two pressure transducers were connected to the same pressure source to check for zero baseline and drifts in linearity. In this manner changes in the pressure gradient exceeding 0.5 mm Hg could be detected unequivocally at all pressure levels. Myocardial contractile force was measured with isometric strain gauge arches (John Warren, Charleston, S. C.). One arch was sewn to the epicardium in the area supplied by the left circumflex coronary artery in an orientation parallel to the superficial fibers. A second strain gauge arch was sewn onto the surface of the heart parallel to the epicardial fibers in the region of the left anterior descending artery distal to the extracted plug. The rationale for the use of these arches in assessing the degree of myocardial ischemia has previously been described.21 A catheter was inserted through the left atria1 appendage to record left ventricular systolic and end-diastolic pressures and the first derivative of left ventricular pressure (dP/dt). All signals including coronary perfusion pressure, pressure in the distal left anterior descending artery, pressure gradient between the left coronary and left anterior descending artery, strain gauge arch deflections and aortic pressure were recorded directly on a multichannel oscillograph. Intracoronary drugs: These agents were administered in doses known not to have systemic effects. Tablets of nitroglycerin, 0.6 mg (Lilly), were dissolved in saline solution to a concentration of 0.6 wg/wland 18 Kg bolus doses were injected into the left coronary arterial perfusion line. Isosorbide dinitrate (kindly supplied as Isordil@ by Dr. Clarence Denton, Ives Laboratories) was administered as a saline solution, 0.25 mg/ml, that also contained mannitol, 0.75 mg/ml. The dose used was 0.5 mg injected slowly over 15 seconds. Saline injections of 2 ml with or without added mannitol had no effect on the variables measured. The doses of intracoronary nitroglycerin and isosorbide dinitrate were chosen to have a near maximal vasodilatory action on the coronary vasculature without an evident sys-

TABLE

temic effect. Each drug produced similar increases in coronary blood flow (Table I). In all animals baseline contractile force, coronary and left ventricular pressures and coronary blood flow were initially recorded. As previously demonstrated, development of collateral vessels in these animals is usually sufficient to produce normal regional contractile force in the potentially ischemic area of the left anterior descending coronary artery, whereas a moderate decrease in coronary perfusion pressure elicits marked ischemic changes in the left anterior descending area but no significant alterations in the normal left circumflex area. 21 In these animals coronary perfusion pressure was decreased until this differential effect on t,he strain gauge arches was observed. At this point either nitroglycerin or isosorbide dinitrate was administered into the left coronary arterial perfusion tubing, and the response of strain gauge arches, coronary pressures and coronary flow recorded. The order of the drugs was randomized. All results are expressed as means f standard error. Student’s t test for independent observations was used to determine the significance of differences.

Results conditions pressure in the distal left anterior descending coronary artery ranged from 40 to 110 mm Hg (average 74 mm Hg); the average gradient between the left coronary and distal left anterior descending arteries was 32 mm Hg (Table I). Coronary flow in the control state averaged 96.5 ml/ min. Coronary perfusion pressure was depressed by an average of 27 mm Hg to produce selective ischemia in the region previously supplied by the occluded left anterior descending artery. IJnder these conditions the strain gauge arch in the left anterior descending artery recorded an average reduction of 33.2 percent in developed contractile force whereas the left circumflex gauge was virtually unaffected (-1.5 percent) (Table I). Nitroglycerin and isosorbide dinitrate: The effects of the vasodilators nitroglycerin and isosorbide dinitrate on the measured variables in a representative experiment are shown in Figure 2. In this animal control coronary perfusion pressure was 112 mm Hg and coronary blood flow 155 ml/min. Peripheral pressure in the left anterior descending artery was 90 mm Hg, and therefore the maximal gradient from the main left coronary artery to the distal left anterior Control:

Under

control

I

Effects of Nitroglycerin (mean + standard error)

and lsosorbide

COrOnarY Perfusion Pressure (mm Hg) Control lschemia + NTG” + ISDN’

107.9 f 6.6 81.3 ? 4.8 81.3 + 4.8 81.3 k 4.8

Dinitrate

Peripheral Coronary Pressure (mm Hg) 75.0 f 52.7 i 60.5 + 61.5 +

8.6 4.8 4.6+ 4.2+

on Coronary

LCA-Distal LAD Pressure Gradient (mm Hg) 32.9 28.6 20.8 19.8

* k * +

4.1 3.8 3.5+ 3.5+

Collateral

Indexes and Contractile

ContractlIe Coronary Blood Flow (ml/min) 96.5 91.6 121.0 127.7

? i + i

13.4 12.1 12.2+ 12.2+

LAD

(A%) -33.2’+7.8 -12.2 + 4.4+ -13.2 i 5.19

Force

Force

(A%,

Duration of Response fmin)

-1.j;.2.1 -0.6 ?- 2.0::: 1.2 i 1.8t

6.7’ i ‘0.5 6.4 i 0.4

LCX

*Measurements represent maximal change after drug administration. $P O.l (not significant). Comparatrve changes Statistical significance of drug-induced changes in the ischemic state: +/’ <0.005; induced by nitroglycerin and isosorbide dinitrate are not statistically significant (P >O.l). ISDN = isosorbide dinitrate; LAD = left anterior descending coronary artery; LCA = main left coronary artery; LCx = left circumflex coronary artery; NTG = nitroglycerin.

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descending artery was only 22 mm Hg. The contractile force in the potentially ischemic area of the left anterior descending artery was unaffected by temporary release of the occlusion of the perfusion tubing of this artery, thus confirming previous observations.21 Lowering of the reservoir decreased coronary perfusion pressure to 85 mm Hg and peripheral coronary pressure to 55 mm Hg, but systemic pressure was unaffected. Coronary perfusion pressure was held constant for the remainder of the experiment. At this level of perfusion the left anterior descending arterial area was clearly ischemic, as shown by the marked reduction in the contractile force. In contrast, the contractile force in the nonischemic left circumflex area was unchanged. Intracoronary administration of isosorbide dinitrate (0.5 mg) transiently increased coronary blood flow by 25 ml/min although systemic hemodynamics were not changed. Peripheral coronary pressure increased by 8 mm Hg and the gradient across the obstruction of the left anterior descending artery decreased an equivalent amount. Concomitantly the contractile force in the left anterior descending region significantly increased by 50 percent of the prenitrate level whereas the left circumflex strain gauge arch was not affected. Intracoronary administration of nitroglycerin (18 pg) caused strikingly similar changes: Peripheral coronary pressure increased by 9 mm Hg and left anterior descending regional contractile force by 80 percent. The duration of these changes was 6.5 minutes for each drug. The average changes for the entire group of ani-

FIGURE 2. Effect of intracoronary isosorbide dinitrate (ISDN) and nitroglycerin (TNG) on the peripheral left anterior descending coronary artery (LAD) pressure, main left coronary arterial (LCA)distal left anterior descending coronary arterial pressure gradient, and contractile force in the areas perfused by the left anterior descending and left circumflex (LCF) arteries. Before administration of the nitrates coronary perfusion pressure had been lowered from the control level of 112 to 85 mm Hg. At this perfusion pressure both vasodilators elicited similar increases in peripheral left anterior descending coronary arterial pressure and left anterior descending area contractile force and decreases in the main left coronary arterial-distal left anterior descending coronary arterial pressure gradient. The left circumflex area contractile force was not significantly altered.

coM7K)L

ET AL.

mals are presented in Table I. Both nitroglycerin and isosorbide dinitrate consistently decreased the degree of ischemia of the left anterior descending arterial region as documented by a significant increase in developed contractile force. The maximal enhancement developed by the myocardium in the left anterior descending area compared with the stable level just before administration of nitroglycerin averaged 31 percent (range 10 to 71 percent). When the contractile force at the peak of the effect of nitroglycerin is compared with the measurement at normal perfusion pressure, it is evident that nitroglycerin can transiently restore the contractile force in the ischemic left anterior descending arterial region toward normal (average 12 percent below control level). Isosorbide dinitrate caused changes that were insignificantly different from those observed after nitroglycerin. Despite these marked changes in the region of the left anterior descending artery, there were only minor insignificant responses of the strain gauge arch in the normal left circumflex area. Both vasodilators increased pressure in the left anterior descending artery distal to the occlusion (average 8 mm Hg for nitroglycerin and 9 mm Hg for isosorbide dinitrate, range 3 to 11 mm Hg). The duration of the changes induced by the vasodilators was noted in each animal. The time at which both contractile force and peripheral coronary pressure returned to within 5 percent of the control level was considered to represent the end of the drug effect. The average effects of both vasodilators were equally prolonged: 6.7 minutes for nitroglycerin and

IISDN 0.5mg

February 1976

ITNG

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18~

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6.4 minutes for isosorbide dinitrate statistically significant [P >0.5]).

ET AL.

(difference

not

Discussion Despite the undisputed efficacy of nitroglycerin in the therapy of ischemic heart disease, isosorbide dinitrate and other long-acting nitrates have not gained widespread acceptance. Clinical trials with both the oral and sublingual preparations of isosorbide have yielded discrepant results.6-16 Whereas studies have documented an increase in exercise tolerance in patients with coronary artery disease 5 to 10 minutes after administration of isosorbide dinitrate,g,15 effects after 1 hour have not been c!early established.g,15 One investigation l5 found no difference between the duration of action of isosorbide dinitrate and nitroglycerin administered in doses causing similar hemodynamic alterations. Perhaps nonstandard exercise protocols, tabulation of different subjective and objective criteria to document efficacy, and administration of drug doses having hemodynamic effects of differing magnitudes explain the plethora of confusing clinical results. Animal studies suggest that isosorbide dinitrate is rapidly denitrated by hepatic enzymes into pharmacologically weak metabolites,17lg and that the effects of this drug should not be expected to be appreciably longer than those of nitrostudies inglycerin. 1g,22 However, plethysmographic dicate that isosorbide dinitrate does exert a definite effect on the peripheral vasculature for at least 1 hour.2X Coronary vascular effects of isosorbide dinitrate: Although there are conflicting reports concerning the peripheral actions of isosorbide dinitrate, there have been relatively few attempts to define the direct effects of this agent on the coronary vasculature. Gensini et a1.24 have shown a direct vasodilatory effect on coronary arteries, whereas others25 have shown an increase in coronary blood flow. However, the response of coronary collateral vessels to isosorbide dinitrate has not been determined. As McGregor and Famz6 observed, dilatation of coronary resistance vessels in a heart with obstructed vessels without concomitant and more prolonged dilatation of collateral channels may be detrimental to the myocardium by initiating a coronary “steal” and further decreasing blood flow to already ischemic areas. Thus, in attempting to define the effects of isosorbide dinitrate on ischemic myocardium, we determined the response of coronary collateral channels and observed that they could be actively dilated by this organic nitrate. This study has demonstrated that isosorbide dinitrate increases coronary pressure in vessels beyond a chronic vascular obstruction as well as contractile force in ischemic areas. These observations lead us to suggest that this agent dilates coronary collateral vessels with subsequent enhancement of collateral blood flow, lessening of ischemia and increased contractility in myocardial areas distal to coronary obstructions. By following the movement of radiopaque

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epicardial markers in dogs and sites of coronary arterial bifurcation visualized during coronary angiography in man, Gensini et al. 27 also concluded that isosorbide dinitrate improves contraction patterns of ischemic myocardial regions. This ability is not unique for isosorbide dinitrate, but appears to be a general property of nitrates. As documented in a prior study,*’ and again confirmed here, nitroglycerin has similar actions. The results from these investigations suggest that coronary collateral vessels are responsive to their metabolic milieu. The collateral vessel at its source traverses normally perfused myocardium, and is not responsive to the needs of the ischemic area. This portion maintains its vasomotor tone, whereas that segment in the ischemic area is maximally dilated. The most marked effects of these vasodilators are noted when the coronary perfusion pressure is mildly decreased, resulting in selective ischemia of the myocardium in the region distal to the occluded vessel. Under these conditions isosorbide dinitrate and nitroglycerin may dilate that portion of the collateral vessel in the normal areas, increasing collateral flow and subsequently contractility in the ischemic area. If no area of the myocardium is initially ischemic, then increases in collateral flow could not improve contractility. On the other hand, if the whole heart is ischemic, then the entire length of the collateral vessel will already be dilated and administration of nitrates will be ineffective.*l Thus, these experiments suggest that nitrates can be expected to directly benefit ischemic myocardium only when regional flow inhomogeneities exist. Duration of coronary vascular responses: The duration of response was similar for the two nitrates tested. Thus, in our model isosorbide dinitrate cannot be considered to be a long-acting preparation. We administered all drugs directly into the coronary circulation specifically to avoid any systemic effects. Thus, we are unable to make observations on the duration of peripheral actions of isosorbide dinitrate. Weisse et al.*s attempted to measure coronary collateral flow during administration of isosorbide dinitrate 2 to 3 hours after obstruction of coronary arterial branches. At this time most animals showed no change in collateral flow. However, these authors used constant intravenous infusions of isosorbide dinitrate and made their initial measurements after 15 minutes. Previous work2g has demonstrated the existence of nitrate tachyphylaxis, and therefore earlier measurements might have been more revealing. Furthermore, Schaper30 has demonstrated that immediately after coronary occlusion collateral channels have a diameter of 40 p and sometimes only one cell layer of smooth muscle. To insure responsiveness of collateral vessels to nitrates, one should await formation of a hyperplastic smooth muscle layer 3 weeks after occlusion. Drug dosage: The standard intracoronary dose of nitroglycerin used in this study was 18 pg, which was chosen to have a maximal dilating effect. The dose of

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isosorbide dinitrate was selected to approximately match the effect of nitroglycerin on total coronary blood flow. With the doses employed there were no significant systemic effects. The doses approximate the amounts assumed to be delivered in the first circulation to the coronary arteries (5 to 10 percent of total administered dose) after absorption of the usual sublingual therapeutic dose in man. However, since the effects of these nitrates on collateral vessels persist for approximately 6 to 7 minutes, the route of administration may not be critical. Clinical implications: The special conditions of our protocol must not be overlooked, and our conclusions cannot be directly applied to the clinical situation. We administered the nitrates directly into the coronary circulation, but only during experimental

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ET AL.

studies is this realized in man.31 Furthermore, canine collateral vessels are often epicardial, whereas human coronary collateral vessels tend to be intramural.30 However, at least one study in man32 has shown that collateral vessels may be dilated by nitrates. Although we have documented that the effects of isosorbide dinitrate and nitroglycerin on the heart are essentially identical and of equal duration, we did not evaluate the peripheral effects of these drugs. It is possible that the effects of isosorbide dinitrate on the peripheral vasculature might have d long time course, thus accounting for claims of clinical efficacy for more than 1 to 2 hours. Our study has demonstrated that the action of isosorbide dinitrate on the coronary vasculature cannot explain this prolonged effect.

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tionship between biotransformation and rational angina pectoris therapy. J Pharmacol Exp Ther 181:489-497, 1972 18. Johnson EM Jr, Harkey A, Biehm DJ, et al: Clearance and metabolism of organic nitrates. J Pharmacol Exp Ther 182:56-62. 1972 19. Bogaert MG, Rosseel MT: Vascular effects of the dinitrate and mononitrate esters of isosorbide, isomannide and isoidide. Naunyn Schmiedebergs Arch Pharmacol275:339-342, 1972 20. Cohen MV, Eldh P: Experimental myocardial infarction in the closed-chest dog: controlled production of large or small areas of necrosis. Am Heart J 86:798-804, 1973 21. Cohen MV, Downey JM, Sonnenblick. EH, et al: The effects of nitroglycerin on coronary collaterals and myocardial contractility. J Clin Invest 52:2836-2847, 1973 22. Wendt RL: Systemic and coronary vascular effects of the 2and the 5-mononitrate esters of isosorbide. J Pharmacol Exp Ther 180:732-742, 1972 23. Winsor T: Effects of nitrates on the peripheral circulation. In, The Study of the Systemic, Coronary and Myocardial Effects of Nitrates, chap 18 (Gensini GG. ed). Springfield, III, Charles C Thomas, 1972. p 267-273 24. Gensini GG, Kelly AE, Da Costa BCB, et al: Quantitative angiography: the measurement of coronary vasomobility in the intact animal and man. Chest 60522-530. 1971 25. Blum SW, Quinn JB, Howe BB, et al: Pharmacologic and biochemical evaluation of organic rlitrates: attempted correlation of activities. J Pharmacol Exp Ther 176:684-69 1, 1971 26. McGregor M, Fam WM: Regulation of coronary blood flow. Bull NY Acad Med 42:940-950, 1966 27. Gensini GG: Patterns of ventricular contraction and myocardial contractility in the intact animal and man: effects of ISDN. In Ref 23, chap 8, p 108-119 28. Welsse AB, &nft A, Khan MI, et al: Effect of nitrate infusions on the systemic and coronary circulations following acute experimental myocardial infarction in the intact dog. Am J Cardiol 301362-370, 1972 29. Cohen MV, Kirk ES: Differential response of large and small coronary arteries to nitroglycerin and angiotensin: autoregulation and tachyphylaxis. Circ Res 33~445-453, 1973 30. Schaper W: The Collateral Circulation of the Heart. Amsterdam, North-Holland Publishing, 1971 31. Ganz W, Marcus HS: Failure of intracoronary nitroglycerin to alleviate pacing-induced angina. Circulation 46:880-889, 1972 32. Goldstein RE, Stinson EB, Scherer JL, et al: lntraoperative coronary collateral function in patients with coronary occlusive disease: nitroglycerin responsiveness and angiographic correlations. Circulation 49:298-308, 1974

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