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Modulation of coronary autoregulatory responses by endothelium-derived nitric oxide
ELSEVIER
International Journal of Cardiology 50 (1995) 207-215
Modulation of coronary autoregulatory responses by endothelium-derived nitric oxide John M. Canty, Jr.*ayb,Thomas P. Smith, Jr. apb ‘Departments of Medicine and Physiology, Stite Universi@ of New York, Buffalo Clinical Center, Room CC-l 72, 462 Grider Street Buffalo, NY142153012 USA bVeterans Administration Medical Center, Buffalo, NI: USA
Abstract There is increasing evidence that endothelium-derived nitric oxide production is an important mechanism contributing to the regulation of myocardial perfusion during ischemiadistal to a coronary stenosis.Studiesin consciouschronically instrumented animalshave extended observationsin isolated arterioles to demonstratethat inhibiting nitric oxide synthasewith L-arginine analogsincreasesthe vulnerability of the myocardiumto ischemia. The variable extent to which endothelium-dependentfunction is impaired in human atherosclerosisraisesthe possibilitythat abnormalitiesin resistancevesselcontrol contribute to the functional signiticanceof a fixed epicardial coronary stenosis.This may explain the wide variability betweenthe physiologicaleffects of a given coronary stenosis and its angiographicseverity. Aggressiveintervention to normalize endothelium-dependentvasodilation and local nitric oxide releasemay have beneficial effects on the functional signitkxnce of a coronary stenosis. Keywords: Endothelium-dependentnitric oxide; rArginine analog; Coronary autoregulation; Myocardial ischemia; Coronary flow reserve
1. Introduction A vast amount of knowledge has accumulated to indicate that endothelium-derived nitric oxide is an important mediator in the control of coronary resistance vessels. This has largely arisen
*Corresponding 8983816.
author, Tel.: + 1716 8983819; Fax: + 1716
due to the availability of L-arginine analogs that can block nitric oxide synthase selectively in intact animals. Initial studies focused upon the role of nitric oxide in modulating vasodilation to endothelium-dependent pharmacologic agonists and the reactive hyperemic response following a brief coronary occlusion. More recent studies have investigated the role of nitric oxide in regulating myocardial perfusion in response to changes in oxygen consumption and coronary pressure. This
0167-5273/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0167-5273(95)02379-B
208
J.M. Can& T.P. Smith /International
Journal of Cardiology 50 (1995) 207-215
ability in the ability of the coronary circulation to autoregulate blood flow in anesthetized animals, our laboratory’s efforts have centered upon examining this phenomena in conscious chronically instrumented dogs studied in the resting state. This avoids potentially confounding factors related to elevated sympathetic tone, anesthesia and acute surgical instrumentation. An example of a typical autoregulatory relation in an unanesthetized animal is shown in Fig. 1. As circumflex pressure is initially reduced by inflating a hydraulic occluder, flow remains nearly constant due to progressive vasodilation of the distal resistance vasculature resulting in an ‘autoregulatory plateau’. Nevertheless, once coronary pressure reaches a critical level (the autoregulatory break-
brief review will focus on selected studies examining autoregulation in conscious chronically instrumented animals that demonstrate the importance of nitric oxide in matching local myocardial perfusion to local vasodilator reserve during autoregulation at reduced pressures distal to a coronary stenosis. 2. Characteristics conscious dogs
of coronary autoregulation
in
When regional coronary pressure is altered in the face of constant global determinants of myocardial oxygen consumption, coronary blood flow is autoregulated over a wide range of coronary arterial pressure [l]. Because of substantial vari-
Autoregulatory c 30 -
Flow (ml/min)
\\
b
Breakpoint f
--g-c
.TeA*Plateau Autoregulatory Relation
2o
, I-
10 1
;f
I/
0
lschemic Autoregulatory Relation
40 Coronary
60 Pressure
80
100
(mm Hg)
Fig. 1. Autoregulatory relation from an unanesthetixed animal studied at rest. The global determinants of myocardial oxygen consumption are kept constant as circumflex coronary artery pressure is reduced in a steady-state fashion. Coronary blood flow is kept nearly constant as pressure is reduced from 100 to 40 mmHg over the autoregulatory plateau. Below 40 mmHg, further reductions in coronary pressure are associated with significant reductions in coronary flow (ischemic autoregulatory relation). The autoregulatory breakpoint represents the pressure at which intrinsic autoregulatory mechanisms are no longer able to maintain subendocardial perfusion constant (reprinted with permission of the American Heart Association [19]).
J.M. Canty, T.P. Smith /International
point), flow becomes pressure dependent and further reductions in coronary pressure are associated with reductions in coronary flow which result in regional myocardial ischemia. Studies from our laboratory in conscious animals have demonstrated that perfusion normally remains constant until coronary pressure is reduced below 40 mmHg under resting conditions and that it falls first in the subendocardium [l]. When myocardial metabolism is increased in a steady-state fashion (e.g. by atrial pacing from 100 to 200 beats/mm, Fig. 2), the autoregulatory plateau narrows and the lower limit of subendocardial autoregulation increases from 40 mmHg to approximately 60 mmHg [2]. This increase in the coronary pressure at which subendocardial ischemia begins is a reflection of both the increase in resting flow required to meet increases in myocardial oxygen
Journal of Cardiology 50 (1995) 207-215
209
consumption during tachycardia, as well as a reduction in the regional vasodilator reserve that occurs due to a reduction in the time available for subendocardial perfusion during diastole. Once coronary pressure falls below the lower pressure limit of subendocardial autoregulation for any given level of demand, reductions in flow are accompanied by concomitant reductions in regional myocardial function assessed by regional wall thickening or subendocardial segment shortening [l-4]. The relation between reductions in wall thickening and coronary pressure (Fig. 3a) is almost identical to the subendocardial coronary autoregulatory relation between pressure and flow. In fact, during steady-state changes in myocardial oxygen consumption produced by pacing, relative reductions in regional function, as assessed by transmural wall thickening, are closely
1.5 -
lSubendocardial Flow (ml/min/g) 0.5 -
Endo Flow A
0’
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Endo
HR loo
Flow HR 200
I
1
I
I
I
20
40
60
80
100
Coronary
Pressure
Distal
(mm Hg)
Fig. 2. The effect of increased demand on subendocardial autoregulatory relations. When heart rate is increased from 100 (circles) to 200 beats/nun (triangles), the autoregulatory plateau narrows. This results in an increase in the lower autoregulatory breakpoint from 40 to 60 mmHg during tachycardia. The increase in the lower autoregulatory breakpoint is related to an upward shift in the autoregulatory plateau (reflecting increased resting flow requirements during tachycardia) and a rightward shift in the ischemic autoregulatory relation which is due to a reduction in the time available for subendccardial perfusion during tachycardia. A similar shift in the subendocardial autoregulatory relation occurs during exercise (modSed and reprinted with permission of the American Heart Association [2D.
210
J.M. Canty, T.P. Smith /International
related to relative reductions in flow in a nearly linear fashion (Fig. 3b) for any given level of steady-state demand [2]. This close coupling is an indirect indication that oxygen extraction in conscious animals is maximal at rest and reductions
A
* E
90 25
Wdl
2o
Thlckenlng
II f
B
IOO 60 I
Wall Thlckening (% control)
Q 60 4. _ 20. “0
i
;+ T 34 -
20
A 5 %WTHRlOO A %WlHR200 46
Subendocardlal
60
60
loo
Flow (% control)
Fig. 3. The interrelation among coronary pressure, subendocardial perfusion and regional myocardial function assessed by wall thickening during autoregulation. The upper panel (a) shows the relationship between coronary pressure and regional function during autoregulation at a heart rate of 100 beats/min. Like subendocardial perfusion, regional wall thickening remains constant until coronary pressure is reduced to the lower autoregulatory breakpoint. Below this, reductions in coronary pressure are associated with pronounced reductions in regional myocardial function reflecting subendocardial ischemia. (b) The relationship between relative reductions in regional myocardial wall thickening and relative reductions in subendocardial perfusion. The subendocardial flow data correspond to measurements in Fig. 2 plotted as a percent of control. During pacing at a rate of 100 beats/min (circles) relative reductions in wall thickening are closely related to relative reductions in subendocardial perfusion on nearly a one-to-one basis. When myocardial oxygen consumption is increased by pacing to 200 beata/min (triangles), relative reductions in wall thickening continue to be closely related to relative reductions in subendocardial perfusion on nearly a one-to-one basis. Thus, in conscious dogs, reductions in myocardial perfusion result in concomitant reductions in function since oxygen extraction in the coronary circulation is mmdmum at rest.
Journal of Cardiology 50 (1995) 207-215
in coronary flow result in proportional reductions in myocardial oxygen delivery. A similar close coupling between subendocardial flow and diastolic function has also been demonstrated [5l. While many studies have assumed that reductions in subendocardial flow occur because the resistance vasculature is maximally vasodilated, there is considerable evidence that this is not always true [6-131. There are a large number of studies which show that intrinsic autoregulatory mechanisms compete with adrenergic vasoconstrictor mechanisms during sympathetic activation. Studies examining autoregulation in anesthetized open-chest animals [6-91 as well as transmural perfusion in exercising dogs [lo-131 have demonstrated that pharmacologically recruitable flow reserve can be present during subendocardial ischemia. Nevertheless, when unanesthetized animals are studied in the resting state in the absence of sympathetic activation, our laboratory has recently shown that intrinsic autoregulatory mechanisms are able to adjust tone in the resistance vasculature to match the local subendocardial vasodilator reserve available at any coronary pressure [14]. As discussed below, the mechanisms responsible for adjusting perfusion during myocardial ischemia in the resting state appear to be very dependent upon the release of nitric oxide in the coronary resistance vasculature. 3. Importance of nitric oxide in regulating during ischemia
flow
Studies performed in isolated coronary resistance vessels have shown that changes in local physical forces have a profound effect on local vascular tone in coronary resistance vessels [U-17]. Kuo and colleagues have demonstrated that coronary resistance vessels dilate in response to changes in local flow and/or shear stress [17]. Like conduit coronary arteries, this mechanism is dependent upon an intact endothelium. Dilation of resistance vessels to sustained increases in steady-flow can be completely abolished by inhibiting nitric oxide release with L-arginine analogs. This contrasts with the relative independence of epicardial conduit artery dilation to in-
J.M. Canty, T.P. Smith /International
hibiting nitric oxide production during sustained increases in flow when the pulsatile flow characteristics are kept constant [18]. The in vitro observations in resistance vessels led our laboratory [19] and others [20] to examine whether nitric oxide release could be an important mechanism responsible for eliciting coronary resistance adjustments during coronary autoregulation in intact animals. Fig. 4a shows the effects of inhibiting nitric oxide production on the coronary autoregulatory relation from a conscious dog studied under resting conditions [19]. In these studies, heart rate was kept constant by pacing and inhibiting nitric oxide production had no effect on resting coronary flow or left ventricular end-diastolic pressure. Nitric oxide synthase was blocked using the L-arginine analog N”-nitro-Larginine methylester &NAME) which markedly attenuated both the myocardial reactive hyperemit response to a 30-s occlusion as well as the receptor-mediated stimulation of nitric oxide synthase following an intracoronary infusion of acetylcholine. Despite the fact that the compressive determinants of subendocardial perfusion were comparable under each circumstance, inhibiting nitric oxide production had a profound effect on the coronary autoregulatory relation. Initial resistance adjustments continued to maintain coronary flow constant as coronary pressure was reduced over the autoregulatory plateau. Nevertheless, there was an increase in the lower autoregulatory breakpoint from 39 to 54 mmHg. In addition, the level of coronary flow at any given pressure below the autoregulatory breakpoint was reduced, reflecting a reduction in the maximum vascular conductance that could be achieved by intrinsic autoregulatory mechanisms after blocking nitric oxide production. Fig. 5 summarizes results from a series of conscious animals studied at rest where the lower autoregulatory breakpoint increased from 45 to 61 mmHg after inhibiting nitric oxide production [19]. This shift occurred in the absence of changes in the compressive determinants of subendocardial perfusion during vasodilation and was not overcome by presumably intense stimuli for metabolic vasodilation in the setting of ischemia. Interestingly, the
211
Journal of Cardiolqy 50 (1995) 207-215
A 39 mm Hg
34mmHg e .e**
30
t
0
20
40
60
Coronary
60
Presssure
loo (mm
120 Hg)
B
40 Coronary
60
80
Pressure
100
120 (mmHg)
Fig. 4. The effects of inhibiting nitric oxide production on coronary autoregulatory relations at rest and following exercise. (a) The effect of inhibiting nitric oxide production under resting conditions [19]. The control relation is shown in gray circles and the black circles are data after inhibiting nitric oxide synthase with N”-nitro-L-arginine methylester &NAME). Inhibiting nitric oxide production does not affect autoregulation as circumflex pressure is initially reduced. Nevertheless, there is a shift in the lower autoregulatory breakpoint with myocardial ischemia occurring at higher coronary pressures despite hemodynamic effects that are comparable between the two conditions. (b) Data obtained by Duncker and Bathe [20] during reductions in coronary pressure produced in dogs that are trained to exercise to a steady-state level of oxygen consumption. The open circles depict the control autoregulatory relation during exercise and the closed circles show the effects of inhibiting nitric oxide production with the L-arginine analog NG-nitro-L-arginine (INN& Inhibiting nitric oxide production shifts the autoregulatory relationship to the right and subendocardial ischemia occurred at a higher coronary pressure than during control exercise. Taken together, these studies indicate that nitric oxide release is an important mechanism regulating resistance vessel tone in the setting of ischemia. Furthermore, when nitric oxide release is impaired, abnormalities in resistance vessel dilation are not overcome by intense metabolic stimuli for coronary vasodilation (Fig. 4b reprinted with permission of the American Heart Association [20]).
J.M. Canty, T.P. Smith / Intemationul Journal of Cardiology 50 (1995) 207-215
212
K”,
Flow (ml/min)
*’
-
10
-** ‘F& *
0
&r*.
1;,‘1
* p < .ool
* 0
20
40
Coronary
60
a0
Pressure
loo (mm
120
140
Hg)
Fig. 5. Summary of the effects of inhibiting nitric oxide production with LNAME on the coronary autoregulatory relation. Under control conditions (circles) coronary blood flow is autoregulated until pressure falls to 45 mmHg in unanesthetized dogs. Despite similar heart rates, resting flow and left ventricular end-diastolic pressures, coronary flow can only be kept constant until pressure falls to 61 mmHg after LNAME (triangles). The shift in the autoregulatory breakpoint was accompanied by a reduction in the slope of the pressure-flow relation during ischemia which indicates that vascular conductance during &hernia is lower after inhibiting nitric oxide production than it is under control conditions. While not shown, subsequent studies [21] demonstrate that these reductions in flow are associated with adenosine recruitable vasodilator reserve which restores flow to values comparable to those obtained under control conditions (reprinted with permission of the American Heart Association 1191).
magnitude of the shift in the lower autoregulatory breakpoint was comparable to that which we found when heart rate was increased from 100 to 200 beats/mm with intact nitric oxide dependent mechanisms (Fig. 2). Subsequent studies by Duncker and Bathe [20] have demonstrated a similar shift in the autoregulatory breakpoint after inhibiting nitric oxide production during steady-state increases in myocardial oxygen consumption produced by exercise (Fig. 4b). A major question related to these observations is whether or not pharmacological vasodilator reserve can be demonstrated when nitroxidergic vasodilation is impaired during ischemia since this is not present in conscious dogs at rest [14]. We have recently completed studies to assess the transmural distribution of myocardial perfusion at controlled coronary pressures after nitric oxide production was blocked with N”-nitro-L-arginine methylester 1211 under resting conditions and after pharmacological vasodilation with intracoro-
nary adenosine. Inhibiting nitric oxide synthase produced reductions in subendocardial and subepicardial perfusion at pressures that were higher than the usual autoregulatory breakpoint of 40 mmHg at comparable heart rates. These studies also demonstrated that the reductions in flow that occur in the setting of &hernia after inhibiting nitric oxide production can be improved and frequently normalized by vasodilation with intracoronary adenosine. Thus, in contrast to the close match between subendocardial perfusion and local vasodilator reserve found in unanesthetized animals at rest [14], inhibiting nitric oxide release in conscious animals results in reductions in regional myocardial blood flow in the setting of ischemia in the presence of pharmacologically recruitable vasodilator reserve. Thus, the tidings in conscious intact animals indicate that inhibiting nitric oxide production increases the vulnerability of the myocardium to ischemia. This can potentially be reversed by pharmacological vasodilation and raises the possibility that the impaired endothelium-derived nitric oxide production that occurs in pathophysiological states could affect the physiological significance of a fixed stenosis because of an associated impairment in coronary resistance vessel control. This will be discussed in more detail below. 4. Clinical implications of impaired production distal to a stenosis
nitric oxide
There is now a large amount of clinical data to indicate that endothelium-dependent vasodilation to pharmacological agonists and physiological stimuli such as flow is impaired to a variable extent in patients with angiographic coronary disease as well as risk factors for coronary atherosclerosis such as hypertension, diabetes and hypercholesterolemia [22]. Studies in isolated arterioles from hypercholesterolemic pigs have demonstrated that similar functional abnormalities can occur in the coronary resistance vasculature in the absence of pathological evidence of atherosclerosis [23]. While impaired endothelium-dependent vasodila-
J.M. Canty, T.P. Smith /International
tion could explain exertional angina1 syndromes that occur in the presence of normal coronary arteries, the lack of nitric oxide production alone seems unlikely to be sufficient to cause myocardial ischemia with anatomically normal coronary arteries. Indeed, studies during pacing 1191 and exercise [24] in the absence of a coronary stenosis in conscious dogs have failed to show that inhibiting nitric oxide synthase attenuates the increase in coronary flow to increased myocardial oxygen demand. Although this could indicate that metabolic stimuli during increased demand overcome the impairment in nitric oxide production, this seems unlikely since similar stimuli cannot overcome impaired nitric oxide production at reduced coronary pressure [19,201. Alternatively, the level to which flow and oxygen consumption increase may not be sufficient to cause flow to increase to a point that nitric oxide production becomes important in contributing to vasodilation at normal coronary pressures. This doesn’t exclude the possibility that impaired nitric oxide production could contribute to these angina1 syndromes and that modulating its production could be accompanied by clinical improvement. As coronary pressure is reduced, the relative contribution of nitric oxide dependent vasodilation increases in relation to other regulatory mechanisms. While speculative, impaired nitric oxide production may affect resistance vessel adjustments distal to a fixed epicardial coronary stenosis in patients with coronary artery disease. The heterogeneous impairment of endotheliumdependent vasodilation found in clinical studies may explain the longstanding clinical observation that anatomically similar epicardial coronary stenoses can have variable degrees of physiological significance during functional stress testing. Previous studies examining the coronary reactive hyperemic response in humans indirectly support this hypothesis. Fig. 6 demonstrates the myocardial reactive hyperemic response obtained in patients undergoing coronary bypass surgery in studies by White and colleagues [25]. The coronary artery was transiently occluded and coronary flow velocity was measured with an epicardial suction cup Doppler probe. In patients without
Journal of Cardiology 50 (1995) 207-215
213
coronary artery disease or left ventricular hypertrophy (left hand panel) coronary flow increased five times the resting level, which is similar to flow reserve values reported in experimental animals, The right hand panel shows the relation between peak and resting velocity in individual arteries from patients with coronary atherosclerosis. While coronary flow reserve should progressively decrease as coronary stenosis severity increases, these investigators found virtually no relation between flow reserve and anatomic stenosis severity. Even though experimental studies have shown that stenoses < 50% in diameter reduction do not affect perfusion during vasodilation, the reactive hyperemic response was extremely variable and much lower than that found in patients without coronary artery disease. While a number of factors contribute to this poor correlation, impaired nitric oxide production in the resistance vasculature could account for the variable attenuation of the reactive hyperemic response. Our laboratory has reported a similar attenuation in peak flow after inhibiting nitric oxide production in conscious chronically instrumented dogs [l&19]. Whether abnormalities in endotheliumdependent vasodilation of resistance vessels could alter the functional significance of a stenosis in patients with coronary artery disease remains to be defined but is supported by the shift in the autoregulatory relation during ischemia observed in conscious dogs at rest [19] and during exercise [20]. The recent demonstration of adenosine recruitable flow reserve during ischemia after nitric oxide production is inhibited in conscious animals [21] raises the intriguing possibility that abnormalities in endothelium-dependent vasodilation of resistance vessels can be reversed pharmacologically. Alternatively, modification of risk factors such as hypercholesterolemia could restore endothelium-dependent vasodilation in the resistance vasculature in a fashion that is similar to that recently demonstrated in large epicardial arteries [26,27]. The reversibility of abnormalities in resistance vessel function could afford new avenues for therapeutic intervention in coronary disease and will require further study.
J.M. Canty,
214
T.P. Smith /International Journal of Camkdogy 50 (l!XV) 207-215 9.6
9.6
.
r = -0.25 6.4
6.4
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-
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-
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-
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o
.
q
.
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0
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60
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Fig. 6. Coronary reactive hyperemic response measured in patients undergoing cardiac surgery using suction cup Doppler velocity probes [WI. The coronary circulation is vasodilated by a 20-s transient occlusion and peak hyperemic velocities are expressed in relation to resting values (coronary flow reserve). In patients without coronary artery disease (left hand graph) peak flow velocity following release of the occlusion increases to between four and five times the corresponding resting values. In contrast, there is an attenuation of the coronary reactive hyperemic response in patients with coronary artery disease. This is surprisingly independent of the anatomic severity of the stenosis and present for stenoses that are < 50% diameter reduction in severity. T’his raises the possibility that these abnormalities are, in part, a reflection of impaired endothelium-dependent vasodilation of the resistance vasculature (reprinted by permission of the New England Journal of Medicine 1984,310: 821).
Acknowledgements Supported by a Grant in Aid from the American Heart Association National Center (93-9661, the Ralph Hochstetter Medical Research Fund in honor of Dr Henry C. and Bertha H. Buswell, and a Merit Review Award from the Veterans Administration. References [l]
Canty JM Jr. Coronary pressure-function and steadystate pressure-flow relations during autoregulation in the unanesthetixed dog. Circ Res 1988; 63: 821-836. [2] Canty JM Jr., Giglia J, Kandath D. Effect of tachycardia on regional function and transmural myocardial perfusion during graded coronary pressure reduction in conscious dogs. Cii Res 1990,82: 1815-1825. [3] Gallagher KP, Matsuxaki M, Osakada G, Kemper WS, Ross J Jr. Effect of exercise on the relationship between myocardial blood flow and systolic wall thickening in dogs with acute coronary stenosis. Ciic Res 1983; 52: 716-729.
Gallagher KP, Matsuxaki M, Koxiol JA, Kemper WS, Ross J Jr. Regional myocardial perfusion and wall thickening during ischemia in conscious dogs. Am J Physiol 1984; 247: H727-H738. PI Farhi ER, Canty JM Jr., Klocke FJ. Effects of graded reductions in coronary perfusion pressure on steady-state diastolic distensibility and isovoltic relaxation in the resting conscious dog. Circulation 1989; 80: 1458-1468. 161 Canty JM Jr., Klocke FJ. Reduced regional myocardial perfusion in the presence of pharmacologic vasodilator reserve. Circulation 1985; 71: 370-377. 171 Aversano T, Becker LC. Persistence of coronary vasodilator reserve despite functionally significant flow reduction. Am J Physiol 1985; 248: H403-H411. [81 Pantely GA, Bristow JD, Swenson W, Ladley HD, Johnson WB, Anselone CG. Incomplete coronary vasodilation during myocardial ischemia in swine. Am J Physiol 1985; 249: H638-H647. 191 Grattan MT, Hanley FL, Stevens MB, Hoffman JIE. Transmural coronary flow reserve patterns in dogs. Am J Physiol 1986,250: H276H283. Heusch G, Guth BD, Seitelberger R, Ross J Jr. Attenum ation of ischemia in dogs with recruitment of coronary vasodilator reserve by nifedipine. Circulation 1987; 75: 141
482-490.
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ml
Seitelberger R, Guth BD, Heusch G, Lee JD, Katayama K, Ross J Jr. Intracoronary cr,-adrenergic receptor blockade attenuates ischemia in conscious dogs during exercise. Circ Res 1988; 62: 436-442. [=I Laxson DD, Dai XZ, Homans DC, Bathe RJ. The role of (Ye and crz-adrenergic receptors in mediation of coronary vasoconstriction in hypoperfused ischemic myocardium during exercise. Circ Res 1989; 65: 1688-1697. [131 Laxson DD, Dai XC, Homans DC, Bathe RJ. Coronary vasodilator reserve in ischemic myocardium of the exercising dog. Circulation 1992; 85: 313-322. t141 Canty JM Jr., Smith TP Jr. Adenosine recruitable flow reserve is absent during myocardial ischemia in conscious dogs studied in the basal state. Circ Res 1995. In press. 1151 Kuo L, Davis MJ, Chilian WM. Myogenic activity in isolated subepicardial and subendocardial coronary arterioles. Am J Physiol 1988; 255: H1558-H1562. Ml Rajagopalan S, Dube S, Canty JM Jr. Regulation of coronary diameter by myogenic mechanisms in arterial microvessels greater than 100 microns in diameter. Am J Physiol 1995; 268: H788-H793. 1171 Kuo L, Davis MJ, Chilian WM. Endothelium-dependent, flow-induced dilation of isolated coronary arterioles. Am J Physiol 1990; 259: H1063-H1070. Ml Canty JM Jr., Schwartz JS. Nitric oxide mediates flowdependent epicardial coronary vasodilation to changes in pulse frequency but not mean flow in conscious dogs. Circulation 1994; 89: 375-384. 1191 Smith TP, Canty JM Jr. Modulation of coronary autoregulatory responses by nitric oxide: evidence for flow-dependent resistance adjustments in conscious dogs. Circ Res 1993; 73: 232-240. DO1 Duncker DJ, Bathe RJ. Inhibition of nitric oxide pro-
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duction aggravates myocardial hypoperfusion during exercise in the presence of a coronary artery stenosis. Circ Res 1994; 74: 629-640. Dll Canty JM Jr. Transmural variations in autoregulation and adenosine recruitable reserve after inhibiting nitric oxide production in conscious dogs [abstract]. Circulation 1993; 88 (Suppl II): I-566. WI Zeiher AM, Drexler H, Wollschlager H, Just H. Endothelial dysfunction of the coronary microvasculature is associated with impaired coronary blood flow regulation in patients with early atherosclerosis. Circulation 1991; 84: 1984-1992. [231 Kuo L, Davis MJ, Cannon MS, Chilian WM. Pathophysiological consequences of atherosclerosis extend into the coronary microcirculation: restoration of endotheliumdependent responses by L-arginine. Circ Res 1992; 70: 465-476. KM Altman JD, Kinn J, Duncker DJ, Bathe RJ. Effect of inhibition of nitric oxide formation on coronary blood flow during exercise in the dog. Cardiovasc Res 1994; 28: 119-124. [Zl White CW, Wright CB, Doty DB et al. Does visual interpretation of the coronary arteriogram predict the physiologic importance of a coronary stenosis? N Engl J Med 1984; 310: 819-824. [261 Treasure CB, Klein JL, Weintraub WS et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995; 332: 481-487. WI Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 1995; 332: 488-493.
International Journal of Cardiology 50 (1995) 207-215
Modulation of coronary autoregulatory responses by endothelium-derived nitric oxide John M. Canty, Jr.*ayb,Thomas P. Smith, Jr. apb ‘Departments of Medicine and Physiology, Stite Universi@ of New York, Buffalo Clinical Center, Room CC-l 72, 462 Grider Street Buffalo, NY142153012 USA bVeterans Administration Medical Center, Buffalo, NI: USA
Abstract There is increasing evidence that endothelium-derived nitric oxide production is an important mechanism contributing to the regulation of myocardial perfusion during ischemiadistal to a coronary stenosis.Studiesin consciouschronically instrumented animalshave extended observationsin isolated arterioles to demonstratethat inhibiting nitric oxide synthasewith L-arginine analogsincreasesthe vulnerability of the myocardiumto ischemia. The variable extent to which endothelium-dependentfunction is impaired in human atherosclerosisraisesthe possibilitythat abnormalitiesin resistancevesselcontrol contribute to the functional signiticanceof a fixed epicardial coronary stenosis.This may explain the wide variability betweenthe physiologicaleffects of a given coronary stenosis and its angiographicseverity. Aggressiveintervention to normalize endothelium-dependentvasodilation and local nitric oxide releasemay have beneficial effects on the functional signitkxnce of a coronary stenosis. Keywords: Endothelium-dependentnitric oxide; rArginine analog; Coronary autoregulation; Myocardial ischemia; Coronary flow reserve
1. Introduction A vast amount of knowledge has accumulated to indicate that endothelium-derived nitric oxide is an important mediator in the control of coronary resistance vessels. This has largely arisen
*Corresponding 8983816.
author, Tel.: + 1716 8983819; Fax: + 1716
due to the availability of L-arginine analogs that can block nitric oxide synthase selectively in intact animals. Initial studies focused upon the role of nitric oxide in modulating vasodilation to endothelium-dependent pharmacologic agonists and the reactive hyperemic response following a brief coronary occlusion. More recent studies have investigated the role of nitric oxide in regulating myocardial perfusion in response to changes in oxygen consumption and coronary pressure. This
0167-5273/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0167-5273(95)02379-B
208
J.M. Can& T.P. Smith /International
Journal of Cardiology 50 (1995) 207-215
ability in the ability of the coronary circulation to autoregulate blood flow in anesthetized animals, our laboratory’s efforts have centered upon examining this phenomena in conscious chronically instrumented dogs studied in the resting state. This avoids potentially confounding factors related to elevated sympathetic tone, anesthesia and acute surgical instrumentation. An example of a typical autoregulatory relation in an unanesthetized animal is shown in Fig. 1. As circumflex pressure is initially reduced by inflating a hydraulic occluder, flow remains nearly constant due to progressive vasodilation of the distal resistance vasculature resulting in an ‘autoregulatory plateau’. Nevertheless, once coronary pressure reaches a critical level (the autoregulatory break-
brief review will focus on selected studies examining autoregulation in conscious chronically instrumented animals that demonstrate the importance of nitric oxide in matching local myocardial perfusion to local vasodilator reserve during autoregulation at reduced pressures distal to a coronary stenosis. 2. Characteristics conscious dogs
of coronary autoregulation
in
When regional coronary pressure is altered in the face of constant global determinants of myocardial oxygen consumption, coronary blood flow is autoregulated over a wide range of coronary arterial pressure [l]. Because of substantial vari-
Autoregulatory c 30 -
Flow (ml/min)
\\
b
Breakpoint f
--g-c
.TeA*Plateau Autoregulatory Relation
2o
, I-
10 1
;f
I/
0
lschemic Autoregulatory Relation
40 Coronary
60 Pressure
80
100
(mm Hg)
Fig. 1. Autoregulatory relation from an unanesthetixed animal studied at rest. The global determinants of myocardial oxygen consumption are kept constant as circumflex coronary artery pressure is reduced in a steady-state fashion. Coronary blood flow is kept nearly constant as pressure is reduced from 100 to 40 mmHg over the autoregulatory plateau. Below 40 mmHg, further reductions in coronary pressure are associated with significant reductions in coronary flow (ischemic autoregulatory relation). The autoregulatory breakpoint represents the pressure at which intrinsic autoregulatory mechanisms are no longer able to maintain subendocardial perfusion constant (reprinted with permission of the American Heart Association [19]).
J.M. Canty, T.P. Smith /International
point), flow becomes pressure dependent and further reductions in coronary pressure are associated with reductions in coronary flow which result in regional myocardial ischemia. Studies from our laboratory in conscious animals have demonstrated that perfusion normally remains constant until coronary pressure is reduced below 40 mmHg under resting conditions and that it falls first in the subendocardium [l]. When myocardial metabolism is increased in a steady-state fashion (e.g. by atrial pacing from 100 to 200 beats/mm, Fig. 2), the autoregulatory plateau narrows and the lower limit of subendocardial autoregulation increases from 40 mmHg to approximately 60 mmHg [2]. This increase in the coronary pressure at which subendocardial ischemia begins is a reflection of both the increase in resting flow required to meet increases in myocardial oxygen
Journal of Cardiology 50 (1995) 207-215
209
consumption during tachycardia, as well as a reduction in the regional vasodilator reserve that occurs due to a reduction in the time available for subendocardial perfusion during diastole. Once coronary pressure falls below the lower pressure limit of subendocardial autoregulation for any given level of demand, reductions in flow are accompanied by concomitant reductions in regional myocardial function assessed by regional wall thickening or subendocardial segment shortening [l-4]. The relation between reductions in wall thickening and coronary pressure (Fig. 3a) is almost identical to the subendocardial coronary autoregulatory relation between pressure and flow. In fact, during steady-state changes in myocardial oxygen consumption produced by pacing, relative reductions in regional function, as assessed by transmural wall thickening, are closely
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Fig. 2. The effect of increased demand on subendocardial autoregulatory relations. When heart rate is increased from 100 (circles) to 200 beats/nun (triangles), the autoregulatory plateau narrows. This results in an increase in the lower autoregulatory breakpoint from 40 to 60 mmHg during tachycardia. The increase in the lower autoregulatory breakpoint is related to an upward shift in the autoregulatory plateau (reflecting increased resting flow requirements during tachycardia) and a rightward shift in the ischemic autoregulatory relation which is due to a reduction in the time available for subendccardial perfusion during tachycardia. A similar shift in the subendocardial autoregulatory relation occurs during exercise (modSed and reprinted with permission of the American Heart Association [2D.
210
J.M. Canty, T.P. Smith /International
related to relative reductions in flow in a nearly linear fashion (Fig. 3b) for any given level of steady-state demand [2]. This close coupling is an indirect indication that oxygen extraction in conscious animals is maximal at rest and reductions
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Fig. 3. The interrelation among coronary pressure, subendocardial perfusion and regional myocardial function assessed by wall thickening during autoregulation. The upper panel (a) shows the relationship between coronary pressure and regional function during autoregulation at a heart rate of 100 beats/min. Like subendocardial perfusion, regional wall thickening remains constant until coronary pressure is reduced to the lower autoregulatory breakpoint. Below this, reductions in coronary pressure are associated with pronounced reductions in regional myocardial function reflecting subendocardial ischemia. (b) The relationship between relative reductions in regional myocardial wall thickening and relative reductions in subendocardial perfusion. The subendocardial flow data correspond to measurements in Fig. 2 plotted as a percent of control. During pacing at a rate of 100 beats/min (circles) relative reductions in wall thickening are closely related to relative reductions in subendocardial perfusion on nearly a one-to-one basis. When myocardial oxygen consumption is increased by pacing to 200 beata/min (triangles), relative reductions in wall thickening continue to be closely related to relative reductions in subendocardial perfusion on nearly a one-to-one basis. Thus, in conscious dogs, reductions in myocardial perfusion result in concomitant reductions in function since oxygen extraction in the coronary circulation is mmdmum at rest.
Journal of Cardiology 50 (1995) 207-215
in coronary flow result in proportional reductions in myocardial oxygen delivery. A similar close coupling between subendocardial flow and diastolic function has also been demonstrated [5l. While many studies have assumed that reductions in subendocardial flow occur because the resistance vasculature is maximally vasodilated, there is considerable evidence that this is not always true [6-131. There are a large number of studies which show that intrinsic autoregulatory mechanisms compete with adrenergic vasoconstrictor mechanisms during sympathetic activation. Studies examining autoregulation in anesthetized open-chest animals [6-91 as well as transmural perfusion in exercising dogs [lo-131 have demonstrated that pharmacologically recruitable flow reserve can be present during subendocardial ischemia. Nevertheless, when unanesthetized animals are studied in the resting state in the absence of sympathetic activation, our laboratory has recently shown that intrinsic autoregulatory mechanisms are able to adjust tone in the resistance vasculature to match the local subendocardial vasodilator reserve available at any coronary pressure [14]. As discussed below, the mechanisms responsible for adjusting perfusion during myocardial ischemia in the resting state appear to be very dependent upon the release of nitric oxide in the coronary resistance vasculature. 3. Importance of nitric oxide in regulating during ischemia
flow
Studies performed in isolated coronary resistance vessels have shown that changes in local physical forces have a profound effect on local vascular tone in coronary resistance vessels [U-17]. Kuo and colleagues have demonstrated that coronary resistance vessels dilate in response to changes in local flow and/or shear stress [17]. Like conduit coronary arteries, this mechanism is dependent upon an intact endothelium. Dilation of resistance vessels to sustained increases in steady-flow can be completely abolished by inhibiting nitric oxide release with L-arginine analogs. This contrasts with the relative independence of epicardial conduit artery dilation to in-
J.M. Canty, T.P. Smith /International
hibiting nitric oxide production during sustained increases in flow when the pulsatile flow characteristics are kept constant [18]. The in vitro observations in resistance vessels led our laboratory [19] and others [20] to examine whether nitric oxide release could be an important mechanism responsible for eliciting coronary resistance adjustments during coronary autoregulation in intact animals. Fig. 4a shows the effects of inhibiting nitric oxide production on the coronary autoregulatory relation from a conscious dog studied under resting conditions [19]. In these studies, heart rate was kept constant by pacing and inhibiting nitric oxide production had no effect on resting coronary flow or left ventricular end-diastolic pressure. Nitric oxide synthase was blocked using the L-arginine analog N”-nitro-Larginine methylester &NAME) which markedly attenuated both the myocardial reactive hyperemit response to a 30-s occlusion as well as the receptor-mediated stimulation of nitric oxide synthase following an intracoronary infusion of acetylcholine. Despite the fact that the compressive determinants of subendocardial perfusion were comparable under each circumstance, inhibiting nitric oxide production had a profound effect on the coronary autoregulatory relation. Initial resistance adjustments continued to maintain coronary flow constant as coronary pressure was reduced over the autoregulatory plateau. Nevertheless, there was an increase in the lower autoregulatory breakpoint from 39 to 54 mmHg. In addition, the level of coronary flow at any given pressure below the autoregulatory breakpoint was reduced, reflecting a reduction in the maximum vascular conductance that could be achieved by intrinsic autoregulatory mechanisms after blocking nitric oxide production. Fig. 5 summarizes results from a series of conscious animals studied at rest where the lower autoregulatory breakpoint increased from 45 to 61 mmHg after inhibiting nitric oxide production [19]. This shift occurred in the absence of changes in the compressive determinants of subendocardial perfusion during vasodilation and was not overcome by presumably intense stimuli for metabolic vasodilation in the setting of ischemia. Interestingly, the
211
Journal of Cardiolqy 50 (1995) 207-215
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Fig. 4. The effects of inhibiting nitric oxide production on coronary autoregulatory relations at rest and following exercise. (a) The effect of inhibiting nitric oxide production under resting conditions [19]. The control relation is shown in gray circles and the black circles are data after inhibiting nitric oxide synthase with N”-nitro-L-arginine methylester &NAME). Inhibiting nitric oxide production does not affect autoregulation as circumflex pressure is initially reduced. Nevertheless, there is a shift in the lower autoregulatory breakpoint with myocardial ischemia occurring at higher coronary pressures despite hemodynamic effects that are comparable between the two conditions. (b) Data obtained by Duncker and Bathe [20] during reductions in coronary pressure produced in dogs that are trained to exercise to a steady-state level of oxygen consumption. The open circles depict the control autoregulatory relation during exercise and the closed circles show the effects of inhibiting nitric oxide production with the L-arginine analog NG-nitro-L-arginine (INN& Inhibiting nitric oxide production shifts the autoregulatory relationship to the right and subendocardial ischemia occurred at a higher coronary pressure than during control exercise. Taken together, these studies indicate that nitric oxide release is an important mechanism regulating resistance vessel tone in the setting of ischemia. Furthermore, when nitric oxide release is impaired, abnormalities in resistance vessel dilation are not overcome by intense metabolic stimuli for coronary vasodilation (Fig. 4b reprinted with permission of the American Heart Association [20]).
J.M. Canty, T.P. Smith / Intemationul Journal of Cardiology 50 (1995) 207-215
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K”,
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Fig. 5. Summary of the effects of inhibiting nitric oxide production with LNAME on the coronary autoregulatory relation. Under control conditions (circles) coronary blood flow is autoregulated until pressure falls to 45 mmHg in unanesthetized dogs. Despite similar heart rates, resting flow and left ventricular end-diastolic pressures, coronary flow can only be kept constant until pressure falls to 61 mmHg after LNAME (triangles). The shift in the autoregulatory breakpoint was accompanied by a reduction in the slope of the pressure-flow relation during ischemia which indicates that vascular conductance during &hernia is lower after inhibiting nitric oxide production than it is under control conditions. While not shown, subsequent studies [21] demonstrate that these reductions in flow are associated with adenosine recruitable vasodilator reserve which restores flow to values comparable to those obtained under control conditions (reprinted with permission of the American Heart Association 1191).
magnitude of the shift in the lower autoregulatory breakpoint was comparable to that which we found when heart rate was increased from 100 to 200 beats/mm with intact nitric oxide dependent mechanisms (Fig. 2). Subsequent studies by Duncker and Bathe [20] have demonstrated a similar shift in the autoregulatory breakpoint after inhibiting nitric oxide production during steady-state increases in myocardial oxygen consumption produced by exercise (Fig. 4b). A major question related to these observations is whether or not pharmacological vasodilator reserve can be demonstrated when nitroxidergic vasodilation is impaired during ischemia since this is not present in conscious dogs at rest [14]. We have recently completed studies to assess the transmural distribution of myocardial perfusion at controlled coronary pressures after nitric oxide production was blocked with N”-nitro-L-arginine methylester 1211 under resting conditions and after pharmacological vasodilation with intracoro-
nary adenosine. Inhibiting nitric oxide synthase produced reductions in subendocardial and subepicardial perfusion at pressures that were higher than the usual autoregulatory breakpoint of 40 mmHg at comparable heart rates. These studies also demonstrated that the reductions in flow that occur in the setting of &hernia after inhibiting nitric oxide production can be improved and frequently normalized by vasodilation with intracoronary adenosine. Thus, in contrast to the close match between subendocardial perfusion and local vasodilator reserve found in unanesthetized animals at rest [14], inhibiting nitric oxide release in conscious animals results in reductions in regional myocardial blood flow in the setting of ischemia in the presence of pharmacologically recruitable vasodilator reserve. Thus, the tidings in conscious intact animals indicate that inhibiting nitric oxide production increases the vulnerability of the myocardium to ischemia. This can potentially be reversed by pharmacological vasodilation and raises the possibility that the impaired endothelium-derived nitric oxide production that occurs in pathophysiological states could affect the physiological significance of a fixed stenosis because of an associated impairment in coronary resistance vessel control. This will be discussed in more detail below. 4. Clinical implications of impaired production distal to a stenosis
nitric oxide
There is now a large amount of clinical data to indicate that endothelium-dependent vasodilation to pharmacological agonists and physiological stimuli such as flow is impaired to a variable extent in patients with angiographic coronary disease as well as risk factors for coronary atherosclerosis such as hypertension, diabetes and hypercholesterolemia [22]. Studies in isolated arterioles from hypercholesterolemic pigs have demonstrated that similar functional abnormalities can occur in the coronary resistance vasculature in the absence of pathological evidence of atherosclerosis [23]. While impaired endothelium-dependent vasodila-
J.M. Canty, T.P. Smith /International
tion could explain exertional angina1 syndromes that occur in the presence of normal coronary arteries, the lack of nitric oxide production alone seems unlikely to be sufficient to cause myocardial ischemia with anatomically normal coronary arteries. Indeed, studies during pacing 1191 and exercise [24] in the absence of a coronary stenosis in conscious dogs have failed to show that inhibiting nitric oxide synthase attenuates the increase in coronary flow to increased myocardial oxygen demand. Although this could indicate that metabolic stimuli during increased demand overcome the impairment in nitric oxide production, this seems unlikely since similar stimuli cannot overcome impaired nitric oxide production at reduced coronary pressure [19,201. Alternatively, the level to which flow and oxygen consumption increase may not be sufficient to cause flow to increase to a point that nitric oxide production becomes important in contributing to vasodilation at normal coronary pressures. This doesn’t exclude the possibility that impaired nitric oxide production could contribute to these angina1 syndromes and that modulating its production could be accompanied by clinical improvement. As coronary pressure is reduced, the relative contribution of nitric oxide dependent vasodilation increases in relation to other regulatory mechanisms. While speculative, impaired nitric oxide production may affect resistance vessel adjustments distal to a fixed epicardial coronary stenosis in patients with coronary artery disease. The heterogeneous impairment of endotheliumdependent vasodilation found in clinical studies may explain the longstanding clinical observation that anatomically similar epicardial coronary stenoses can have variable degrees of physiological significance during functional stress testing. Previous studies examining the coronary reactive hyperemic response in humans indirectly support this hypothesis. Fig. 6 demonstrates the myocardial reactive hyperemic response obtained in patients undergoing coronary bypass surgery in studies by White and colleagues [25]. The coronary artery was transiently occluded and coronary flow velocity was measured with an epicardial suction cup Doppler probe. In patients without
Journal of Cardiology 50 (1995) 207-215
213
coronary artery disease or left ventricular hypertrophy (left hand panel) coronary flow increased five times the resting level, which is similar to flow reserve values reported in experimental animals, The right hand panel shows the relation between peak and resting velocity in individual arteries from patients with coronary atherosclerosis. While coronary flow reserve should progressively decrease as coronary stenosis severity increases, these investigators found virtually no relation between flow reserve and anatomic stenosis severity. Even though experimental studies have shown that stenoses < 50% in diameter reduction do not affect perfusion during vasodilation, the reactive hyperemic response was extremely variable and much lower than that found in patients without coronary artery disease. While a number of factors contribute to this poor correlation, impaired nitric oxide production in the resistance vasculature could account for the variable attenuation of the reactive hyperemic response. Our laboratory has reported a similar attenuation in peak flow after inhibiting nitric oxide production in conscious chronically instrumented dogs [l&19]. Whether abnormalities in endotheliumdependent vasodilation of resistance vessels could alter the functional significance of a stenosis in patients with coronary artery disease remains to be defined but is supported by the shift in the autoregulatory relation during ischemia observed in conscious dogs at rest [19] and during exercise [20]. The recent demonstration of adenosine recruitable flow reserve during ischemia after nitric oxide production is inhibited in conscious animals [21] raises the intriguing possibility that abnormalities in endothelium-dependent vasodilation of resistance vessels can be reversed pharmacologically. Alternatively, modification of risk factors such as hypercholesterolemia could restore endothelium-dependent vasodilation in the resistance vasculature in a fashion that is similar to that recently demonstrated in large epicardial arteries [26,27]. The reversibility of abnormalities in resistance vessel function could afford new avenues for therapeutic intervention in coronary disease and will require further study.
J.M. Canty,
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T.P. Smith /International Journal of Camkdogy 50 (l!XV) 207-215 9.6
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Fig. 6. Coronary reactive hyperemic response measured in patients undergoing cardiac surgery using suction cup Doppler velocity probes [WI. The coronary circulation is vasodilated by a 20-s transient occlusion and peak hyperemic velocities are expressed in relation to resting values (coronary flow reserve). In patients without coronary artery disease (left hand graph) peak flow velocity following release of the occlusion increases to between four and five times the corresponding resting values. In contrast, there is an attenuation of the coronary reactive hyperemic response in patients with coronary artery disease. This is surprisingly independent of the anatomic severity of the stenosis and present for stenoses that are < 50% diameter reduction in severity. T’his raises the possibility that these abnormalities are, in part, a reflection of impaired endothelium-dependent vasodilation of the resistance vasculature (reprinted by permission of the New England Journal of Medicine 1984,310: 821).
Acknowledgements Supported by a Grant in Aid from the American Heart Association National Center (93-9661, the Ralph Hochstetter Medical Research Fund in honor of Dr Henry C. and Bertha H. Buswell, and a Merit Review Award from the Veterans Administration. References [l]
Canty JM Jr. Coronary pressure-function and steadystate pressure-flow relations during autoregulation in the unanesthetixed dog. Circ Res 1988; 63: 821-836. [2] Canty JM Jr., Giglia J, Kandath D. Effect of tachycardia on regional function and transmural myocardial perfusion during graded coronary pressure reduction in conscious dogs. Cii Res 1990,82: 1815-1825. [3] Gallagher KP, Matsuxaki M, Osakada G, Kemper WS, Ross J Jr. Effect of exercise on the relationship between myocardial blood flow and systolic wall thickening in dogs with acute coronary stenosis. Ciic Res 1983; 52: 716-729.
Gallagher KP, Matsuxaki M, Koxiol JA, Kemper WS, Ross J Jr. Regional myocardial perfusion and wall thickening during ischemia in conscious dogs. Am J Physiol 1984; 247: H727-H738. PI Farhi ER, Canty JM Jr., Klocke FJ. Effects of graded reductions in coronary perfusion pressure on steady-state diastolic distensibility and isovoltic relaxation in the resting conscious dog. Circulation 1989; 80: 1458-1468. 161 Canty JM Jr., Klocke FJ. Reduced regional myocardial perfusion in the presence of pharmacologic vasodilator reserve. Circulation 1985; 71: 370-377. 171 Aversano T, Becker LC. Persistence of coronary vasodilator reserve despite functionally significant flow reduction. Am J Physiol 1985; 248: H403-H411. [81 Pantely GA, Bristow JD, Swenson W, Ladley HD, Johnson WB, Anselone CG. Incomplete coronary vasodilation during myocardial ischemia in swine. Am J Physiol 1985; 249: H638-H647. 191 Grattan MT, Hanley FL, Stevens MB, Hoffman JIE. Transmural coronary flow reserve patterns in dogs. Am J Physiol 1986,250: H276H283. Heusch G, Guth BD, Seitelberger R, Ross J Jr. Attenum ation of ischemia in dogs with recruitment of coronary vasodilator reserve by nifedipine. Circulation 1987; 75: 141
482-490.
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Seitelberger R, Guth BD, Heusch G, Lee JD, Katayama K, Ross J Jr. Intracoronary cr,-adrenergic receptor blockade attenuates ischemia in conscious dogs during exercise. Circ Res 1988; 62: 436-442. [=I Laxson DD, Dai XZ, Homans DC, Bathe RJ. The role of (Ye and crz-adrenergic receptors in mediation of coronary vasoconstriction in hypoperfused ischemic myocardium during exercise. Circ Res 1989; 65: 1688-1697. [131 Laxson DD, Dai XC, Homans DC, Bathe RJ. Coronary vasodilator reserve in ischemic myocardium of the exercising dog. Circulation 1992; 85: 313-322. t141 Canty JM Jr., Smith TP Jr. Adenosine recruitable flow reserve is absent during myocardial ischemia in conscious dogs studied in the basal state. Circ Res 1995. In press. 1151 Kuo L, Davis MJ, Chilian WM. Myogenic activity in isolated subepicardial and subendocardial coronary arterioles. Am J Physiol 1988; 255: H1558-H1562. Ml Rajagopalan S, Dube S, Canty JM Jr. Regulation of coronary diameter by myogenic mechanisms in arterial microvessels greater than 100 microns in diameter. Am J Physiol 1995; 268: H788-H793. 1171 Kuo L, Davis MJ, Chilian WM. Endothelium-dependent, flow-induced dilation of isolated coronary arterioles. Am J Physiol 1990; 259: H1063-H1070. Ml Canty JM Jr., Schwartz JS. Nitric oxide mediates flowdependent epicardial coronary vasodilation to changes in pulse frequency but not mean flow in conscious dogs. Circulation 1994; 89: 375-384. 1191 Smith TP, Canty JM Jr. Modulation of coronary autoregulatory responses by nitric oxide: evidence for flow-dependent resistance adjustments in conscious dogs. Circ Res 1993; 73: 232-240. DO1 Duncker DJ, Bathe RJ. Inhibition of nitric oxide pro-
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duction aggravates myocardial hypoperfusion during exercise in the presence of a coronary artery stenosis. Circ Res 1994; 74: 629-640. Dll Canty JM Jr. Transmural variations in autoregulation and adenosine recruitable reserve after inhibiting nitric oxide production in conscious dogs [abstract]. Circulation 1993; 88 (Suppl II): I-566. WI Zeiher AM, Drexler H, Wollschlager H, Just H. Endothelial dysfunction of the coronary microvasculature is associated with impaired coronary blood flow regulation in patients with early atherosclerosis. Circulation 1991; 84: 1984-1992. [231 Kuo L, Davis MJ, Cannon MS, Chilian WM. Pathophysiological consequences of atherosclerosis extend into the coronary microcirculation: restoration of endotheliumdependent responses by L-arginine. Circ Res 1992; 70: 465-476. KM Altman JD, Kinn J, Duncker DJ, Bathe RJ. Effect of inhibition of nitric oxide formation on coronary blood flow during exercise in the dog. Cardiovasc Res 1994; 28: 119-124. [Zl White CW, Wright CB, Doty DB et al. Does visual interpretation of the coronary arteriogram predict the physiologic importance of a coronary stenosis? N Engl J Med 1984; 310: 819-824. [261 Treasure CB, Klein JL, Weintraub WS et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995; 332: 481-487. WI Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 1995; 332: 488-493.