Role of ;2 Adrenergic Receptors in Human Atherosclerotic Coronary Arteries
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循环学杂志 2005年第1期
the Divisions of Cardiology (E.B., F.P., G.G., P.C., G.D.L., M.C.)
Internal Medicine (G.I.), Federico II University of Naples, Italy
the Cardiovascular Center OLVZ, Aalst, Belgium (E.B., J.B., B.D.B., W.W.).
Abstract
Background— Adrenergic regulation of coronary vasomotion is balanced between 1-adrenergic–mediated (1-AR) constriction and ;2-adrenergic–mediated (;2-AR) relaxation. This study aimed at assessing the role of ;2-ARs in normal, mildly atherosclerotic, and stenotic human coronary arteries.
Methods and Results— During intracoronary (IC) infusion of increasing doses of the ;2-AR agonist salbutamol (0.15, 0.3, and 0.6 μg/min) and the endothelial vasodilator acetylcholine (1, 3, and 10 μg/min), we measured (1) changes in lumen diameter (LD) by quantitative coronary angiography in 34 normal, 55 mildly atherosclerotic, and 42 stenotic coronary artery segments and (2) changes in average peak velocity (APV) and coronary blood flow (CBF) with the use of Doppler flow wire in 11 normal, 10 mildly atherosclerotic, and 11 stenotic coronary arteries. In 6 of 11 stenotic coronary arteries, the protocol was repeated after an IC bolus (12 μg/kg) of the -adrenergic blocker phentolamine. In 6 of 11 normal coronary arteries, the protocol was repeated after an IC infusion (60 μmol/min) of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide inhibitor. Neither salbutamol IC infusion nor acetylcholine significantly changed heart rate or blood pressure, whereas L-NMMA slightly increased blood pressure. In normal coronary arteries, salbutamol increased LD (LD max %: 11±2, P<0.05), APV (APV max %: 53±17, P<0.05), and CBF (CBF max %: 57±17, P<0.05), whereas L-NMMA caused a blunted APV (APV max %: 27±6, P<0.05) and CBF (CBF max %: 29±6, P<0.05) response to salbutamol. In mildly atherosclerotic coronary arteries, the salbutamol increase in LD (LD max %: 10±2, P<0.05), APV (APV max %: 33±12, P<0.05), and CBF (CBF max %: 37±12, P<0.05) was preserved. In stenotic coronary arteries, salbutamol induced a paradoxical reduction in LD (LD max %: –6±2, P<0.05), APV (APV max %: –15±9, P<0.05), and CBF (CBF max %: –15±6, P<0.05), which was no longer observed after phentolamine. Acetylcholine increased LD (LD max %: 14±3, P<0.05), APV (APV max %: 61±20, P<0.05), and CBF (CBF max %: 67±19, P<0.05) in normal coronary arteries. In mildly atherosclerotic coronary arteries, acetylcholine induced a significant reduction in LD (LD max %: –15±2, P<0.05) and no changes in APV (APV max %: –6±13, P=NS) and CBF (CBF max %: –10±13, P=NS). In stenotic coronary arteries, acetylcholine significantly reduced LD (LD max %: –15±3, P<0.05), APV (APV max %: –15±9, P<0.05), and CBF (CBF max %: –15±6, P<0.05).
Conclusions— In severely atherosclerotic coronary arteries, ;2-adrenergic vasodilatation is impaired, and this might contribute to alter the vasomotor balance, further precipitating myocardial ischemia during sympathetic activation.
Key Words: receptors, adrenergic, alpha ; receptors, adrenergic, beta ; atherosclerosis ; endothelium ; acetylcholine
Introduction
Adrenergic stimulation plays a key role in the regulation of coronary vasomotor tone, and it is modulated by atherosclerosis such that vasodilation is turned into vasoconstriction. Cold pressor test and mental stress, 2 common maneuvers causing adrenergic activation, induce vasodilation in normal coronary arteries and vasoconstriction in stenotic coronary arteries.1,2
It has been advocated that a combination of endothelial dysfunction and increased -adrenergic receptor responsiveness accounts for this phenomenon.3,4 Consistently, pretreatment with -adrenergic blockers is able to reverse this trend and prevent myocardial ischemia.5,6 We have recently demonstrated in humans that intravenous dobutamine, an 1-, ;1-, and ;2-adrenergic receptor agonist, vasodilates angiographically normal coronary arteries, whereas a lack of vasomotion to dobutamine was observed in stenotic coronary arteries. In these vessels, pretreatment with phentolamine restored dobutamine-induced vasomotion.7
;2-Adrenergic receptors (;2-ARs) are expressed into coronary vascular wall and are important mediators of the adrenergic tone.8–12 The present study aimed at assessing the role of ;2-ARs in normal coronary arteries and testing the hypothesis that the shift of the vasomotor balance toward constriction in atherosclerotic coronary arteries is a result of not only an enhanced -adrenergic tone but also an impairment of the ;2-AR responsiveness.
Methods
Patients and Catheterization Protocol
The study population consisted of 33 patients with stable angina (Canadian Cardiovascular Society class II or III) and normal left ventricular ejection fraction referred for coronary angiography because of a positive or nonconclusive stress test; among these, 11 patients had normal coronary arteries and 22 had single-vessel disease. Cardiac medications, except for aspirin and statins, were withheld in all patients for at least 36 hours before the protocol.
A 6F sheath was introduced into the femoral artery, and a 6F guiding catheter was engaged into the coronary ostium. Five thousand units of heparin was given to all patients. On average, the duration of the protocol was 30 minutes, and no untoward effects or complications occurred. Informed consent was obtained from all patients before the diagnostic catheterization, in accordance with the protocol approved by the local ethics committees.
Experimental Protocols
Figure 1 summarizes the study protocols. All patients underwent the following protocol: after a baseline period of 5 minutes, an intracoronary (IC) administration of the selective ;2-adrenergic receptor agonist salbutamol was performed at 0.15, 0.3, and 0.6 μg/min at a constant infusion rate of 1.25 mL/min for 3 minutes for each dose. These doses of salbutamol were shown not to significantly affect cardiac inotropism and chronotropism.13
Five minutes after salbutamol infusion, 5 patients with angiographically normal coronary arteries and 10 patients with single-vessel disease received an IC administration of the endothelial vasodilator acetylcholine at 1, 3, and 10 μg/min at a constant infusion rate of 1.25 mL/min for 3 minutes for each dose.14
In another group of 6 patients with single-vessel disease, an IC bolus of the -adrenergic blocker phentolamine (12 μg/kg) was given 5 minutes after salbutamol infusion, and 3 minutes later, the salbutamol protocol was repeated.15
In another group of 6 patients with angiographically normal coronary arteries, the salbutamol protocol was repeated after an IC infusion of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 60 μmol/min, for 6 minutes).16 All patients received an IC bolus of nitrates (300 μg) at the end of the protocols.
Data Acquisition
Data were recorded at every step of the protocols: at baseline, at the end of each dose of salbutamol, at the end of each dose of acetylcholine, at the end of L-NMMA infusion, and 3 minutes after phentolamine and nitrates (Figure 1).
Hemodynamic Data
Heart rate and blood pressure were digitally recorded (Marquette 1000 Ex, Mac-Laboratory System) during the entire study protocols.
Angiographic Data
Vessel dimensions and vessel dimension changes along the protocols were measured on angiograms, acquired according to the above steps, by quantitative coronary angiography, as previously described.7 In each patient, an average of 3.8 segments were selected in one projection on the baseline angiogram. As shown in Table 1, coronary artery segments were pooled and analyzed separately as follows: (1) normal segments (n=34) from patients with angiographically smooth coronary arteries; (2) mildly atherosclerotic segments (n=55) from the adjacent coronary artery in patients with single-vessel disease; and (3) stenotic segments (n=42) from the stenotic coronary artery in patients with single-vessel disease.
The contrast medium used was the non-ionic, hypo-osmolar, monomer ioversol (Optiray 350, Guerbet).
Coronary Blood Flow
A 0.014-in flexible Doppler angioplasty guidewire (FloWire, Volcano Therapeutics Inc) was advanced in 11 normal coronary arteries of 11 patients with angiographically normal vessels. In 10 patients with single-vessel disease, the Doppler wire was positioned in the adjacent mildly atherosclerotic coronary artery (ie, nonstenotic), whereas in another 11 patients with single-vessel disease, the wire was positioned in the stenotic coronary artery. In one case, coronary blood flow (CBF) measurements could not be performed because of poor quality of the Doppler signal. The Doppler guidewire was connected to the 15-MHz pulsed Doppler velocimeter (ComboMap, Volcano Therapeutics Inc). Doppler velocity spectra were analyzed to measure average peak velocity (APV). CBF (mL/min) was calculated according to the following formula: ( x MLD2)/(APV/8).
Statistical Analysis
Data are expressed as mean±SEM. Statistical comparison was made by ANOVA for repeated measurements to compare, within the patients, the effects of different doses of the drugs being tested. Post hoc analysis was performed with the Newman-Keuls test. Reproducibility among the measurements, calculated as previously described,17 is as follows: (1) lumen diameter (LD), 5±3%; (2) APV at baseline, 5±5%; (3) APV at hyperemia, 4±4%; CBF, 7±6%. Statistical analysis was performed with Graph Pad Prism version 2.0. Probability values of P>0.05 were considered statistically not significant.
Results
Clinical and Hemodynamic Data
Similarly, acetylcholine did not change heart rate (peak acetylcholine heart rate: 74±4 bpm, P=NS) or mean blood pressure (peak acetylcholine mean blood pressure: 105±5 mm Hg, P=NS), and the intracoronary infusion could be completed in 5 patients with normal coronary arteries and in 7 patients with single-vessel disease. Because of coronary spasm and angina with ST-segment depression, acetylcholine was stopped in 3 patients with single-vessel disease (at the first dose in 1 patient, at the second dose in 2 patients). Response at the maximal acetylcholine dose was considered for statistical comparison.
L-NMMA slightly increased mean blood pressure (peak mean blood pressure: 109±4 mm Hg, P=0.07 versus baseline), whereas no significant changes were observed in heart rate (peak heart rate: 78±4 bpm, P=NS).
Angiographic Data
As shown in Figure 2 (top), salbutamol IC infusion induced a significant dose-response increase in LD in normal segments (LD max %: 11±2, P<0.05 versus baseline). In mildly atherosclerotic segments, the increase in LD to salbutamol was comparable (LD max %: 10±2, P<0.05 versus baseline) to normal segments. In stenotic segments, a small constriction was observed only at 0.3 μg/min of salbutamol (LD max %: –6±2, P<0.05 versus baseline).
Acetylcholine IC infusion significantly increased LD in normal segments (LD max %: 14±3, P<0.05 versus baseline), whereas a significant reduction of LD was observed in mildly atherosclerotic (LD max %: –15±2, P<0.05 versus baseline) and stenotic segments (LD max %: –15±3, P<0.05 versus baseline) (Figure 3, top).
Phentolamine IC bolus did not change LD (LD %: 2±3, P=NS versus baseline). After phentolamine, salbutamol did not significantly change LD in mildly atherosclerotic segments (LD max %: 9±4, P<0.05 versus baseline; P=NS versus before phentolamine) or in stenotic segments (LD max %: 6±3, P=NS versus baseline) (Figure 4, top).
IC infusion of L-NMMA was associated with a small reduction in LD of normal segments (LD %: –5±3, P<0.05 versus baseline). After L-NMMA, the dose-dependent increase in LD induced by salbutamol was unchanged (LD max %: 9±2, P=NS versus baseline) (Figure 5, top).
IC nitrates significantly increased LD in normal segments (LD %: 39±6, P<0.05 versus baseline) and to a minor extent in mildly atherosclerotic (LD %: 26±3, P<0.05 versus baseline) and in stenotic segments (LD %: 13±2, P<0.05 versus baseline).
CBF Data
In normal coronary arteries, salbutamol significantly increased APV (APV max %: 53±17, P<0.05 versus baseline) and CBF (CBF max %: 57±17, P<0.05 versus baseline). In mildly atherosclerotic coronary arteries, the salbutamol-induced increases in APV (APV max %: 33±12, P<0.05 versus baseline) and CBF (CBF max %: 37±12, P<0.05 versus baseline), even though less pronounced, were not significantly different compared with normal coronary arteries. In stenotic arteries, salbutamol infusion was associated with a significant reduction in APV (APV max %: –15±9, P<0.05 versus baseline) and CBF (CBF max %: –15±6, P<0.05 versus baseline) (Figure 2, center and bottom).
Acetylcholine significantly increased APV (APV max %: 61±20, P<0.05 versus baseline) and CBF (CBF max %: 67±19, P<0.05 versus baseline) in normal coronary arteries. In mildly atherosclerotic coronary arteries, no significant changes in APV (APV max %: –6±13, P=NS) or in CBF (CBF max %: –10±13, P=NS) were observed after acetylcholine. In stenotic coronary arteries, acetylcholine reduced both APV (APV max %: –31±9, P<0.05 versus baseline) and CBF (CBF max %: –33±9, P<0.05 versus baseline) (Figure 3, center and bottom).
In stenotic coronary arteries, phentolamine IC did not significantly change APV (APV max %: –14±8, P=NS) or CBF (CBF max %: –16±9, P=NS). After phentolamine, salbutamol did not significantly change APV (APV max %: 19±10, P=NS versus baseline) or CBF (CBF max %: 21±11, P=NS versus baseline) (Figure 4, center and bottom).
In normal coronary arteries, IC infusion of L-NMMA reduced the APV (APV %: –15±4, P<0.05 versus baseline) and CBF (CBF %: –22±8, P<0.05 versus baseline). After L-NMMA, salbutamol-induced increases in APV (APV max %: 27±6, P<0.05 versus baseline) and CBF (CBF max %: 29±6, P<0.05 versus baseline) were blunted but remained significant (Figure 5, center and bottom).
IC nitrates significantly increased APV and CBF in normal (APV %: 26±5% and CBF %: 34±6%, P<0.05 versus baseline) and mildly atherosclerotic coronary arteries (APV %: 23±6 and CBF %: 29±6, P<0.05 versus baseline). In stenotic coronary arteries, nitrates did not change APV (APV %: 2±8, P=NS) or CBF (CBF %: 5±8, P=NS).
Discussion
The present study evaluated ;2-adrenergic receptor response at the macrocirculatory (lumen dimension changes) and at the microcirculatory level (APV and calculated CBF changes). In normal coronary arteries, a significant vasodilation to ;2-adrenergic receptor stimulation was observed at both levels that appears to be partially endothelium-mediated. In mildly atherosclerotic coronary arteries, this vasodilation is reduced but preserved. In stenotic coronary arteries, salbutamol IC infusion induced a paradoxical vasoconstriction that is no longer observed after phentolamine.
;-Adrenergic Receptors in Normal Coronary Arteries
The coronary vasomotor balance is such that ;1- and ;2-adrenergic receptors contribute to the vasodilatory drive, opposing the vasoconstrictive forces represented primarily by 1-adrenergic receptor hyperresponsiveness and endothelial dysfunction. Both ;1- and ;2-adrenergic receptors are expressed on coronary endothelial and vascular smooth muscle cells,8–10 even though ;-adrenergic receptors expressed on these latter cells have been reported to play a prevalent role.12,18 Furthermore, the distribution of ;-adrenergic receptors in the coronary circulation is heterogeneous, ;2-adrenergic receptors being more important for the regulation of the coronary resistance vessels.11,12,18,19 Consistently, our data in normal coronary arteries showed a significant increase in LD of the epicardial vessel and even more in APV, with a net increase in CBF of >50%. In these coronary arteries, acetylcholine induced a significant vasodilation, suggesting a preserved endothelial function. Inhibition of nitric oxide synthase with L-NMMA did not affect salbutamol vasodilation at the epicardial level, but the microcirculatory response was attenuated, suggesting that there is an endothelium-dependent component to ;2-adrenergic–mediated vasodilation in this compartment.
;-Adrenergic Receptors in Atherosclerotic Coronary Arteries
In atherosclerotic coronary arteries, adrenergic stimulation by cold pressor test and mental stress is known to induce paradoxical vasoconstriction.1,2 In addition, we have recently demonstrated that intravenous dobutamine, an 1-, ;1-, and ;2-adrenergic receptor agonist, is associated with blunted vasodilation in mildly atherosclerotic coronary arteries and lack of vasomotion in stenotic coronary arteries.7 The present data have been obtained with local (IC) infusion of doses of salbutamol that did not change heart rate or blood pressure.
In this setting, we found that in (1) mildly atherosclerotic coronary arteries, ;2-adrenergic receptor vasodilation is reduced but preserved, in accordance with previous data supporting a prevalent role of ;2-adrenergic receptors of vascular smooth muscle cells.12,20 In these coronary arteries, acetylcholine induced a paradoxical vasoconstriction, suggesting the presence of some degree of endothelial dysfunction already at this stage of atherosclerosis. Conversely, IC nitrates induced a significant vasodilation, corroborating the finding of a preserved function of the vascular tunica media. In (2) stenotic coronary arteries, salbutamol, unexpectedly, induced a reduction of both LD and APV, with a consequent decrease in CBF; yet during salbutamol IC infusion, 2 patients of 16 with stenotic coronary arteries had clinical symptoms of angina. This apparent paradox could be explained by a salbutamol -adrenergic–mediated effect. In fact, salbutamol may have stimulated presynaptic ;2-adrenergic receptors, with subsequent norepinephrine release.13,21 Consistently, after pretreatment with phentolamine, an 1-/2-adrenergic receptor blocker, vasoconstriction to salbutamol is no longer observed. Not surprisingly, acetylcholine induces a paradoxical vasoconstriction in these coronary arteries, demonstrating endothelial dysfunction. The IC bolus of nitrates induced a significant vasodilation of the stenotic epicardial vessel, demonstrating that vasodilatory response to direct smooth muscle cell stimulation is preserved.
Clinical Implications
Previous data from Kern et al22,23 have suggested that ;-blockers (intravenous propranolol) could potentiate coronary vasoconstriction in patients with coronary artery disease undergoing a cold pressor test because of an unopposed -adrenergic vasomotor tone. On the contrary, Gaglione et al24 showed a significant vasodilation of stenotic coronary arteries after intracoronary propranolol in patients undergoing supine bicycle stress testing. Finally, Bortone et al25 have shown that propranolol administered intravenously is able to significantly decrease coronary luminal area of both normal and stenotic coronary arteries at rest but conversely can induce coronary vasodilation during exercise. They concluded that the reduction in myocardial oxygen consumption and the prevention of exercise-induced stenosis vasoconstriction might explain the beneficial effect of ;-blocker treatment in most patients with coronary artery disease. Our data further extend these observations by supporting an impairment of coronary ;2-adrenergic receptors in stenotic coronary arteries. In this condition, a direct influence of ;-blockers on the coronary vasomotor tone is less effective, and most of the beneficial effect might be consequent to the reduced myocardial oxygen consumption.
Some early reports showed that a therapy with nebulized salbutamol in asthmatic patients could induce myocardial ischemia and unmask coronary artery disease.26,27 This finding was explained primarily by an increase in myocardial O2 consumption secondary to an increase in heart rate induced by salbutamol. Our data propose a novel mechanism potentially explaining salbutamol-provoked ischemia. In fact, at doses not able to increase heart rate or blood pressure, salbutamol induces a paradoxical vasoconstriction in stenotic coronary arteries, which in 2 patients led to clinical symptoms of angina.
Limitations
The paradoxical constriction of the microcirculation to salbutamol could alternatively be explained by a fall of the CBF downstream from the stenosis, secondary to the vasoconstriction of the epicardial vessel. Despite this limitation, the lack of a significant vasomotion to salbutamol after -blockade does still support the notion that ;2-adrenergic receptors are impaired at microcirculatory level.
The attenuation of salbutamol-induced vasodilation after L-NMMA could be a result of the inhibition of the endothelial ;2-adrenergic receptor component or, less specifically, of the inhibition of a flow-mediated component. Our data do not allow us to distinguish between these 2 components, even though Sun et al18 have reported, in isolated human coronary arterioles, a preserved vasodilation to norepinephrine after nitric oxide synthase inhibition and mechanical removal of the endothelium.
Conclusions
The present study confirms that in normal coronary arteries, there is an important role for ;2-adrenergic receptor–mediated coronary vasomotion that is partially mediated by the endothelium, especially at the microcirculatory level. In the presence of mild atherosclerosis, ;2-adrenergic receptor vasodilation is preserved. In stenotic coronary arteries, an impairment of ;2-adrenergic receptor response is associated with a paradoxical vasoconstriction to salbutamol that is -adrenergic–mediated. The present findings suggest that an impairment of coronary ;2-adrenergic receptor response also contributes to alter the vasomotor balance in the setting of coronary atherosclerosis, further precipitating myocardial ischemia during sympathetic activation.
References
Nabel EG, Ganz P, Gordon JB, Alexander RW, Selwyn AP. Dilation of normal and constriction of atherosclerotic coronary arteries caused by cold pressor test. Circulation. 1988; 77: 43–52.
Yeung AC, Vekshtein VI, Krantz DS, Vita JA, Ryan TJ Jr, Ganz P, Selwyn AP. The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress. N Engl J Med. 1991; 325: 1551–1556.
Jones CJ, DeFily DV, Patterson JL, Chilian WM. Endothelium-dependent relaxation competes with 1- and 2-adrenergic constriction in the canine epicardial coronary microcirculation. Circulation. 1993; 87: 1264–1274.
Vita JA, Treasure CB, Yeung AC, Vekshtein VI, Fantasia GM, Fish RD, Ganz P, Selwyn AP. Patients with evidence of coronary endothelial dysfunction as assessed by acetylcholine infusion demonstrate marked increase in sensitivity to constrictor effects of catecholamines. Circulation. 1992; 85: 1390–1397.
Kern MJ, Horowitz JD, Ganz P, Gaspar J, Colucci WS, Lorell BH, Barry WH, Mudge GH Jr. Attenuation of coronary vascular resistance by selective alpha1-adrenergic blockade in patients with coronary artery disease. J Am Coll Cardiol. 1985; 5: 840–846.
Julius BK, Vassalli G, Mandinov L, Hess OM. Alpha-adrenoceptor blockade prevents exercise-induced vasoconstriction of stenotic coronary arteries. J Am Coll Cardiol. 1999; 33: 1499–1505.
Barbato E, Bartunek J, Wyffels E, Wijns W, Heyndrickx GR, De Bruyne B. Effects of intravenous dobutamine on coronary vasomotion in humans. J Am Coll Cardiol. 2003; 42: 1596–1601.
Vatner SF, Hintze TH, Macho P. Regulation of large coronary arteries by beta-adrenergic mechanisms in the conscious dog. Circ Res. 1982; 51: 56–66.
Hodgson JM, Cohen MD, Szentpetery S, Thames MD. Effects of regional - and ;-blockade on resting and hyperemic coronary blood flow in conscious, unstressed humans. Circulation. 1989; 79: 797–809.
Ferro A, Kaumann AJ, Brown MJ. Beta-adrenoceptor subtypes in human coronary artery: desensitization of beta2-adrenergic vasorelaxation by chronic beta1-adrenergic stimulation in vitro. J Cardiovasc Pharmacol. 1995; 25: 134–141.
Parent R, al-Obaidi M, Lavallee M. Nitric oxide formation contributes to ;-adrenergic dilation of resistance coronary vessels in conscious dogs. Circ Res. 1993; 73: 241–251.
Ghaleh B, Bea ML, Dubois-Rande JL, Giudicelli JF, Hittinger L, Berdeaux A. Endothelial modulation of ;-adrenergic dilation of large coronary arteries in conscious dogs. Circulation. 1995; 92: 2627–2635.
Newton GE, Azevedo ER, Parker JD. Inotropic and sympathetic responses to the intracoronary infusion of a ;2-receptor agonist: a human in vivo study. Circulation. 1999; 99: 2402–2407.
Zeiher AM, Drexier H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans: effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest. 1993; 92: 652–662.
Gregorini L, Marco J, Kozakova M, Palombo C, Anguissola GB, Marco I, Bernies M, Cassagneau B, Distante A, Bossi IM, Fajadet J, Heusch G. -Adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation. 1999; 99: 482–490.
Quyyumi AA, Dakak N, Andrews NP, Gilligan DM, Panza JA, Cannon RO III. Contribution of nitric oxide to metabolic coronary vasodilation in the human heart. Circulation. 1995; 92: 320–326.
Barbato E, Aarnoudse W, Aengevaeren WR, Werner G, Klauss V, Bojara W, Herzfeld I, Oldroyd KG, Pijls NHJ, De Bruyne B. Validation of coronary flow reserve measurements by thermodilution in clinical practice. Eur Heart J. 2004; 25: 219–223.
Sun D, Huang A, Mital S, Kichuk MR, Marboe CC, Addonizio LJ, Michler RE, Koller A, Hintze TH, Kaley G. Norepinephrine elicits ;2-receptor–mediated dilation of isolated human coronary arterioles. Circulation. 2002; 106: 550–555.
Berdeaux A, Garnier M, Boissier JR, Giudicelli JF. The role of beta-adrenoceptors in coronary blood flow distribution in normal and ischemic canine myocardium. Eur J Pharmacol. 1979; 53: 261–271.
Corr L, Burnstock G, Poole-Wilson P. Responses of the rabbit epicardial coronary artery to acetylcholine and adrenoceptor agonists. Cardiovasc Res. 1991; 25: 256–262.
Boudreau G, Peronnet F, De Champlain J, Nadeau R. Presynaptic effects of epinephrine on norepinephrine release from cardiac sympathetic nerves in dogs. Am J Physiol. 1993; 265 (1 pt 2): H205–H211.
Kern MJ, Ganz P, Horowitz JD, Gaspar J, Barry WH, Lorell BH, Grossman W, Mudge GH Jr. Potentiation of coronary vasoconstriction by ;-adrenergic blockade in patients with coronary artery disease. Circulation. 1983; 67: 1178–1185.
Kern MJ, Petru MA, Ferry DR, Eilen SD, Barr WK, Porter CB, O’Rourke RA. Regional coronary vasoconstriction after combined beta-adrenergic and calcium channel blockade in patients with coronary artery disease. J Am Coll Cardiol. 1985; 5: 1438–1450.
Gaglione A, Hess OM, Corin WJ, Ritter M, Grimm J, Krayenbuehl HP. Is there coronary vasoconstriction after intracoronary beta-adrenergic blockade in patients with coronary artery disease; J Am Coll Cardiol. 1987; 10: 299–310.
Bortone AS, Hess OM, Gaglione A, Suter T, Nonogi H, Grimm J, Krayenbuehl HP. Effect of intravenous propranolol on coronary vasomotion at rest and during dynamic exercise in patients with coronary artery disease. Circulation. 1990; 81: 1225–1235.
Shovlin CL, Tam FW. Salbutamol nebuliser and precipitation of critical cardiac ischaemia. Lancet. 1990; 336: 1258.
Montgomery HE, Gill J, Pumphrey CW. Unsuspected coronary artery disease revealed by administration of nebulised salbutamol. Br Heart J. 1994; 72: 181.(Emanuele Barbato, MD; Fed)
Internal Medicine (G.I.), Federico II University of Naples, Italy
the Cardiovascular Center OLVZ, Aalst, Belgium (E.B., J.B., B.D.B., W.W.).
Abstract
Background— Adrenergic regulation of coronary vasomotion is balanced between 1-adrenergic–mediated (1-AR) constriction and ;2-adrenergic–mediated (;2-AR) relaxation. This study aimed at assessing the role of ;2-ARs in normal, mildly atherosclerotic, and stenotic human coronary arteries.
Methods and Results— During intracoronary (IC) infusion of increasing doses of the ;2-AR agonist salbutamol (0.15, 0.3, and 0.6 μg/min) and the endothelial vasodilator acetylcholine (1, 3, and 10 μg/min), we measured (1) changes in lumen diameter (LD) by quantitative coronary angiography in 34 normal, 55 mildly atherosclerotic, and 42 stenotic coronary artery segments and (2) changes in average peak velocity (APV) and coronary blood flow (CBF) with the use of Doppler flow wire in 11 normal, 10 mildly atherosclerotic, and 11 stenotic coronary arteries. In 6 of 11 stenotic coronary arteries, the protocol was repeated after an IC bolus (12 μg/kg) of the -adrenergic blocker phentolamine. In 6 of 11 normal coronary arteries, the protocol was repeated after an IC infusion (60 μmol/min) of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide inhibitor. Neither salbutamol IC infusion nor acetylcholine significantly changed heart rate or blood pressure, whereas L-NMMA slightly increased blood pressure. In normal coronary arteries, salbutamol increased LD (LD max %: 11±2, P<0.05), APV (APV max %: 53±17, P<0.05), and CBF (CBF max %: 57±17, P<0.05), whereas L-NMMA caused a blunted APV (APV max %: 27±6, P<0.05) and CBF (CBF max %: 29±6, P<0.05) response to salbutamol. In mildly atherosclerotic coronary arteries, the salbutamol increase in LD (LD max %: 10±2, P<0.05), APV (APV max %: 33±12, P<0.05), and CBF (CBF max %: 37±12, P<0.05) was preserved. In stenotic coronary arteries, salbutamol induced a paradoxical reduction in LD (LD max %: –6±2, P<0.05), APV (APV max %: –15±9, P<0.05), and CBF (CBF max %: –15±6, P<0.05), which was no longer observed after phentolamine. Acetylcholine increased LD (LD max %: 14±3, P<0.05), APV (APV max %: 61±20, P<0.05), and CBF (CBF max %: 67±19, P<0.05) in normal coronary arteries. In mildly atherosclerotic coronary arteries, acetylcholine induced a significant reduction in LD (LD max %: –15±2, P<0.05) and no changes in APV (APV max %: –6±13, P=NS) and CBF (CBF max %: –10±13, P=NS). In stenotic coronary arteries, acetylcholine significantly reduced LD (LD max %: –15±3, P<0.05), APV (APV max %: –15±9, P<0.05), and CBF (CBF max %: –15±6, P<0.05).
Conclusions— In severely atherosclerotic coronary arteries, ;2-adrenergic vasodilatation is impaired, and this might contribute to alter the vasomotor balance, further precipitating myocardial ischemia during sympathetic activation.
Key Words: receptors, adrenergic, alpha ; receptors, adrenergic, beta ; atherosclerosis ; endothelium ; acetylcholine
Introduction
Adrenergic stimulation plays a key role in the regulation of coronary vasomotor tone, and it is modulated by atherosclerosis such that vasodilation is turned into vasoconstriction. Cold pressor test and mental stress, 2 common maneuvers causing adrenergic activation, induce vasodilation in normal coronary arteries and vasoconstriction in stenotic coronary arteries.1,2
It has been advocated that a combination of endothelial dysfunction and increased -adrenergic receptor responsiveness accounts for this phenomenon.3,4 Consistently, pretreatment with -adrenergic blockers is able to reverse this trend and prevent myocardial ischemia.5,6 We have recently demonstrated in humans that intravenous dobutamine, an 1-, ;1-, and ;2-adrenergic receptor agonist, vasodilates angiographically normal coronary arteries, whereas a lack of vasomotion to dobutamine was observed in stenotic coronary arteries. In these vessels, pretreatment with phentolamine restored dobutamine-induced vasomotion.7
;2-Adrenergic receptors (;2-ARs) are expressed into coronary vascular wall and are important mediators of the adrenergic tone.8–12 The present study aimed at assessing the role of ;2-ARs in normal coronary arteries and testing the hypothesis that the shift of the vasomotor balance toward constriction in atherosclerotic coronary arteries is a result of not only an enhanced -adrenergic tone but also an impairment of the ;2-AR responsiveness.
Methods
Patients and Catheterization Protocol
The study population consisted of 33 patients with stable angina (Canadian Cardiovascular Society class II or III) and normal left ventricular ejection fraction referred for coronary angiography because of a positive or nonconclusive stress test; among these, 11 patients had normal coronary arteries and 22 had single-vessel disease. Cardiac medications, except for aspirin and statins, were withheld in all patients for at least 36 hours before the protocol.
A 6F sheath was introduced into the femoral artery, and a 6F guiding catheter was engaged into the coronary ostium. Five thousand units of heparin was given to all patients. On average, the duration of the protocol was 30 minutes, and no untoward effects or complications occurred. Informed consent was obtained from all patients before the diagnostic catheterization, in accordance with the protocol approved by the local ethics committees.
Experimental Protocols
Figure 1 summarizes the study protocols. All patients underwent the following protocol: after a baseline period of 5 minutes, an intracoronary (IC) administration of the selective ;2-adrenergic receptor agonist salbutamol was performed at 0.15, 0.3, and 0.6 μg/min at a constant infusion rate of 1.25 mL/min for 3 minutes for each dose. These doses of salbutamol were shown not to significantly affect cardiac inotropism and chronotropism.13
Five minutes after salbutamol infusion, 5 patients with angiographically normal coronary arteries and 10 patients with single-vessel disease received an IC administration of the endothelial vasodilator acetylcholine at 1, 3, and 10 μg/min at a constant infusion rate of 1.25 mL/min for 3 minutes for each dose.14
In another group of 6 patients with single-vessel disease, an IC bolus of the -adrenergic blocker phentolamine (12 μg/kg) was given 5 minutes after salbutamol infusion, and 3 minutes later, the salbutamol protocol was repeated.15
In another group of 6 patients with angiographically normal coronary arteries, the salbutamol protocol was repeated after an IC infusion of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 60 μmol/min, for 6 minutes).16 All patients received an IC bolus of nitrates (300 μg) at the end of the protocols.
Data Acquisition
Data were recorded at every step of the protocols: at baseline, at the end of each dose of salbutamol, at the end of each dose of acetylcholine, at the end of L-NMMA infusion, and 3 minutes after phentolamine and nitrates (Figure 1).
Hemodynamic Data
Heart rate and blood pressure were digitally recorded (Marquette 1000 Ex, Mac-Laboratory System) during the entire study protocols.
Angiographic Data
Vessel dimensions and vessel dimension changes along the protocols were measured on angiograms, acquired according to the above steps, by quantitative coronary angiography, as previously described.7 In each patient, an average of 3.8 segments were selected in one projection on the baseline angiogram. As shown in Table 1, coronary artery segments were pooled and analyzed separately as follows: (1) normal segments (n=34) from patients with angiographically smooth coronary arteries; (2) mildly atherosclerotic segments (n=55) from the adjacent coronary artery in patients with single-vessel disease; and (3) stenotic segments (n=42) from the stenotic coronary artery in patients with single-vessel disease.
The contrast medium used was the non-ionic, hypo-osmolar, monomer ioversol (Optiray 350, Guerbet).
Coronary Blood Flow
A 0.014-in flexible Doppler angioplasty guidewire (FloWire, Volcano Therapeutics Inc) was advanced in 11 normal coronary arteries of 11 patients with angiographically normal vessels. In 10 patients with single-vessel disease, the Doppler wire was positioned in the adjacent mildly atherosclerotic coronary artery (ie, nonstenotic), whereas in another 11 patients with single-vessel disease, the wire was positioned in the stenotic coronary artery. In one case, coronary blood flow (CBF) measurements could not be performed because of poor quality of the Doppler signal. The Doppler guidewire was connected to the 15-MHz pulsed Doppler velocimeter (ComboMap, Volcano Therapeutics Inc). Doppler velocity spectra were analyzed to measure average peak velocity (APV). CBF (mL/min) was calculated according to the following formula: ( x MLD2)/(APV/8).
Statistical Analysis
Data are expressed as mean±SEM. Statistical comparison was made by ANOVA for repeated measurements to compare, within the patients, the effects of different doses of the drugs being tested. Post hoc analysis was performed with the Newman-Keuls test. Reproducibility among the measurements, calculated as previously described,17 is as follows: (1) lumen diameter (LD), 5±3%; (2) APV at baseline, 5±5%; (3) APV at hyperemia, 4±4%; CBF, 7±6%. Statistical analysis was performed with Graph Pad Prism version 2.0. Probability values of P>0.05 were considered statistically not significant.
Results
Clinical and Hemodynamic Data
Similarly, acetylcholine did not change heart rate (peak acetylcholine heart rate: 74±4 bpm, P=NS) or mean blood pressure (peak acetylcholine mean blood pressure: 105±5 mm Hg, P=NS), and the intracoronary infusion could be completed in 5 patients with normal coronary arteries and in 7 patients with single-vessel disease. Because of coronary spasm and angina with ST-segment depression, acetylcholine was stopped in 3 patients with single-vessel disease (at the first dose in 1 patient, at the second dose in 2 patients). Response at the maximal acetylcholine dose was considered for statistical comparison.
L-NMMA slightly increased mean blood pressure (peak mean blood pressure: 109±4 mm Hg, P=0.07 versus baseline), whereas no significant changes were observed in heart rate (peak heart rate: 78±4 bpm, P=NS).
Angiographic Data
As shown in Figure 2 (top), salbutamol IC infusion induced a significant dose-response increase in LD in normal segments (LD max %: 11±2, P<0.05 versus baseline). In mildly atherosclerotic segments, the increase in LD to salbutamol was comparable (LD max %: 10±2, P<0.05 versus baseline) to normal segments. In stenotic segments, a small constriction was observed only at 0.3 μg/min of salbutamol (LD max %: –6±2, P<0.05 versus baseline).
Acetylcholine IC infusion significantly increased LD in normal segments (LD max %: 14±3, P<0.05 versus baseline), whereas a significant reduction of LD was observed in mildly atherosclerotic (LD max %: –15±2, P<0.05 versus baseline) and stenotic segments (LD max %: –15±3, P<0.05 versus baseline) (Figure 3, top).
Phentolamine IC bolus did not change LD (LD %: 2±3, P=NS versus baseline). After phentolamine, salbutamol did not significantly change LD in mildly atherosclerotic segments (LD max %: 9±4, P<0.05 versus baseline; P=NS versus before phentolamine) or in stenotic segments (LD max %: 6±3, P=NS versus baseline) (Figure 4, top).
IC infusion of L-NMMA was associated with a small reduction in LD of normal segments (LD %: –5±3, P<0.05 versus baseline). After L-NMMA, the dose-dependent increase in LD induced by salbutamol was unchanged (LD max %: 9±2, P=NS versus baseline) (Figure 5, top).
IC nitrates significantly increased LD in normal segments (LD %: 39±6, P<0.05 versus baseline) and to a minor extent in mildly atherosclerotic (LD %: 26±3, P<0.05 versus baseline) and in stenotic segments (LD %: 13±2, P<0.05 versus baseline).
CBF Data
In normal coronary arteries, salbutamol significantly increased APV (APV max %: 53±17, P<0.05 versus baseline) and CBF (CBF max %: 57±17, P<0.05 versus baseline). In mildly atherosclerotic coronary arteries, the salbutamol-induced increases in APV (APV max %: 33±12, P<0.05 versus baseline) and CBF (CBF max %: 37±12, P<0.05 versus baseline), even though less pronounced, were not significantly different compared with normal coronary arteries. In stenotic arteries, salbutamol infusion was associated with a significant reduction in APV (APV max %: –15±9, P<0.05 versus baseline) and CBF (CBF max %: –15±6, P<0.05 versus baseline) (Figure 2, center and bottom).
Acetylcholine significantly increased APV (APV max %: 61±20, P<0.05 versus baseline) and CBF (CBF max %: 67±19, P<0.05 versus baseline) in normal coronary arteries. In mildly atherosclerotic coronary arteries, no significant changes in APV (APV max %: –6±13, P=NS) or in CBF (CBF max %: –10±13, P=NS) were observed after acetylcholine. In stenotic coronary arteries, acetylcholine reduced both APV (APV max %: –31±9, P<0.05 versus baseline) and CBF (CBF max %: –33±9, P<0.05 versus baseline) (Figure 3, center and bottom).
In stenotic coronary arteries, phentolamine IC did not significantly change APV (APV max %: –14±8, P=NS) or CBF (CBF max %: –16±9, P=NS). After phentolamine, salbutamol did not significantly change APV (APV max %: 19±10, P=NS versus baseline) or CBF (CBF max %: 21±11, P=NS versus baseline) (Figure 4, center and bottom).
In normal coronary arteries, IC infusion of L-NMMA reduced the APV (APV %: –15±4, P<0.05 versus baseline) and CBF (CBF %: –22±8, P<0.05 versus baseline). After L-NMMA, salbutamol-induced increases in APV (APV max %: 27±6, P<0.05 versus baseline) and CBF (CBF max %: 29±6, P<0.05 versus baseline) were blunted but remained significant (Figure 5, center and bottom).
IC nitrates significantly increased APV and CBF in normal (APV %: 26±5% and CBF %: 34±6%, P<0.05 versus baseline) and mildly atherosclerotic coronary arteries (APV %: 23±6 and CBF %: 29±6, P<0.05 versus baseline). In stenotic coronary arteries, nitrates did not change APV (APV %: 2±8, P=NS) or CBF (CBF %: 5±8, P=NS).
Discussion
The present study evaluated ;2-adrenergic receptor response at the macrocirculatory (lumen dimension changes) and at the microcirculatory level (APV and calculated CBF changes). In normal coronary arteries, a significant vasodilation to ;2-adrenergic receptor stimulation was observed at both levels that appears to be partially endothelium-mediated. In mildly atherosclerotic coronary arteries, this vasodilation is reduced but preserved. In stenotic coronary arteries, salbutamol IC infusion induced a paradoxical vasoconstriction that is no longer observed after phentolamine.
;-Adrenergic Receptors in Normal Coronary Arteries
The coronary vasomotor balance is such that ;1- and ;2-adrenergic receptors contribute to the vasodilatory drive, opposing the vasoconstrictive forces represented primarily by 1-adrenergic receptor hyperresponsiveness and endothelial dysfunction. Both ;1- and ;2-adrenergic receptors are expressed on coronary endothelial and vascular smooth muscle cells,8–10 even though ;-adrenergic receptors expressed on these latter cells have been reported to play a prevalent role.12,18 Furthermore, the distribution of ;-adrenergic receptors in the coronary circulation is heterogeneous, ;2-adrenergic receptors being more important for the regulation of the coronary resistance vessels.11,12,18,19 Consistently, our data in normal coronary arteries showed a significant increase in LD of the epicardial vessel and even more in APV, with a net increase in CBF of >50%. In these coronary arteries, acetylcholine induced a significant vasodilation, suggesting a preserved endothelial function. Inhibition of nitric oxide synthase with L-NMMA did not affect salbutamol vasodilation at the epicardial level, but the microcirculatory response was attenuated, suggesting that there is an endothelium-dependent component to ;2-adrenergic–mediated vasodilation in this compartment.
;-Adrenergic Receptors in Atherosclerotic Coronary Arteries
In atherosclerotic coronary arteries, adrenergic stimulation by cold pressor test and mental stress is known to induce paradoxical vasoconstriction.1,2 In addition, we have recently demonstrated that intravenous dobutamine, an 1-, ;1-, and ;2-adrenergic receptor agonist, is associated with blunted vasodilation in mildly atherosclerotic coronary arteries and lack of vasomotion in stenotic coronary arteries.7 The present data have been obtained with local (IC) infusion of doses of salbutamol that did not change heart rate or blood pressure.
In this setting, we found that in (1) mildly atherosclerotic coronary arteries, ;2-adrenergic receptor vasodilation is reduced but preserved, in accordance with previous data supporting a prevalent role of ;2-adrenergic receptors of vascular smooth muscle cells.12,20 In these coronary arteries, acetylcholine induced a paradoxical vasoconstriction, suggesting the presence of some degree of endothelial dysfunction already at this stage of atherosclerosis. Conversely, IC nitrates induced a significant vasodilation, corroborating the finding of a preserved function of the vascular tunica media. In (2) stenotic coronary arteries, salbutamol, unexpectedly, induced a reduction of both LD and APV, with a consequent decrease in CBF; yet during salbutamol IC infusion, 2 patients of 16 with stenotic coronary arteries had clinical symptoms of angina. This apparent paradox could be explained by a salbutamol -adrenergic–mediated effect. In fact, salbutamol may have stimulated presynaptic ;2-adrenergic receptors, with subsequent norepinephrine release.13,21 Consistently, after pretreatment with phentolamine, an 1-/2-adrenergic receptor blocker, vasoconstriction to salbutamol is no longer observed. Not surprisingly, acetylcholine induces a paradoxical vasoconstriction in these coronary arteries, demonstrating endothelial dysfunction. The IC bolus of nitrates induced a significant vasodilation of the stenotic epicardial vessel, demonstrating that vasodilatory response to direct smooth muscle cell stimulation is preserved.
Clinical Implications
Previous data from Kern et al22,23 have suggested that ;-blockers (intravenous propranolol) could potentiate coronary vasoconstriction in patients with coronary artery disease undergoing a cold pressor test because of an unopposed -adrenergic vasomotor tone. On the contrary, Gaglione et al24 showed a significant vasodilation of stenotic coronary arteries after intracoronary propranolol in patients undergoing supine bicycle stress testing. Finally, Bortone et al25 have shown that propranolol administered intravenously is able to significantly decrease coronary luminal area of both normal and stenotic coronary arteries at rest but conversely can induce coronary vasodilation during exercise. They concluded that the reduction in myocardial oxygen consumption and the prevention of exercise-induced stenosis vasoconstriction might explain the beneficial effect of ;-blocker treatment in most patients with coronary artery disease. Our data further extend these observations by supporting an impairment of coronary ;2-adrenergic receptors in stenotic coronary arteries. In this condition, a direct influence of ;-blockers on the coronary vasomotor tone is less effective, and most of the beneficial effect might be consequent to the reduced myocardial oxygen consumption.
Some early reports showed that a therapy with nebulized salbutamol in asthmatic patients could induce myocardial ischemia and unmask coronary artery disease.26,27 This finding was explained primarily by an increase in myocardial O2 consumption secondary to an increase in heart rate induced by salbutamol. Our data propose a novel mechanism potentially explaining salbutamol-provoked ischemia. In fact, at doses not able to increase heart rate or blood pressure, salbutamol induces a paradoxical vasoconstriction in stenotic coronary arteries, which in 2 patients led to clinical symptoms of angina.
Limitations
The paradoxical constriction of the microcirculation to salbutamol could alternatively be explained by a fall of the CBF downstream from the stenosis, secondary to the vasoconstriction of the epicardial vessel. Despite this limitation, the lack of a significant vasomotion to salbutamol after -blockade does still support the notion that ;2-adrenergic receptors are impaired at microcirculatory level.
The attenuation of salbutamol-induced vasodilation after L-NMMA could be a result of the inhibition of the endothelial ;2-adrenergic receptor component or, less specifically, of the inhibition of a flow-mediated component. Our data do not allow us to distinguish between these 2 components, even though Sun et al18 have reported, in isolated human coronary arterioles, a preserved vasodilation to norepinephrine after nitric oxide synthase inhibition and mechanical removal of the endothelium.
Conclusions
The present study confirms that in normal coronary arteries, there is an important role for ;2-adrenergic receptor–mediated coronary vasomotion that is partially mediated by the endothelium, especially at the microcirculatory level. In the presence of mild atherosclerosis, ;2-adrenergic receptor vasodilation is preserved. In stenotic coronary arteries, an impairment of ;2-adrenergic receptor response is associated with a paradoxical vasoconstriction to salbutamol that is -adrenergic–mediated. The present findings suggest that an impairment of coronary ;2-adrenergic receptor response also contributes to alter the vasomotor balance in the setting of coronary atherosclerosis, further precipitating myocardial ischemia during sympathetic activation.
References
Nabel EG, Ganz P, Gordon JB, Alexander RW, Selwyn AP. Dilation of normal and constriction of atherosclerotic coronary arteries caused by cold pressor test. Circulation. 1988; 77: 43–52.
Yeung AC, Vekshtein VI, Krantz DS, Vita JA, Ryan TJ Jr, Ganz P, Selwyn AP. The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress. N Engl J Med. 1991; 325: 1551–1556.
Jones CJ, DeFily DV, Patterson JL, Chilian WM. Endothelium-dependent relaxation competes with 1- and 2-adrenergic constriction in the canine epicardial coronary microcirculation. Circulation. 1993; 87: 1264–1274.
Vita JA, Treasure CB, Yeung AC, Vekshtein VI, Fantasia GM, Fish RD, Ganz P, Selwyn AP. Patients with evidence of coronary endothelial dysfunction as assessed by acetylcholine infusion demonstrate marked increase in sensitivity to constrictor effects of catecholamines. Circulation. 1992; 85: 1390–1397.
Kern MJ, Horowitz JD, Ganz P, Gaspar J, Colucci WS, Lorell BH, Barry WH, Mudge GH Jr. Attenuation of coronary vascular resistance by selective alpha1-adrenergic blockade in patients with coronary artery disease. J Am Coll Cardiol. 1985; 5: 840–846.
Julius BK, Vassalli G, Mandinov L, Hess OM. Alpha-adrenoceptor blockade prevents exercise-induced vasoconstriction of stenotic coronary arteries. J Am Coll Cardiol. 1999; 33: 1499–1505.
Barbato E, Bartunek J, Wyffels E, Wijns W, Heyndrickx GR, De Bruyne B. Effects of intravenous dobutamine on coronary vasomotion in humans. J Am Coll Cardiol. 2003; 42: 1596–1601.
Vatner SF, Hintze TH, Macho P. Regulation of large coronary arteries by beta-adrenergic mechanisms in the conscious dog. Circ Res. 1982; 51: 56–66.
Hodgson JM, Cohen MD, Szentpetery S, Thames MD. Effects of regional - and ;-blockade on resting and hyperemic coronary blood flow in conscious, unstressed humans. Circulation. 1989; 79: 797–809.
Ferro A, Kaumann AJ, Brown MJ. Beta-adrenoceptor subtypes in human coronary artery: desensitization of beta2-adrenergic vasorelaxation by chronic beta1-adrenergic stimulation in vitro. J Cardiovasc Pharmacol. 1995; 25: 134–141.
Parent R, al-Obaidi M, Lavallee M. Nitric oxide formation contributes to ;-adrenergic dilation of resistance coronary vessels in conscious dogs. Circ Res. 1993; 73: 241–251.
Ghaleh B, Bea ML, Dubois-Rande JL, Giudicelli JF, Hittinger L, Berdeaux A. Endothelial modulation of ;-adrenergic dilation of large coronary arteries in conscious dogs. Circulation. 1995; 92: 2627–2635.
Newton GE, Azevedo ER, Parker JD. Inotropic and sympathetic responses to the intracoronary infusion of a ;2-receptor agonist: a human in vivo study. Circulation. 1999; 99: 2402–2407.
Zeiher AM, Drexier H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans: effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest. 1993; 92: 652–662.
Gregorini L, Marco J, Kozakova M, Palombo C, Anguissola GB, Marco I, Bernies M, Cassagneau B, Distante A, Bossi IM, Fajadet J, Heusch G. -Adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation. 1999; 99: 482–490.
Quyyumi AA, Dakak N, Andrews NP, Gilligan DM, Panza JA, Cannon RO III. Contribution of nitric oxide to metabolic coronary vasodilation in the human heart. Circulation. 1995; 92: 320–326.
Barbato E, Aarnoudse W, Aengevaeren WR, Werner G, Klauss V, Bojara W, Herzfeld I, Oldroyd KG, Pijls NHJ, De Bruyne B. Validation of coronary flow reserve measurements by thermodilution in clinical practice. Eur Heart J. 2004; 25: 219–223.
Sun D, Huang A, Mital S, Kichuk MR, Marboe CC, Addonizio LJ, Michler RE, Koller A, Hintze TH, Kaley G. Norepinephrine elicits ;2-receptor–mediated dilation of isolated human coronary arterioles. Circulation. 2002; 106: 550–555.
Berdeaux A, Garnier M, Boissier JR, Giudicelli JF. The role of beta-adrenoceptors in coronary blood flow distribution in normal and ischemic canine myocardium. Eur J Pharmacol. 1979; 53: 261–271.
Corr L, Burnstock G, Poole-Wilson P. Responses of the rabbit epicardial coronary artery to acetylcholine and adrenoceptor agonists. Cardiovasc Res. 1991; 25: 256–262.
Boudreau G, Peronnet F, De Champlain J, Nadeau R. Presynaptic effects of epinephrine on norepinephrine release from cardiac sympathetic nerves in dogs. Am J Physiol. 1993; 265 (1 pt 2): H205–H211.
Kern MJ, Ganz P, Horowitz JD, Gaspar J, Barry WH, Lorell BH, Grossman W, Mudge GH Jr. Potentiation of coronary vasoconstriction by ;-adrenergic blockade in patients with coronary artery disease. Circulation. 1983; 67: 1178–1185.
Kern MJ, Petru MA, Ferry DR, Eilen SD, Barr WK, Porter CB, O’Rourke RA. Regional coronary vasoconstriction after combined beta-adrenergic and calcium channel blockade in patients with coronary artery disease. J Am Coll Cardiol. 1985; 5: 1438–1450.
Gaglione A, Hess OM, Corin WJ, Ritter M, Grimm J, Krayenbuehl HP. Is there coronary vasoconstriction after intracoronary beta-adrenergic blockade in patients with coronary artery disease; J Am Coll Cardiol. 1987; 10: 299–310.
Bortone AS, Hess OM, Gaglione A, Suter T, Nonogi H, Grimm J, Krayenbuehl HP. Effect of intravenous propranolol on coronary vasomotion at rest and during dynamic exercise in patients with coronary artery disease. Circulation. 1990; 81: 1225–1235.
Shovlin CL, Tam FW. Salbutamol nebuliser and precipitation of critical cardiac ischaemia. Lancet. 1990; 336: 1258.
Montgomery HE, Gill J, Pumphrey CW. Unsuspected coronary artery disease revealed by administration of nebulised salbutamol. Br Heart J. 1994; 72: 181.(Emanuele Barbato, MD; Fed)