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Journal of the American College of Cardiology Vol. 33, No. 6, 1999 © 1999 by the American College of Cardiology ISSN 0735-1097/99/$20.00 Published by Elsevier Science Inc. PII S0735-1097(99)00053-4 Endothelial Function Alpha-Adrenoceptor Blockade Prevents Exercise-Induced of Stenotic Coronary Arteries Barbara K. Julius, MD,* Giuseppe Vassalli, MD,* Lazar Mandinov, MD,† Otto M. Hess, MD† Zurich and Bern, Switzerland

OBJECTIVES The study aimed to evaluate the role of alpha- mechanisms during dynamic exercise in both normal and stenotic coronary arteries. BACKGROUND Paradoxical vasoconstriction of stenotic coronary arteries has been reported during dynamic exercise and may be due to several factors such as alpha-adrenergic drive, a decreased release of , platelet aggregation with release of serotonin, or a passive collapse of the vessel wall. METHODS Twenty-six patients were studied at rest, during two levels of supine bicycle exercise and after 1.6 mg sublingual nitroglycerin. The alpha-blocker was given to 16 patients before exercise, five of whom had also taken a beta-adrenergic-blocker the same morning. Ten patients served as controls. The cross-sectional areas of a normal and a stenotic coronary vessel were determined by biplane quantitative coronary arteriography. RESULTS In the normal vessel segments, coronary cross-sectional area did not change after phentol- amine injection, but increased in all patient groups similarly during exercise. Although coronary vasoconstriction existed in stenotic vessel segments in control patients, phentolamine-treated patients showed exercise-induced without difference in patients with and without chronic beta-blockade. CONCLUSIONS Exercise-induced vasoconstriction of stenotic coronary arteries is prevented by intracoronary administration of phentolamine. There was no difference in coronary vasomotion between patients receiving phentolamine alone and patients receiving phentolamine in addition to a beta-blocker. This finding suggests that exercise-induced vasoconstriction is mediated not only by endothelial dysfunction but also by alpha-adrenergic mechanisms. (J Am Coll Cardiol 1999;33:1499–505) © 1999 by the American College of Cardiology

Coronary vasomotor tone plays an important role in the The exact mechanism that is responsible for the reported pathophysiology of angina pectoris. An increase in vasomo- stenosis vasoconstriction is not clear but may involve several tor tone of stenotic arteries may result in a decrease in factors such as an enhanced sympathetic stimulation during coronary blood flow and, thus, may precipitate myocardial exercise, endothelial dysfunction with reduced nitric oxide ischemia. A reduction in exercise-induced angina pectoris (NO) release or production, increased platelet aggregation and an increase in physical working capacity have been with release of serotonin and thromboxane A2, or a passive reported in patients with stable angina pectoris after intra- collapse of the stenotic vessel segment within the stenosis due coronary administration of phentolamine (1,2) or in- to the increase in flow velocity during exercise (Venturi effect).

doramine, a selective alpha1-adrenoceptor antagonist (3). Because changes in coronary vasomotor tone underlie Stenotic coronary arteries have shown paradoxical vasocon- neurogenic mechanisms, particular interest has focused on striction during isometric (4) but also dynamic exercise (5). the link between myocardial ischemia and alpha-adrenergic This exercise-induced narrowing of the stenotic arteries has tone during exercise. Thus, the purpose of the present study been prevented by intracoronary administration of nitro- was to assess the influence of alpha-adrenergic mechanisms glycerin (4) or diltiazem in doses that did not induce on coronary vasomotion in normal and stenotic coronary systemic vascular effects (6). arteries during dynamic exercise.

METHODS From the Department of Internal Medicine, Cardiology, *University Hospital, Study population. Twenty-six patients (mean age 54 Ϯ 8 Zurich, and †Inselspital, Bern, Switzerland. Manuscript received May 19, 1998; revised manuscript received October 29, 1998, years) with coronary artery disease and stable angina pecto- accepted January 20, 1999. ris were included in the present analysis. Biplane coronary 1500 Julius et al. JACC Vol. 33, No. 6, 1999 Alpha-adrenergic Coronary Vasoconstriction May 1999:1499–505

exercise. Biplane left coronary angiography was performed Abbreviations and Acronyms at the end of the diagnostic coronary angiography. For the ANOVAϭ analysis of variance purpose of the present study protocol, the left coronary C ϭ controls artery was selected to have a normal and a stenotic vessel ϭ CSA cross-sectional area segment for quantitative analysis. The study was, NS ϭ not significant P ϭ patients receiving intracoronary phentolamine therefore, infused over the guiding catheter into the left ϭ P(␣) patients receiving only phentolamine coronary artery. Eight milliliters of a nonionic contrast ϭ R P(␣ ϩ ␤) patients on chronic beta-blockade receiving material (Jopamiro 370 ) was injected into the left coronary phentolamine artery at a flow rate of 4 ml/s using an electrogram-triggered ϭ SD standard deviation power-injector. First, biplane coronary angiography was carried out at rest with the patients’ legs elevated and attached to the bicycle ergometer. Angiography was performed on a Bicor Siemens angiography was performed at rest, during supine bicycle system (Siemens Albis AG, Zurich) using cinefilm at a rate exercise and after sublingual nitroglycerin. Patients who of 25 frames/s. Further biplane coronary angiograms were fulfilled the following baseline criteria were included in the performed after administration of 2 mg intracoronary phen- study: 1) a history of stable, effort-related angina pectoris tolamine (Infusion time: 5 min; 0.4 mg/min). Two levels of and 2) coronary artery stenosis clearly visible on angiography supine bicycle exercise were performed for 2 min in each for quantitative evaluation. The first 10 of the studied patient. Biplane coronary angiography was repeated imme- patients did not receive any premedication prior to exercise diately after each exercise level while the patient was asked and they served as controls (C). The remaining 16 patients to hold his breath. Finally, coronary angiography was obtained before exercise 2 mg intracoronary phentolamine, carried out 5 min following administration of 1.6 mg a nonselective alpha-blocker (P). Although 11 patients of sublingual nitroglycerin. Aortic and pulmonary artery pres- this group did not have any vasoactive substances for at least sures were recorded continuously during exercise and were 24 h before the study (P␣), five patients who were on measured for subsequent analysis immediately before each chronic cardioselective beta-blockade ( or ateno- angiogram. No adverse event occurred during the study, and lol) had been instructed to take this also on the there were no complications with regard to this study morning of the study (P␣ ϩ ␤). protocol. Functional classification according to the New York Heart Association was 1.9 Ϯ 0.6 in controls and 1.8 Ϯ 0.9 Quantitative coronary angiography. Quantitative angio- in the phentolamine-treated patients (not significant [NS]). graphy was carried out with a semiautomatic computer In the phentolamine-treated group, 4/11 patients had one- system (7–9). The system is based on a 35-mm film vessel disease, 4/11 patients had two-vessel disease, and projector (Tagarno 35 CX, Horsens, Denmark), a slow scan 3/11 patients had three-vessel disease. Two patients who CCD-camera for image digitation and a computer work- were pretreated with a beta-adrenergic-blocker and then station (Apollo DN 3000, Wangen, Switzerland) for image received phentolamine during the study protocol were storing and processing. Contour detection was carried out suffering from one-vessel disease, one had a two-vessel with the use of a geometric-densitometric edge detection disease and two had a three-vessel disease. Of the control algorithm (8,10,11). The method for quantitative evaluation patients one-vessel disease was present in 4/10 patients, of coronary angiography has been described in detail else- two-vessel disease was found in 3/10 patients, and three- where (5,7,10,11). vessel disease was present in 3/10 patients. Maximal stenosis Both a normal and a stenotic vessel segment were chosen severity for patients with phentolamine was Ͻ70% in three, for quantitative analysis. In each patient at least one stenotic 70% to 90% in four and Ͼ90% in three cases. For patients vessel was selected for analysis on the basis of clear visual- with alpha- and beta-blockade stenosis, severity amounted ization without overlapping vessels. The normal vessel to 70% to 90% in 4 patients and Ͻ70% in 1 patient. One segment was selected from a disease-free vessel when control patient had a Ͻ70% stenosis, seven had 70% to 90% possible, otherwise an uninvolved prestenotic vessel segment stenoses, and 2 had Ͼ90% stenoses. Left ventricular ejection was chosen at least four catheter-widths from the center of fraction averaged 61 Ϯ 8% in controls and 64 Ϯ 6% in the stenosis, which was not used for quantiative evaluation phentolamine-treated patients (NS). (Fig. 1). Cardiac catheterization. The study protocol was approved Statistical analysis. Statistical comparisons of hemody- by the local ethics committee, and written informed consent namic and angiographic data among as well as between the was obtained from all patients. Vasoactive substances were patients were carried out by a two-way analysis of variance withheld for at least 24 h before catheterization except in (ANOVA) for repeated measurements. If this test was the five patients who received chronically a cardioselective significant, the Scheffe´procedure was applied to determine beta-blocker. The catheter was inserted through the right the intra- and intergroup statistical differences. A p-value of femoral artery and was kept in place during supine bicycle less than 0.05 was considered to indicate statistical signifi- JACC Vol. 33, No. 6, 1999 Julius et al. 1501 May 1999:1499–505 Alpha-adrenergic Coronary Vasoconstriction

Figure 1. Quantitative coronary angiography of the left anterior descending coronary artery in a patient with moderate lesion in Aldrigde projection. Automatic evaluation of the stenotic segment was performed by computer analysis. The proximal and distal Figure 2. Rate-pressure product (RPP) and mean pulmonary reference segments are marked with two lines. The minimal artery pressure (mPAP) at rest (R), after intracoronary adminis- luminal diameter was 2.6 mm at Rest, 2.7 mm after intracoronary tration of phentolamine (Drug), during two levels of supine bicycle phentolamine (Reg), 2.6 mm during the first (Ex 1) and 2.6 mm exercise (Ex1; Ex2), and after sublingual nitroglycerin administra- during the second (Ex 2) exercise level, and amounted to 3.0 mm tion (NTG). Note the significant rise of both parameters during after sublingual nitroglycerin (NTG). exercise. However, patients on chronic beta-blockade reached a lower rate-pressure product than did the two other groups. Open circles ϭ alpha-blockers; solid circles ϭ alpha- plus beta- ϭ ϭ cance. Data in all tables and figures are reported as mean Ϯ blockers; solid triangles control group. NTG nitroglycerin. *p Ͻ 0.05 versus alpha- plus beta-blockers. 1 standard deviation (SD).

RESULTS Coronary cross-sectional area (CSA). Percent changes in Clinical findings. Patients in the two groups did not differ coronary CSA of the normal and stenotic vessels are with respect to age, gender and functional classification illustrated in Figure 3. The size of the normal vessel according to the New York Heart Association or baseline remained unchanged after administration of intracoronary hemodynamic values. Left ventricular ejection fraction was phentolamine (105 Ϯ 7.8%), but increased during exercise Ϯ Ϯ slightly lower in patients on chronic beta-blockade (P(␣ ϩ ␤)) (C: 113 11%; P: 117 18%; NS) as well as after when compared with those without beta-blockers. Baseline administration of sublingual nitroglycerin (C: 123 Ϯ 15%; hemodynamic data are summarized in Table 1. Physical P: 132 Ϯ 21%; NS). There was no difference in patients working capacity was similar in the two groups (C: 109 Ϯ with or without chronic beta-blockade after phentolamine Ϯ Ϯ Ϯ 25 W, P: 100 21 W; NS). Angina pectoris during supine administration (P(␣): 104 11%, P(␣ ϩ ␤): 107 10%; NS). Ϯ bicycle exercise was present in four out of ten patients (40%) During exercise, CSA increased in both groups (P(␣): 117 Ϯ in C and 5 out of 16 patients in P (31%). Heart rate did not 11% and P(␣ ϩ ␤): 118 28%; NS) and the CSA was Ϯ change after intracoronary phentolamine injection and in- maximally dilated after sublingual nitroglycerin (P(␣): 136 Ϯ creased to a similar extent in the two groups during exercise. 20% and P(␣ ϩ ␤): 125 22%; NS). Patients on chronic beta-blockade had a significantly lower Coronary CSA of the stenotic vessel remained unchanged Ϯ Ϯ rate-pressure product than did controls or P(␣) (14.3 2.7 after intracoronary administration of phentolamine (104 vs. 20.8 Ϯ 3.8 and 18.7 Ϯ 3.8 mm Hg/min⅐103, respec- 8%). While phentolamine-treated patients showed exercise- tively; p Ͻ 0.05) (Fig. 2). Mean aortic and mean pulmonary induced vasodilation (113 Ϯ 8%), there was coronary artery pressures remained unchanged after intracoronary vasoconstriction during exercise in controls (85 Ϯ 23%; p Ͻ phentolamine administration but increased similarly in all 0.001). Vasodilation of the stenotic vessel segment was groups during exercise (Table 2). similar after sublingual nitroglycerin in both groups (C:

Table 1. Hemodynamic Data LVEDP MAP MPAP CI EF (mm Hg) (mm Hg) (mm Hg) (l/min/m2) (%) Controls 14 Ϯ 6 101 Ϯ 11 19 Ϯ 6 2.8 Ϯ 1.0 61 Ϯ 8 ␣-Blocker 10 Ϯ 3 102 Ϯ 16 18 Ϯ 6 2.8 Ϯ 0.6 66 Ϯ 4 ␣ ϩ ␤-Blocker 11 Ϯ 292Ϯ 914Ϯ 5 2.9 Ϯ 1.0 58 Ϯ 6 C vs. ␣ NS NS NS NS NS C vs. ␣ ϩ ␤ NS NS NS NS NS ␣ vs. ␣ ϩ ␤ NS NS NS NS p Ͻ 0.05 LVEDP, left ventricular end-diastolic pressure; MAP, mean aortic pressure; MPAP, mean pulmonary artery pressure; CI, cardiac index; EDV, end-diastolic volume; ␣, patients receiving phentolamine; ␣ ϩ ␤, patients on chronic beta-blockade receiving phentolamine before supine bicycle exercise testing; C, controls. 1502 Julius et al. JACC Vol. 33, No. 6, 1999 Alpha-adrenergic Coronary Vasoconstriction May 1999:1499–505

Table 2. Exercise Data HR MAP MPAP RPP (beats/min) (mm Hg) (mm Hg) (103 mm Hg/min) Ex (Watt) BExBExBExBEx Controls 109 Ϯ 25 66 Ϯ 15 112 Ϯ 29 101 Ϯ 10 116 Ϯ 23 19 Ϯ 640Ϯ 10 9.9 Ϯ 2 20.8 Ϯ 3.8 ␣-Blocker 95 Ϯ 21 67 Ϯ 13 111 Ϯ 15 102 Ϯ 16 120 Ϯ 13 18 Ϯ 635Ϯ 13 9.8 Ϯ 3 18.7 Ϯ 2.5 ␣ ϩ ␤-Blocker 112 Ϯ 18 59 Ϯ 12 102 Ϯ 10 92 Ϯ 9 108 Ϯ 13 14 Ϯ 435Ϯ 3 7.0 Ϯ 2 14.3 Ϯ 2.7 C vs. ␣ NS NS NS NS NS NS NS NS NS C vs. ␣ ϩ ␤ NS NS NS NS NS NS NS NS NS ␣ vs. ␣ ϩ ␤ NS NS NS NS NS NS NS p Ͻ 0.05 p Ͻ 0.05 Ex ϭ exercise; B ϭ baseline; HR ϭ heart rate; MAP ϭ mean aortic pressure; MPAP ϭ mean pulmonary artery pressure; RPP ϭ rate pressure product; ␣ ϭ patients receiving phentolamine; ␣ ϩ ␤ ϭ patients on chronic beta-blockade receiving phentolamine before supine bicycle exercise testing; C ϭ controls.

116 Ϯ 19%; P: 119 Ϯ 14%; NS), but was less in the stenotic release (12,13); a stimulation of cardio- than in the normal vessel segment (p Ͻ 0.05). There was no myocytes with a positive inotropic effect and prolongation difference in the behavior of the stenotic vessel segments in of contraction by increasing intracellular calcium- patients with and those without chronic beta-blockade after concentration (14,15); increased platelet aggregation (16) Ϯ phentolamine administration (P(␣): 102 7%, P(␣ ϩ ␤): and an enhanced release of endothelium-derived growth Ϯ Ϯ 109 5%) as well as during exercise (P(␣): 112 8% and factors (17). Data on the contribution of vascular alpha1- Ϯ P(␣ ϩ ␤): 113 10%) and after nitroglycerin administration and alpha2-adrenoceptors to the constriction of the large Ϯ Ϯ (P(␣): 119 15% and P(␣ ϩ ␤): 119 10%) (all NS). For epicardial conductance and small resistance vessels as well as absolute values, see Table 3. The main findings are also collateral vessels are controversial (18). illustrated in Figure 3. Alpha-adrenergic vasomotion in normal coronary arter- DISCUSSION ies. Alpha- dependent vasomotion of the normal coronary arteries is of minor physiologic importance, be- Alpha-adrenoceptor activation causes a number of different cause resistance of the epicardial coronary arteries contrib- reactions in the intact heart including the activation of utes only 5% to total coronary resistance (19). In the sympathetic nerve endings with feedback inhibition of presence of beta-adrenergic blockade, the increase in epi-

Figure 3. Responses of normal and stenotic coronary arteries to dynamic exercise after intracoronary phentolamine administration in patients without (␣; upper panel) and with chronic beta-blockade (␣ ϩ ␤; lower panel). For comparison purposes, data are shown also for controls (C). Coronary cross-sectional area (CSA) is expressed in percent of resting luminal area. Normal vessel size remained unchanged after phentolamine administration and increased during exercise both before and after administration of phentolamine or nitroglycerin. The CSA of the stenotic vessel segments also remained unchanged after phentolamine administration. However, in phentolamine-treated patients with or without chronic beta-blockade, paradoxical stenosis vasoconstriction was prevented during exercise. Coronary vasoconstriction was reversible after nitroglycerin administration. JACC Vol. 33, No. 6, 1999 Julius et al. 1503 May 1999:1499–505 Alpha-adrenergic Coronary Vasoconstriction

Table 3. Coronary Cross-Sectional Area: Absolute Values which may be involved in the narrowing of stenotic coronary Rest Phentolamine Exercise NTG arteries (4,5). This narrowing of the epicardial coronary (mm2) (mm2) (mm2) (mm2) segments can be prevented by administration of intracoro- nary nitroglycerin or the calcium-antagonist diltiazem, Stenosis Controls 1.9 Ϯ 1.0 1.7 Ϯ 1.4 2.2 Ϯ 1.2 probably owing to the direct vasodilating properties of these ␣-Blocker 3.4 Ϯ 3.3 3.5 Ϯ 3.5 3.7 Ϯ 3.3 4.0 Ϯ 4.4 two agents. ␣ ϩ ␤-Blocker 4.0 Ϯ 2.8 4.3 Ϯ 2.9 4.4 Ϯ 2.9 4.6 Ϯ 2.8 The precise mechanism responsible for exercise-induced vasoconstriction of stenotic vessel segments is not clear. Normal segment Besides an activation of the alpha-adrenergic sympathetic Controls 6.1 Ϯ 3.8 6.8 Ϯ 4.6 7.3 Ϯ 4.5 nervous system, endothelial dysfunction with a decreased ␣-Blocker 3.4 Ϯ 0.9 3.6 Ϯ 1.1 4.0 Ϯ 1.3 4.7 Ϯ 1.5 production and/or release of nitric oxide, increased platelet ␣ ϩ ␤ Ϯ Ϯ Ϯ Ϯ -Blocker 8.0 4.3 8.6 4.7 9.3 3.4 10 3.9 activation with release of serotonin and thromboxane A2, ␣-Blocker indicates patients receiving phentolamine and ␣ ϩ ␤-Blocker patients on and a passive collapse of the normal vessel wall within the chronic beta-blockade receiving phentolamine before supine bicycle exercise testing. stenotic lesion (Venturi phenomenon) have been considered as potential mechanisms. In the present study, nonselective alpha-adrenoceptor blockade with intracoronary phentol- cardial coronary resistance during sympathetic nerve stim- amine was able to prevent vasoconstriction of the stenotic ulation is even less pronounced than that of total coronary arteries during exercise. These findings suggest that alpha- resistance (19,20). Conversely, the decrease in epicardial adrenergic activation plays an important role in exercise- coronary diameter during cardiac sympathetic nerve stimu- induced vasoconstriction of stenotic coronary segments lation is minimal in the presence of chronic beta-blockade although it may not explain all mechanisms such as why the (21). Alpha -, as well as alpha -adrenoceptors, however, 1 2 stenotic vessel becomes reactive to circulating cat- appear to be involved in norepinephrine-induced vasocon- echolamines but not the normal vessel. Preexisting endo- striction of human epicardial coronary arteries (22). Never- thelial dysfunction may render the stenotic vessel sensitive theless, previous experimental and clinical data are conflict- to circulating ; in other words, the function- ing, and there is ongoing discussion on the influence of ing endothelium releases NO, which overruns the vasocon- alpha-adrenergic stimulation on coronary vasomotor tone. strictor effects of the alpha-adrenergic system. Blockade of Orlick and co-workers (23) postulated the presence of these vasoconstrictor effects prevents, therefore, exercise- alpha-adrenergic constrictor tone, because normally inner- induced vasoconstriction. vated patients had a higher resting coronary resistance and Previous data showed a decrease in exercise-induced a higher coronary arterio-venous oxygen difference than did ST-segment and a reduction in angina pectoris cardiac transplant recipients. This difference was, however, after intracoronary phentolamine administration (1). An abolished by a nonselective alpha-blockade with phentol- increase in exercise capacity after oral administration of amine (23). No evidence for an influence of alpha- phentolamine (2) and indoramine (3), a selective alpha - adrenoceptors on a resting coronary tone has been found by 1 adrenoceptor blocker has been reported in patients with others in similar patient populations (24,25). Our data stable angina pectoris. Phentolamine was also able to prevent confirm the relatively minor contributions of alpha- coronary vasoconstriction during cold pressor testing (27) and adrenergic influences on coronary vasomotion of normal during isometric exercise (4), which are associated with stim- coronary arteries, as alpha-adrenergic blockade did not ulation of the sympathetic nervous system (28). significantly affect epicardial coronary artery dimensions and In the absence of beta-blockade, alpha-blockade may had no influence on coronary vasomotor tone at rest as well result in a decrease in coronary vascular resistance during as during exercise in patients with or without alpha- exercise due to presynaptic disinhibition of neuronal epi- blockade. nephrine release, which results in an increase in oxygen Alpha-adrenergic vasomotion in stenotic coronary arter- requirements. This may lead to metabolic vasodilation in ies. Compared with the normal coronary arteries, signifi- addition to the attenuation of alpha-adrenergic coronary cant alpha-adrenergic constriction of the stenotic coronary vasoconstriction. In the present study, chronic beta- arteries can be induced by cardiac sympathetic nerve stim- blockade was present in 5 of 16 phentolamine-treated ulation, resulting in the precipitation of myocardial ischemia patients. Because coronary vasomotion in patients with and with regional wall-motion abnormalities and net lactate without beta-blockade did not differ among each other, the production (26). In an experimental model, post-stenotic direct effect on arterial adrenoceptors appears to be more coronary vasoconstriction that was prevented by intravenous important than metabolic vasodilation. phentolamine or selective alpha2-blockade with Although the various effects of alpha-adrenergic blockade in the absence as well as in the presence of acute beta- on post-stenotic coronary vasomotion have been previously blockade was observed (26). evaluated in dogs (26,29–31), the present study documents Under clinical conditions, sympathetic nerve activation for the first time a direct effect of alpha-adrenergic blockade may be induced by isometric as well as dynamic exercise, on coronary stenosis vasomotion during exercise in humans. 1504 Julius et al. JACC Vol. 33, No. 6, 1999 Alpha-adrenergic Coronary Vasoconstriction May 1999:1499–505

The effects of alpha-adrenergic blockade were, however, used. This issue was addressed in canine experiments as well small in the normal vessel segment (Fig. 3) but large in the as in humans, but the results are controversial. Gwirtz and stenotic segment. This may be explained by the fact that the colleagues (29) reported that post-stenotic vasoconstriction adrenergic vascular effects become much more prominent during sympathetic nerve activation is abolished by selective when there is endothelial dysfunction with a reduced release alpha1-antagonists, whereas Heusch and co-workers or production of NO. Beta-blocker administration may have (26,30,31) found that it was mediated by alpha2- increased this response, which was, however, not the case in adrenoceptors. The existence of alpha2-adrenoceptors in the present study. One might have expected an even larger human coronary arteries has been documented by Indolfi effect owing to the blocking of the beta-mediated vasocon- and co-workers (24). A reduction in exercise-induced ST- stricting effects, which did not become evident. segment depression and an increase in exercise capacity were observed in patients with stable angina pectoris treated with Clinical implications. Endothelial dysfunction is assumed the selective alpha -antagonist indoramine (3), whereas to occur in most stenotic coronary arteries, resulting in a 1 exercise-induced ST-segment depression in a similar patient decreased flow to the post-stenotic regions, which may group was more attenuated by the nonselective alpha- precipitate myocardial ischemia during exercise. The func- antagonist phentolamine than the selective alpha - tional abnormalities of the endothelium and the enhanced 1 antagonist indoramine, suggesting an important role for alpha-adrenergic sympathetic nervous system are probably vascular alpha -adrenoceptors in human coronary circula- responsible for the occurrence of stenosis vasoconstriction 2 tion (37). during exercise. Interestingly, a positive feedback mecha- nism between myocardial ischemia and post-stenotic coro- Conclusions. Nonselective alpha-adrenoceptor blockade nary vasoconstriction has been described by Heusch and with intracoronary phentolamine is able to prevent exercise- co-workers in the canine model (31). Exercise-induced induced vasoconstriction of stenotic coronary arteries during vasoconstriction of the coronary arteries after balloon- exercise. This observation suggests that alpha-adrenergic induced endothelial denudation has been previously shown sympathetic nerve activation plays an important role in by Berdeaux and co-workers in dogs (32). Similarly, an coronary stenosis vasomotion and may aggravate myocardial inhibitory role of the endothelium against alpha-adrenergic ischemia during exercise in patients with stable angina nerve stimulation has been reported by Main et al. (33) in pectoris. These effects are probably unmasked as a conse- isolated coronary artery rings from dogs with . quence of endothelial dysfunction with a decreased produc- Endothelial cells of large canine and porcine coronary tion and reduced release of endogenous vasodilators from arteries possess alpha2-adrenoceptors. Their activation by the stenotic vessel segments leading to enhanced coronary norepinephrine causes release of an endothelium-derived vasoconstriction during exercise. relaxant factor, which in turn attenuates norepinephrine- induced vasoconstriction mediated by alpha1-adrenergic Reprint requests and correspondence: Dr. Otto M. Hess, Pro- coronary vasoconstriction. Conversely, loss of endothelial fessor of Cardiology, Swiss Heart Center, Inselspital, 3010 Bern, function in atherosclerotic coronary arteries may predispose Switzerland. to enhanced alpha-adrenergic coronary vasoconstriction (34–36). Alpha-blocking agents in general have rarely been used in REFERENCES the treatment of coronary artery disease. Although these 1. Berkenboom GM, Abramowitz M, Vandermoten P, Degre SG. 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