View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 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 Vasoconstriction 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-adrenergic 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 nitric oxide, 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 phentolamine 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 vasodilation 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 6 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 ANOVA5 analysis of variance purpose of the present study protocol, the left coronary C 5 controls artery was selected to have a normal and a stenotic vessel 5 CSA cross-sectional area segment for quantitative analysis. The study drug was, NS 5 not significant P 5 patients receiving intracoronary phentolamine therefore, infused over the guiding catheter into the left 5 P(a) patients receiving only phentolamine coronary artery. Eight milliliters of a nonionic contrast 5 R P(a 1 b) 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 5 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 (Pa), five patients who were on measured for subsequent analysis immediately before each chronic cardioselective beta-blockade (metoprolol or ateno- angiogram. No adverse event occurred during the study, and lol) had been instructed to take this medication also on the there were no complications with regard to this study morning of the study (Pa 1 b). protocol. Functional classification according to the New York Heart Association was 1.9 6 0.6 in controls and 1.8 6 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 ,70% in three, for quantitative analysis. In each patient at least one stenotic 70% to 90% in four and .90% 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 ,70% in 1 patient. One segment was selected from a disease-free vessel when control patient had a ,70% stenosis, seven had 70% to 90% possible, otherwise an uninvolved prestenotic vessel segment stenoses, and 2 had .90% stenoses. Left ventricular ejection was chosen at least four catheter-widths from the center of fraction averaged 61 6 8% in controls and 64 6 6% in the stenosis, which was not used for quantiative evaluation phentolamine-treated patients (NS). (Fig. 1). Cardiac catheterization. The study protocol