The Effect of Atherosclerosis on the Vasomotor Response of Coronary Arteries to Mental Stress
List of authors.Abstract
Background.
Mental stress can cause angina in patients with coronary artery disease, but Its effects on coronary vasomotion and blood flow are poorly understood. Because atherosclerosis affects the reactivity of coronary arteries to various stimuli, such as exercise, we postulated that atherosclerosis might also influence the vasomotor response of coronary arteries to mental stress.
Methods.
We studied 26 patients who performed mental arithmetic under stressful conditions during cardiac catheterization. (An additional four patients who did not perform the mental arithmetic served as controls.) Coronary segments were classified on the basis of angiographic findings as smooth, irregular, or stenosed. In 15 of the patients without focal stenoses in the left anterior descending artery, acetylcholine (10—8 to 10—6 mol per liter) was infused into the artery to test endothelium-dependent vasodilation. Changes in coronary blood flow were measured with an intracoronary Doppler catheter in these 15 patients.
Results.
The response of the coronary arteries to mental stress varied from 38 percent constriction to 29 percent dilation, whereas the change in coronary blood flow varied from a decrease of 48 percent to an increase of 42 percent. The direction and magnitude of the change in the coronary diameter were not predicted by the changes in the heart rate, blood pressure, or plasma norepinephrine level. Segments with stenoses (n = 7) were constricted by a mean (±SE) of 24±4 percent, and irregular segments (n = 20) by 9±3 percent, whereas smooth segments (n = 25) did not change significantly (dilation, 3±3 percent; P<0.002). Coronary blood flow increased by 10±10 percent in smooth vessels, whereas the flow in irregular vessels decreased by 27±5 percent. The degree of constriction or dilation during mental stress correlated with the response to the infusions of acetylcholine (P<0.0003, r = 0.58).
Conclusions.
Atherosclerosis disturbs the normal vasomotor response (no change or dilation) of large coronary arteries to mental stress; in patients with atherosclerosis paradoxical constriction occurs during mental stress, particularly at points of stenosis. This vasomotor response correlates with the extent of atherosclerosis in the artery and with the endothelium-dependent response to an infusion of acetylcholine. These data suggest that in atherosclerosis unopposed constriction caused by a local failure of endothelium-dependent dilation causes the coronary arteries to respond abnormally to mental stress. (N Engl J Med 1991;325:1551–6.)
Methods
Selection of Patients
Patients referred for diagnostic cardiac catheterization for the evaluation of chest-pain syndromes or determination of the extent of coronary artery disease were asked to participate in the study. Patients with unstable angina, myocardial infarction within the previous six months, a history of congestive heart failure, valvular heart disease, or severe peripheral vascular disease were excluded. Informed consent was obtained in accordance with the requirements of the Brigham and Women's Hospital Committee for the Protection of Human Subjects from Research Risks. Vasoactive medications, including nitrates, calcium-channel blockers, beta-blockers, and angiotensin-converting—enzyme inhibitors, were withheld for 24 hours before catheterization. Long-acting betablockers were withheld for 24 to 36 hours before study. The patients were allowed to use sublingual nitroglycerin, if necessary, up to the morning of the catheterization, but no patient had an episode of chest pain while the medications were withheld.
All catheterizations were performed in the morning. The patients were minimally sedated (25 mg of diphenhydramine and 1 mg of midazolam) and received anticoagulation with 5000 U of heparin. Diagnostic catheterization of the right and left heart was performed by the standard percutaneous Judkins technique. Patients were excluded from the study if any of the following anatomical or hemodynamic findings were present: any narrowing of the left main artery, clinically important proximal three-vessel disease, elevated left ventricular filling pressures (pulmonary-artery wedge pressure, >16 mm Hg), or abnormal left ventricular systolic function (ejection fraction, <45 percent). In addition, if the left anterior descending artery had stenosis of more than 50 percent, or if severe stenoses were present in the circumflex artery and the right coronary artery, the intracoronary infusion of acetylcholine was omitted, and only mental-stress testing was performed.
Study Protocol
After completion of the diagnostic catheterization, an additional 5000 U of heparin was given intravenously and an 8-French guiding catheter was positioned in the ostium of the left coronary artery. A 2.5-French (tip diameter) Doppler infusion catheter (Millar Instruments, Houston) was positioned in the proximal portion of the left anterior descending coronary artery. The use of this device to assess changes in coronary blood flow has been described in detail elsewhere.7 , 18 19 20 Throughout the study, coronary blood flow velocity and the pressures in the femoral artery and the coronary guiding catheter were monitored continuously; an electrocardiogram was recorded continuously throughout the study. In patients who were to undergo mental-stress testing only, the Doppler catheter was not used.
Intracoronary Infusion of Acetylcholine
Serial infusions of acetylcholine in 5 percent dextrose at a rate of 0.8 ml per minute were administered selectively into the left anterior descending artery through the lumen of the Doppler catheter with use of an infusion pump (Harvard Apparatus, South Natick, Mass.), as follows. A two-minute control infusion of 5 percent dextrose in sterile water was given; next, three two-minute infusions of acetylcholine (at 0.14, 1.4, and 14.0 μg per minute) were given, yielding final estimated intracoronary blood concentrations of 10—8 to 10—6 mol per liter, assuming a blood flow of 80 ml per minute in the left anterior descending artery.5 , 14 , 15 , 21 The infusion was stopped and subsequent doses were omitted whenever substantial constriction was observed. Next, the control infusion was repeated for five minutes. The mental-stress test was then conducted.
Mental-Stress Testing
A control period of 10 minutes was initiated, with the room lights turned down, the ambient noise reduced to the lowest possible level, and the patient encouraged to relax. A base-line arterial blood sample for measurement of catecholamines (norepinephrine and epinephrine) was withdrawn through the side arm of the femoral arterial sheath. After the control period, an investigator who was unknown to the patient turned on the room lights and instructed the patient to subtract seven from a three-digit number as quickly and as accurately as possible. During this test (which lasted 2 to 2.5 minutes), the patient was intentionally frustrated by being asked to speak louder and by being corrected frequently. At the peak blood-pressure response, an arterial blood sample was withdrawn for a second determination of catecholamine levels. A second control period of five minutes was followed by the collection of a third sample of blood for measurement of catecholamines. Intracoronary nitroglycerin (40 μg) was then given over a period of 2.5 minutes.22 In a control group of four patients, the same protocol was followed, except that instead of being subjected to mental stress, the patients were asked in a nonstressful manner to count upward slowly from one.
Coronary Angiography
At the end of each part of the study (control period, intracoronary acetylcholine infusion, mental-stress testing, and nitroglycerin infusion), the electrocardiogram, blood pressure, and coronary blood flow velocity (if applicable) were recorded, and coronary angiography was then performed. For each angiogram, a single bolus of nonionic contrast medium (Omnipaque, Winthrop—Breon Laboratories, New York) was injected with a power injector (Medrad, Pittsburgh) into the left coronary artery at a rate of 7 ml per second for a total of 9 ml. A cineangiographic system (Polydiagnostic-C, Phillips Medical Systems, Shelton, Conn.) was set to position the arterial segment under study in the center of each field of view and at a single position in space (isocenter).5 , 6 , 14 , 16 Epinephrine and norepinephrine concentrations were determined by radioenzymatic assay by the method described by Peuler and Johnson.23
Classification and Analysis of Arterial Segments
Two coronary segments per patient were selected blindly by two experienced angiographers. The primary criterion for selection was the segments' availability for analysis (i.e., they had to be nonoverlapping segments, free of side branches, and at least 8 mm in length). The segments selected were distal to the Doppler catheter, if one was present. All these segments were then blindly classified as smooth, irregular, or stenosed.5 , 6 , 14 Using a previously validated, automated system of quantitative angiography,5 , 6 , 14 , 24 , 25 we measured the diameter of each segment before and after each intracoronary infusion of acetylcholine, before and after mental-stress testing, and after nitroglycerin infusion. The precision of a single estimate is within ±5 percent.26 Calibrated grids, filmed at isocenter, were used to scale the data from pixels to millimeters. Fixed anatomical positions were used to identify for analysis the same segment of interest after each drug infusion and after mental-stress testing.
Estimation of Changes in Coronary Blood Flow
Changes in coronary blood flow were estimated by correcting changes in the mean flow velocity, as measured by the Doppler catheter, for changes from the base-line value in estimated cross-sectional areas of the vessel.6 , 18 , 19 , 27
Statistical Analysis
All data are expressed as means ±SE. All P values of less than 0.05 (two-tailed) were considered to indicate statistical significance. Changes in systolic, diastolic, and mean blood pressure; heart rate; and coronary blood flow during the infusions of acetylcholine were compared with base-line values by means of the Wilcoxon signed-rank test for paired data.28 Changes in the product of the heart rate and the systolic blood pressure and in norepinephrine and epinephrine levels during mental-stress testing were compared with base-line values with the same statistical test.
The vasomotor responses were expressed in terms of the percent change in the coronary diameter as compared with base line. The change in the mean diameter in response to mental stress for each patient was correlated with age, cholesterol level, the blood pressure—heart rate response, and catecholamine levels with use of the Spearman correlation coefficient. The relation of sex to these responses was analyzed with the Wilcoxon rank-sum test.28 The associations of the change in diameter in each segment in response to mental stress with the classification of the coronary segment as smooth, irregular, or stenosed by the blinded investigator and with the response to acetylcholine were assessed with Kruskal—Wallis analysis of variance and the Spearman correlation coefficient, respectively. All these variables were further analyzed by multivariate regression.
Results
Characteristics of the Patients
Thirty patients with a mean age of 57±2 years (range, 31 to 72) were enrolled in the study. Twenty were men, and 10 were women. The patients who presented with typical anginal symptoms had Canadian Cardiovascular Society Class I or II angina. Among the 30 patients, 13 had a positive exercise test, 5 had a negative test, and 12 had a nondiagnostic test. Eleven patients had smooth coronary arteries or minor luminal irregularities, 11 had one-vessel disease (>50 percent stenosis), 3 had two-vessel disease, and 5 had three-vessel disease. The left ventricular ejection fractions of all patients were normal. The mean serum cholesterol level was 204±8 mg per deciliter (5.28±0.21 mmol per liter). Twenty-six patients underwent mental-stress testing; the remaining four patients served as controls. Fifteen of the 26 patients received intracoronary infusions of acetylcholine; however, to minimize risk, the highest dose of acetylcholine was not given when visible constriction was observed (5 patients).
Hemodynamic and Catecholamine Responses
Table 1.
Table 1. Hemodynamic and Catecholamine Responses to Mental Stress. Table 1 summarizes the hemodynamic and the neurohumoral responses to mental stress. The mean arterial norepinephrine level increased by 28 percent, whereas the epinephrine level increased only slightly, from 316.6 pmol per liter to 365.7 pmol per liter (from 58 to 67 pg per milliliter; P not significant). Two patients had their typical angina during mental-stress testing. In the control patients, there were no differences in any of the measurements between the control period and the nonstressful counting. Acetylcholine infusion produced no significant changes in heart rate, blood pressure, symptoms, or electrocardiographic findings.
Response of Epicardial Arteries to Mental Stress
A total of 52 coronary-artery segments in 26 patients were analyzed. The mean diameter at rest was 1.6±0.7 mm (range, 0.75 to 3.4). The vasomotor response varied from 38 percent constriction to 29 percent dilation. The mean response of the two segments in each patient correlated inversely with age (P<0.03) but was not related to sex, the total serum cholesterol level, the blood pressure—heart rate product, or increases in the norepinephrine levels.
Figure 1.
Figure 1. Effects of Mental Stress on the Diameter of Stenosed, Irregular, and Smooth Epicardial Coronary-Artery Segments. The change in diameter is expressed as the percent change from the base-line value (±SE). In the stenosed segments (n = 7), mental stress caused constriction of 24±4 percent; in irregular segments (n = 20), it caused constriction of 9±3 percent; the smooth segments (n = 25) were substantially unchanged (dilation, 3±3 percent). The changes differed significantly among the groups (P<0.002 by analysis of variance).
Figure 2.
Figure 2. Coronary Angiogram of a Stenotic Left Anterior Descending Artery (Upper Panel) and the Responses of the Coronary Segment Indicated by the Arrow to Acetylcholine, Mental Stress, and Nitroglycerin (Lower Panel). Figure 3. 
Figure 3. Coronary Angiogram of a Smooth Left Anterior Descending Artery (Upper Panel) and the Responses of the Coronary Segment Indicated by the Arrow to Acetylcholine, Mental Stress, and Nitroglycerin (Lower Panel). There was a significant relation between the classification of the coronary segments (smooth, irregular, or stenosed) and the response to mental stress (Fig. 1). The segments in each group dilated equally in response to nitroglycerin (22 percent, 23 percent, and 24 percent, respectively), suggesting that there were no significant differences in vascular tone at base line among the groups. There were also no significant differences in base-line diameter in the three groups. Figure 2 shows the response of one stenotic segment to the acetylcholine infusion and to mental stress, and Figure 3 the response of one smooth segment.
Eight coronary segments in the four control patients were analyzed. The mean base-line diameter was 1.7±0.2 mm (range, 1.2 to 2.6). These control-artery segments remained unchanged (mean dilation, 3±2 percent) after nonstressful counting; this response was significantly different from the constriction seen in the irregular segments (P = 0.01) and the segments with stenoses (P = 0.02).
Response to Mental Stress and Acetylcholine
Figure 4.
Figure 4. Relation between the Percent Change in Diameter in Response to Mental Stress and the Change in Response to Acetylcholine (10—7 mol per liter) in the Same Coronary Segments. There was a significant association (P<0.0003, r = 0.58) between the two responses. The shaded areas encompass the majority of the data points for which there was concordance between the two responses.
The response to mental stress was correlated with the vasomotor response to acetylcholine at concentrations of 10—8 and 10—7 mol per liter (Fig. 4). There was a significant correlation between the response to mental stress and the response to acetylcholine (P<0.003, r = 0.47 for 10—8 mol per liter; P<0.0003, r = 0.58 for 10—7 mol per liter). Stepwise multivariate regression analysis demonstrated that the response to acetylcholine was the most significant predictor of the vasomotor response to mental stress (P<0.008).
Coronary Blood-Flow Response
Twelve of the 15 patients who had adequate Doppler signals were examined. There were no significant correlations between coronary blood flow and changes in blood pressure, heart rate, or the blood pressure—heart rate product. Patients with smooth coronary arteries (n = 5) had either no change or an increase in blood flow (10±10 percent), whereas those who had irregular or stenosed arteries (n = 7) had a decrease of 27±5 percent in flow (P<0.005). In the four control patients, there was no significant change in blood flow (increase, 2±5 percent). Blood flow increased in response to acetylcholine, with a mean increase of 51 percent at a concentration of 10—7 mol per liter. This response did not correlate with the extent of atherosclerosis as demonstrated angiographically.
Discussion
This study shows that angiographically smooth coronary arteries usually either do not change or dilate in response to mental stress, whereas any degree of atherosclerosis results in abnormal constriction in both irregular and stenosed vessel segments. In addition, the vasomotor response of epicardial arteries to mental stress correlates with the local response to acetylcholine, an agent used to assess endothelial vasodilator function. These results suggest that atherosclerosis causes an abnormal vasomotor reaction to mental stress, with paradoxical constriction, and that this response probably reflects local endothelial dysfunction.
In the angiographically normal coronary arteries, mental stress produced an increase in coronary blood flow, reflecting an increase in myocardial oxygen demand, as has previously been demonstrated.29 , 30 In the presence of atherosclerosis, however, there was a small decrease in regional coronary blood flow, despite a similar increase in the blood pressure—heart rate product and in plasma norepinephrine levels. Such inappropriate decreases in coronary blood flow have been demonstrated previously in atherosclerotic coronary arteries; their occurrence suggests that in patients with coronary artery disease, vasoconstriction overcomes the metabolic demand for an increase in blood flow during mental stress.7 , 31 Minor decreases in epicardial coronary-artery diameter at points of stenosis may lead to substantial increases in resistance and a decline in flow. In this study, however, the observed changes in the diameter of epicardial coronary arteries alone were probably not sufficient to account for the decreases in flow, especially in the vessels with only luminal irregularities. Thus, it is likely that constriction of resistance vessels also had a role in the observed changes in blood flow. This mechanism is supported by experimental studies, which have provided ample evidence that the function of resistance vessels is impaired in atherosclerosis.32 33 344
Mental-stress testing has been used extensively to induce myocardial ischemia in patients with coronary artery disease.1 , 3 , 29 , 30 , 35 Several studies have shown that mental stress can increase the heart rate, systolic blood pressure, and circulating levels of catecholamines.30 , 35 , 36 Studies have also shown that mental stress is a relatively specific and effective Stressor of the cardiac sympathetic system.36 , 37 In this study, we were able to demonstrate evidence of increased sympathetic activity similar to that described in other studies.
The net vasomotor response of the epicardial coronary arteries to mental stress is probably a result of several opposing forces. The large epicardial coronary arteries undergo predominantly α1-adrenergic-receptor—mediated vasoconstriction with minor β1-adrenergic-receptor—mediated vasodilation.38 39 40 In addition, the intact endothelium diminishes the constrictive effect of the catecholamines, probably by the α2-adrenergic-receptor—mediated release of endothelium-derived relaxing factor.41 Intact endothelium may also inhibit the release of norepinephrine from sympathetic-nerve terminals and may take up and metabolize norepinephrine.42 , 43 Martin et al. demonstrated that the basal release of endothelium-derived relaxing factor can attenuate catecholamine-mediated vasoconstriction.44 Preliminary evidence suggests that in humans endothelial dysfunction in atherosclerotic coronary arteries also results in increased sensitivity to the constrictive effect of catecholamines.25 These studies have shown that atherosclerosis reduces dilation and causes abnormal constrictor responses that correlate with independent local evidence of endothelial vasodilator dysfunction. It is likely that increased blood flow19 and higher catecholamine levels45 can increase the release of endothelium-derived relaxing factor. Thus, we speculate that in patients with normal coronary arteries, the intense α-adrenergic—mediated constriction in response to sympathetic stimulation is counteracted by endothelium-mediated vasodilation. In patients with atherosclerosis, however, endothelium-dependent vasodilation is deficient, resulting in unopposed vasoconstriction.
This study demonstrates that the vasomotor response of normal epicardial coronary arteries to mental stress is either no change or limited dilation. Both mild and more advanced atherosclerosis disturb this response, resulting in paradoxical vasoconstriction. In segments with atherosclerotic stenosis, this constriction probably accounts for the decrease in regional coronary blood flow observed in patients with severe stenoses and, together with an increase in metabolic demand, leads to myocardial ischemia during mental stress.1 Thus, stress appears to disclose the functional problem — abnormal constriction — that reflects the failure of endothelium-dependent vasodilation that is the fundamental disturbance in vascular biology of atherosclerosis.
References (45)
1. Deanfield JE, Shea M, Kensett M, et al. . Silent myocardial ischemia due to mental stress . Lancet 1984;2:1001–5.
2. Barry J, Selwyn AP, Nabel EG, et al. . Frequency of ST-segment depression produced by mental stress in stable angina pectoris from coronary artery disease . Am J Cardiol 1988;61:989–93.
3. Rozanski A, Bairey CN, Krantz DS, et al. . Mental stress and the induction of silent myocardial ischemia in patients with coronary artery disease . N Engl J Med 1988;318:1005–12.
4. Gage JE, Hess OM, Murakami T, Ritter M, Grimm J, Krayenbuehl HP. . Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin . Circulation 1986;73:865–76.
5. Gordon JB, Ganz P, Nabel EG, et al. . Atherosclerosis influences the vasomotor response of epicardial coronary arteries to exercise . J Clin Invest 1989;83:1946–52.
6. Nabel EG, Ganz P, Gordon JB, Alexander RW, Selwyn AP. . Dilation of normal and constriction of atherosclerotic coronary arteries caused by the cold pressor test . Circulation 1988;77:43–52.
7. Nabel EG, Selwyn AP, Ganz P. . Paradoxical narrowing of atherosclerotic arteries induced by increases in heart rate . Circulation 1990;81:850–9.
8. Furchgott RF. . Role of endothelium in responses of vascular smooth muscle . Circ Res 1983;53:557–73.
9. Habib JB, Bossaller C, Wells S, Williams C, Morrisett JD, Henry PD. . Preservation of endothelium-dependent vascular relaxation in cholesterolfed rabbits by treatment with the calcium blocker PN200110 . Circ Res 1986;58:305–9.
10. Sreeharan N, Jayakody R, Senaratne M, Thomson AB, Kappagoda CT. . Endothelium-dependent relaxation and experimental atherosclerosis in the rabbit aorta . Can J Physiol Pharmacol 1986;64:1451–3.
11. Shimokawa H, Vanhoutte PM. . Impaired endothelium-dependent relaxation to aggregating platelets and related vasoactive substances in porcine coronary arteries in hypercholesterolemia and atherosclerosis . Circ Res 1989; 64:900–14.
12. Minor RL Jr, Myers PR, Guerra R Jr, Bates JN, Harrison DG. . Diet-induced atherosclerosis increases the release of nitrogen oxides from rabbit aorta . J Clin Invest 1990;86:2109–16.
13. Tagawa H, Tomoike H, Nakamura M. . Putative mechanisms of the impairment of endothelium-dependent relaxation of the aorta with atheromatous plaque in heritable hyperlipidemic rabbits . Circ Res 1991;68:330–7.
14. Ludmer PL, Selwyn AP, Shook TL, et al. . Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries . N Engl J Med 1986;315:104–51.
15. Fish R, Nabel E, Selwyn A, et al. . Responses of coronary arteries of cardiac transplant patients to acetylcholine . J Clin Invest 1988;81:21–31.
16. Vita JA, Treasure CB, Nabel EG, et al. . Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease . Circulation 1990;81:491–7.
17. Yasue H, Matsuyama K, Matsuyama K, Okumura K, Morikani Y, Ogawa H. . Responses of angiographically normal human coronary arteries to intracoronary injection of acetylcholine by age and segment: possible role of early coronary atherosclerosis . Circulation 1990;81:482–90.
18. Sibley DH, Millar HD, Hartley CJ, Whitlow PL. . Subselective measurement of coronary blood flow velocity using a steerable Doppler catheter . J Am Coll Cardiol 1986;8:1332–40.
19. Cox DA, Vita JA, Treasure CB, et al. . Atherosclerosis impairs flow-mediated dilation of coronary arteries in humans . Circulation 1989;80:458–65.
20. Treasure CB, Vita JA, Cox DA, et al. . Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy . Circulation 1990;81:772–9.
21. Ganz W, Tamura K, Marcus HS, Donoso R, Yoshida S, Swan HJC. . Measurement of coronary sinus blood flow by continuous thermodilution in man . Circulation 1971;44:181–95.
22. Brown BG, Bolson E, Peterson RB, Pierce CD, Dodge HT. . The mechanisms of nitroglycerin action: stenosis vasodilation as a major component of the drug response . Circulation 1981;64:1089–97.
23. Peuler JD, Johnson GA. . Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine . Life Sci 1977; 21:625–36.
24. Kirkeedie R, Fung P, Smalling R, Gould R. . Automated evaluation of vessel diameter from arteriograms . IEEE Trans Comput Soc Comput Cardiol1982: 215–8.
25. Vita JA, Treasure CB, Fish RD, et al. . Endothelial dysfunction leads to increased coronary constriction to catecholamines in patients with early atherosclerosis . J Am Coll Cardiol 1990;15:158A. abstract.
26. Sandor T, Spears J. . Statistical considerations on the precision of assessing blood vessel diameter in cine coronary angiography . Comput Biomed Res 1985;18:531–43.
27. Wilson RF, Laughlin DE, Ackell PH, et al. . Transluminal, subselective measurement of coronary artery blood flow velocity and vasodilator reserve in man . Circulation 1985;72:82–92.
28. Wallenstein S, Zucker CL, Fleiss JL. . Some statistical methods useful in circulation research . Circ Res 1980;47:1–9.
29. Bassan MM, Marcus HS, Ganz W. . The effect of mild-to-moderate mental stress on coronary hemodynamics in patients with coronary artery disease . Circulation 1980;62:933–5.
30. Specchia G, de Servi S, Falcone C, et al. . Mental arithmetic stress testing in patients with coronary artery disease . Am Heart J 1984;108:56–63.
31. Lange RA, Cigarroa RG, Yancy CW Jr, et al. . Cocaine-induced coronary-artery vasoconstriction . N Engl J Med 1989;321:1557–62.
32. Yamamoto H, Bossaller C, Cartwright J Jr, Henry PD. . Videomicroscopic demonstration of defective cholinergic arteriolar vasodilation in atherosclerotic rabbit . J Clin Invest 1988;81:1752–8.
33. Osborne J, Siegman M, Sedar A, Mooers S, Lefer A. . Lack of endothelium-dependent relaxation in coronary resistance arteries of cholesterol-fed rabbits . Am J Physiol 1989;256:C591–C597.
34. Sellke FW, Armstrong ML, Harrison DG, . Endothelium-dependent vascular relaxation is abnormal in the coronary microcirculation of atherosclerotic primates . Circulation 1990;81:1586–93.
35. Freyschuss U, Hjemdahl P, Juhlin-Dannfelt A, Linde B. . Cardiovascular and sympathoadrenal responses to mental stress: influence of β-blockade . Am J Physiol 1988;255:H1443–H1451.
36. Meredith IT, Esler MD, Eisenhofer G, Jennings GL. . The effects of simple daily life stresses on cardiac sympathetic activity, myocardial oxygen consumption and hemodynamics . Circulation 1990;82:Suppl III:III-516. abstract.
37. Robertson D, Johnson GA, Robertson RM, Nies AS, Shand DG, Oates JA. . Comparative assessment of stimuli that release neuronal and adrenomedullary catecholamines in man . Circulation 1979;59:637–43.
38. Toda N. . Alpha-adrenoceptor subtypes and diltiazem actions in isolated human coronary arteries . Am J Physiol 1986;250:H718–H724.
39. Cohen RA, Shepherd JT, Vanhoutte PM. . Effects of the adrenergic transmitter on epicardial coronary arteries . Fed Proc 1984;43:2862–6.
40. Heusch G. . Alpha-adrenergic mechanisms in myocardial ischemia . Circulation 1990;81:1–13.
41. Cocks TM, Angus JA. . Endothelium-dependent relaxation of coronary arteries by noradrenaline and serotonin . Nature 1983;305:627–30.
42. Cohen RA, Weisbrod RM. . Endothelium inhibits norepinephrine release from adrenergic nerves of rabbit carotid artery . Am J Physiol 1988;254: H871–H878.
43. Cohen RA, Zitnay KM, Weisbrod RM, Tesfamariam B. . Influence of the endothelium on tone and the response of isolated pig coronary artery to norepinephrine . J Pharmacol Exp Ther 1988;244:550–5.
44. Martin W, Furchgott RF, Villani GM, Jothianandan D. . Depression of contractile responses in rat aorta by spontaneously released endothelium-derived relaxing factor . J Pharmacol Exp Ther 1986;237:529–38.
45. Vanhoutte PM, Shimokawa H. . Endothelial-derived relaxing factor and coronary vasospasm . Circulation 1989;80:1–9.
Citing Articles (440)
Figures/Media
- Table 1. Hemodynamic and Catecholamine Responses to Mental Stress.
Table 1. Hemodynamic and Catecholamine Responses to Mental Stress. - Figure 1. Effects of Mental Stress on the Diameter of Stenosed, Irregular, and Smooth Epicardial Coronary-Artery Segments.
Figure 1. Effects of Mental Stress on the Diameter of Stenosed, Irregular, and Smooth Epicardial Coronary-Artery Segments. The change in diameter is expressed as the percent change from the base-line value (±SE). In the stenosed segments (n = 7), mental stress caused constriction of 24±4 percent; in irregular segments (n = 20), it caused constriction of 9±3 percent; the smooth segments (n = 25) were substantially unchanged (dilation, 3±3 percent). The changes differed significantly among the groups (P<0.002 by analysis of variance).
- Figure 2. Coronary Angiogram of a Stenotic Left Anterior Descending Artery (Upper Panel) and the Responses of the Coronary Segment Indicated by the Arrow to Acetylcholine, Mental Stress, and Nitroglycerin (Lower Panel).
Figure 2. Coronary Angiogram of a Stenotic Left Anterior Descending Artery (Upper Panel) and the Responses of the Coronary Segment Indicated by the Arrow to Acetylcholine, Mental Stress, and Nitroglycerin (Lower Panel). - Figure 3. Coronary Angiogram of a Smooth Left Anterior Descending Artery (Upper Panel) and the Responses of the Coronary Segment Indicated by the Arrow to Acetylcholine, Mental Stress, and Nitroglycerin (Lower Panel).
Figure 3. Coronary Angiogram of a Smooth Left Anterior Descending Artery (Upper Panel) and the Responses of the Coronary Segment Indicated by the Arrow to Acetylcholine, Mental Stress, and Nitroglycerin (Lower Panel). - Figure 4. Relation between the Percent Change in Diameter in Response to Mental Stress and the Change in Response to Acetylcholine (10—7 mol per liter) in the Same Coronary Segments.
Figure 4. Relation between the Percent Change in Diameter in Response to Mental Stress and the Change in Response to Acetylcholine (10—7 mol per liter) in the Same Coronary Segments. There was a significant association (P<0.0003, r = 0.58) between the two responses. The shaded areas encompass the majority of the data points for which there was concordance between the two responses.
