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Both atenolol and propranolol blunt the fibrinolytic response to exercise but not resting fibrinolytic potential
Both Atenolol and Propranolol Blunt the Fibrinolytic Response to Exercise But Not Resting Fibrinolytic Potential Bo Fernhall, PhD, Linda M. Szymanski, PhD, Patrick A. Gorman, Gary H. Kamimori, PhD, and Craig M. Kessler, MD ow fibrinolytic activity and high levels of coagulation markers are related to the incidence of ischL emic cardiovascular disease, reinfarction, and thromboembolic events.1–3 Acute physical exercise is a potent stimulator of fibrinolysis and coagulation.4 –7 The ability to increase fibrinolytic activity and maintain hemostatic balance in response to maximal exercise is often used to detect abnormalities that are not necessarily evident at rest6 and may be predictive of future cardiovascular events.8 Beta blockers prevent reinfarction and are effective for treatment of hypertension and angina.9 Their influence on hemostasis is unclear and timolol has been related to an increased occurrence of left ventricular thrombi in patients with acute myocardial infarction.10 Only a few studies have evaluated the effect of  blockade on fibrinolysis during exercise,11 and have shown inconsistent results. During exercise, no studies have evaluated the effect of selective and nonselective  blockade on fibrinolytic activity, with simultaneous measurements of in vivo markers of coagulation activation. Measures of fibrinolysis and coagulation activation are needed to obtain a more complete picture of hemostatic balance. The purpose of this study was to evaluate the effect of propranolol and atenolol on fibrinolytic markers and coagulation activation at rest and after maximal exercise using a randomized, double-blind crossover design. •••
Twelve healthy men volunteered to participate in the study (mean age 23.9 ⫾ 4.5 years, mean weight 86.2 ⫾ 11.7 kg; mean height 180 ⫾ 7.8 cm; mean body mass index 26.7 ⫾ 3.7). No subject reported any recent health problems, and none was taking any medication. Subjects were excluded if they had a history of diabetes, hypertension or hypotension, thrombotic disorders, hyperlipidemia, asthma, smoking, or any cardiovascular disorders. All subjects signed informed consent before participation and the study was approved by the University Medical Center Institutional Review Board. The subjects received propranolol (120 mg/day), atenolol (75 mg/day), or a placebo in a double-blind, From the Exercise Science Programs and The Division of Cardiology, The George Washington University Medical Center, Washington; the Department of Neurobiology and Behavior, Walter Reed Army Institute of Research, Washington; and the Division of Hematology-Oncology, Georgetown University Medical Center, Washington, DC. Dr. Fernhall’s address is: Exercise Science Department, Syracuse University, 820 Comstock Avenue, Room 201, Syracuse, New York 13244. Manuscript received January 17, 2000; revised manuscript received and accepted June 29, 2000.
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©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 December 15, 2000
MD,
randomized, crossover fashion. They received the medication for 3 days and were tested on day 3, 1 hour after taking the medication. Subjects reported to the laboratory in a fasted state (12 hours) between 7 and 9 A.M. to control for the influence of diurnal variations. After 1-hour supine rest, subjects were moved to a seated position for 5 minutes followed by measurements of resting heart rate and blood pressure. Subjects completed a maximal exercise test performed to volitional fatigue on an electronically braked cycle ergometer (SensorMedics, Yorba Linda, California) with oxygen uptake measurements (SensorMedics Vmax). Resting blood samples were obtained after 5 minutes of seated rest. Postexercise samples were obtained in a seated position within 1 minute of exercise termination. Blood was collected via venipuncture with minimal stasis from an antecubital vein. Tubes were immediately placed on ice and subsequently centrifuged at 2,600 g for 25 minutes. Plasma was aliquoted and stored at ⫺80°C until analyzed. Hematocrit and hemoglobin were measured using an automated cell counter (Baker System 9000 Series; Biochem Immunosystems, Allentown, Pennsylvania). Plasma volume changes were estimated from the hematocrit and hemoglobin values.12 Tissue plasminogen activator activity (t-PA) was determined by measuring the amidolytic activity of plasmin on a chromogenic substrate (S-2251) using commercially available kits (Coatest t-PA; Chromogenix, Mo¨lndal, Sweden). Plasminogen activator inhibitor (PAI-1) activity was determined by measuring the amidolytic activity of plasmin on a chromogenic substrate (S2403) performed in the presence of excess t-PA (Coatest PAI). t-PA and PAI-1 antigen levels were determined using commercially available enzyme-linked immunoassay kits (IMUBIND Total tPA, and IMUBIND PAI-1; American Diagnostica, Inc., Greenwich, Connecticut). Prothrombin fragment 1 ⫹ 2 (F 1 ⫹ 2) was measured using an enzyme-linked immunoassay (Thrombonostika F1.2, Organon Teknika, Durham, North Carolina). Epinephrine and norepinephrine were isolated using alumina extraction kits (Chromsystems, Munich, Germany) and high-performance liquid chromatography with electrochemical detection was used to determine their plasma concentration as described by Schneider et al.13 All samples from each subject were analyzed at one time to control for potential interassay variations. Descriptive statistics were calculated for all variables. A 3 ⫻ 2 (drug condition by rest and exercise) analysis of variance with repeated measures was used to evaluate t-PA and PAI-1 activities and antigens, 0002-9149/00/$–see front matter PII S0002-9149(00)01242-X
TABLE 1 Mean (⫾ SD) Resting and Maximal Cardiorespiratory, Hematologic, and Catecholamine Responses During Treatments
•••
This study demonstrates that neither selective (atenolol) nor nonseVariable Atenolol Propanolol Placebo lective (propranolol)  blockade significantly altered fibrinolytic activity Resting heart rate (beats/min) 53 ⫾ 5 55 ⫾ 11 62 ⫾ 12* Resting systolic blood pressure 110 ⫾ 12 114 ⫾ 11 120 ⫾ 14* at rest as measured by t-PA and (mm Hg) PAI-1 activity and antigen levels. Resting diastolic blood pressure 72 ⫾ 11 74 ⫾ 8 78 ⫾ 8* However, in response to maximal ex(mm Hg) † ercise, atenolol and propranolol atMaximal heart rate (beats/min) 139 ⫾ 14 127 ⫾ 11 186 ⫾ 13 Maximal systolic blood pressure 193 ⫾ 36 182 ⫾ 34 218 ⫾ 33† tenuated the fibrinolytic response, as (mm Hg) evidenced by a lesser increase in Maximal diastolic blood pressure 76 ⫾ 13 78 ⫾ 8 82 ⫾ 7* t-PA activity and a lesser reduction (mm Hg) in PAI-1 activity than responses with Maximal oxygen uptake 38.4 ⫾ 7 37.1 ⫾ 7 37.5 ⫾ 6 placebo. Activation of coagulation at (ml 䡠 kg⫺1 䡠 min⫺1) Resting t-PA activity (IU 䡠 ml⫺1) 1.9 ⫾ 0.5 2.0 ⫾ 0.6 1.9 ⫾ 0.5 rest and during exercise was unalMaximal t-PA activity (IU 䡠 ml⫺1) 6.3 ⫾ 2.5‡ 6.6 ⫾ 2.3‡ 8.0 ⫾ 2.5§ tered by  blockade in this study. To ⫺1 Resting t-PA antigen (ng 䡠 ml ) 6.8 ⫾ 1.7 6.6 ⫾ 1.7 6.3 ⫾ 1.4 our knowledge, the present study is ⫺1 ‡ ‡ ‡ Maximal t-PA antigen (ng 䡠 ml ) 16.6 ⫾ 6.1 15.8 ⫾ 5.3 17.2 ⫾ 7.8 the first to evaluate the various fiResting PAI-1 activity (AU 䡠 ml⫺1) 14.0 ⫾ 11 10.3 ⫾ 10.4 12.5 ⫾ 7.9 Maximal PAI-1 activity (AU 䡠 ml⫺1) 8.0 ⫾ 8.8‡ 6.8 ⫾ 7.9‡ 4.3 ⫾ 5.5§ brinolytic system components as Resting PAI-1 antigen (ng 䡠 ml⫺1) 44.7 ⫾ 26 44.4 ⫾ 20 42.4 ⫾ 20 well as coagulation activation during ⫺1 Maximal PAI-1 antigen (ng 䡠 ml ) 38.7 ⫾ 21 37.6 ⫾ 13 42.2 ⫾ 20 the interaction of  blockade and exResting F 1⫹ 2 (nM) 0.62 ⫾ 0.2 0.75 ⫾ 0.2 0.64 ⫾ 0.25 ercise. Maximal F 1⫹ 2 (nM) 0.55 ⫾ 0.1 2.7 ⫾ 5.7 0.59 ⫾ 0.2 Our findings are in agreement Resting epinephrine (pg 䡠 ml⫺1) 129 ⫾ 104 110 ⫾ 74 129 ⫾ 87 ⫺1 § ‡ Maximal epinephrine (pg 䡠 ml ) 172 ⫾ 77 287 ⫾ 113 200 ⫾ 101‡ with other investigators who have reResting norepinephrine (pg 䡠 ml⫺1) 565 ⫾ 152 681 ⫾ 361 668 ⫾ 377 ported no change in fibrinolytic variMaximal norepinephrine (pg 䡠 ml⫺1) 1,846 ⫾ 821§ 2,523 ⫾ 1,493‡ 2,348 ⫾ 942‡ ables at rest after nonselective  *Placebo significantly different from atenolol (p ⬍0.05). blockade.11 Teger-Nilsson et al14 † Placebo significantly different from both atenolol and propranolol (p ⬍0.05). suggested that fibrinolysis may be ‡ Significant change from rest (p ⬍0.05). controlled by 2 stimulation, espe§ Significant change from rest to exercise between placebo and both atenolol and propranolol (p cially under conditions of enhanced ⬍0.05). adrenergic stimulation, such as stress or catecholamine infusion. The restand F 1 ⫹ 2 levels before and after exercise. A Tukey ing conditions in our study cannot be described as post hoc analysis was used if statistical significance stressful. Furthermore, circulating catecholamine levwas found. The level of significance was set at p els did not differ among patients taking drugs in the resting state. Consequently, in the absence of adren⬍0.05. The results are displayed in Table 1. Heart rate and ergic stimulation,  blockade may not influence fibriblood pressure attained during maximal exercise were nolysis. Atenolol did not alter resting fibrinolytic acsignificantly lower during therapy with both atenolol tivity, which is in agreement with existing data.15 and propranolol compared with placebo. There was no The increase in fibrinolytic activity after a bout of difference in maximal oxygen consumption among physical exercise4 –7 is at least partially mediated by therapies. Beta blockade had no effect on t-PA activity adrenergic stimulation.14,16 Consequently, nonselecat rest. Exercise increased t-PA activity during all tive  blockade can significantly decrease the fibrinodrug conditions. The increase with exercise was lytic response to exercise,11 and the fibrinolytic regreater during placebo than during atenolol and pro- sponse to adrenaline infusions can be blocked by pranolol administration. There was no difference be- nonselective  blockade.17 Our data show that protween results with atenolol and propranolol. The t-PA pranolol reduced the exercise-induced increase in antigen levels were similar among all patients at rest, t-PA activity, and attenuated the exercise-induced reand increased with exercise in all conditions. The duction in PAI-1 activity. However, attenuation in PAI-1 activity was also similar during rest and de- fibrinolytic activity occurred without differences in creased with exercise in all treatment conditions. The circulating catecholamines after exercise during proexercise-induced decrease in PAI-1 activity was pranolol administration compared with placebo adgreater during placebo than during therapy with either ministration. Although catecholamines have been atenolol or propranolol. The PAI-1 antigen levels did shown to be elevated during exercise after propranolol not differ between testing at rest, and they did not administration,18 this may simply be related to relative change with exercise. The F 1 ⫹ 2 did not change with exercise intensity, because exercise capacity deexercise and was not different between treatment con- creased with propranolol in that study, whereas it was ditions. Epinephrine or norepinephrine did not differ unchanged in our study. We also found that atenolol between conditions at rest. Both epinephrine and nor- attenuated the decrease in PAI-1 activity, significantly epinephrine levels increased with exercise, but the affecting the overall fibrinolytic response to exercise. increase was greater during therapy with placebo and This reduction also corresponded to a lower level of propranolol than with atenolol. circulating catecholamines after exercise with atenolol BRIEF REPORTS
1399
than with placebo. Similar findings were reported by Held et al8 in a large sample of patients with coronary artery disease. Neither  blockade nor exercise significantly affected coagulation activation. The lack of an exerciseinduced effect is not surprising. Existing data suggest that long duration, high-intensity exercise is needed to produce appreciable increases in F 1 ⫹ 2.19 Thus, the exercise stimulus in the present study may not have been sufficient to produce significant increases in F 1 ⫹ 2. Because  blockade decreases mortality and cardiac events, it seems paradoxical that it would also decrease fibrinolytic potential. It is possible that the overall effect of  blockade on blood pressure and autonomic activity overrides the relatively small effect of decreased fibrinolytic activity. Furthermore, at this time it is not known if the changes in fibrinolytic potential with exercise in our study actually translates to increased risk for thrombotic events, but this warrants further investigation. In summary, we found that atenolol and propranolol attenuated the fibrinolytic response to exercise, but neither medication altered resting fibrinolytic potential. 1. Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic
activity, clotting factors, and long term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993;342:1076 –1079. 2. Hamsten A, DeFaire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987;4:3–9. 3. Kienast J, Thompson SG, Raskino C, Pelzer H, Fechtrup C, Ostermann H, van de Loo J. Prothrombin activation fragment 1⫹2 and thrombin antithrombin III complexes in patients with angina pectoris: relation to the presence and severity of coronary atherosclerosis. Thromb Haemost 1993;70:550 –553.
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4. Fernhall B, Szymanski LM, Gorman PA, Milani J, Paup DC, Kessler CM. Fibrinolytic activity is similar in physically active men with and without a history of myocardial infarction. Arterioscler Thromb Vasc Biol 1997;17:1106 –1113. 5. Fernhall B, Szymanski LM, Gorman PA, Milani J, Paup DC, Kessler CM. Fibrinolytic activity is not dependent upon exercise mode in post-myocardial infarction patients. Eur J Appl Physiol 1998;78:247–252. 6. Szymanski LM, Pate RR, Durstine JL. Effects of maximal exercise and venous occlusion on fibrinolytic activity in physically active and inactive men. J Appl Physiol 1994;77:2305–2310. 7. Szymanski LM, Pate RR. Fibrinolytic responses to moderate intensity exercise: comparison of physically active and inactive men. Arterscler Thromb 1994;14: 1746 –1750. 8. Held C, Hjemdahl P, Rehnqvist N, Wallen H, Bjorklander I, Eriksson SV, Forslund L, Wiman B. Fibrinolytic variables and cardiovascular prognosis in patients with stable angina pectoris treated with verapamil or metropolol. Circulation 1997;95:2380 –2386. 9. Beta-blocker Heart Attack Trial Research Group. A randomized trial of propanolol in patients with acute myocardial infarction. JAMA 1982;247:1707– 1713. 10. Johannessen KA, Nordrehaug JE, von der Lippe G. Increased occurrence of left ventricular thrombi during early treatment with timolol in patients with acute myocardial infarction. Circulation 1987;75:151–155. 11. El-Sayed MS. Extrinsic plasminogen activator response to exercise after a single dose of propanolol. Med Sci Sports Exerc 1992;24:327–332. 12. Dill BD, Costill D. Calculation of percentage changes in volumes of blood, plasma, and red cells in dehydration. J Appl Physiol 1974;37:247–248. 13. Schneider DA, Kamimori GH, Wu SY, McEniery MT, Solomon C. Plasma catecholamine and ventilatory responses to cycling after propranolol treatment. Med Sci Sports Exerc 1995;27:1616 –1620. 14. Teger-Nilsson AC, Larsson PT, Hjemdahl P, Olsson G. Fibrinogen and plasminogen activator inhibitor-1 levels in hypertension and coronary artery disease. Circulation 1991;84(suppl VI):VI-72–VI-77. 15. Larsson PT, Wiman B, Olsson G, Angelin B, Hjemdahl P. Influence of metoprolol treatment on sympatho-adrenal activation of fibrinolysis. Thromb Heamost 1990;63:482– 487. 16. Chandler WL, Levy WC, Stratton JR. The circulatory regulation of TPA and UPA secretion, clearance, and inhibition during exercise and during infusion of isoproterenol and phenylephedrine. Circulation 1995;92:2984 –2994. 17. Gader AM, DaCosta J, Cash JD. The effect of propanolol, alpenolol, and practolol on the fibrinolytic and factor VIII responses to adrenaline and salbutamol in man. Thromb Res 1974;4:25–33. 18. Schneider DA, McGuiggen ME, Kamimori GH. A comparison of the blood lactate and plasma catecholamine thresholds in untrained male subjects. Int J Sports Med 1992;13:563–566. 19. Weiss C, Seitel G, Bartsch P. Coagulation and fibrinolysis after moderate and very heavy exercise in healthy male subjects. Med Sci Sports Exerc 1998;30: 246 –251.
DECEMBER 15, 2000
Twelve healthy men volunteered to participate in the study (mean age 23.9 ⫾ 4.5 years, mean weight 86.2 ⫾ 11.7 kg; mean height 180 ⫾ 7.8 cm; mean body mass index 26.7 ⫾ 3.7). No subject reported any recent health problems, and none was taking any medication. Subjects were excluded if they had a history of diabetes, hypertension or hypotension, thrombotic disorders, hyperlipidemia, asthma, smoking, or any cardiovascular disorders. All subjects signed informed consent before participation and the study was approved by the University Medical Center Institutional Review Board. The subjects received propranolol (120 mg/day), atenolol (75 mg/day), or a placebo in a double-blind, From the Exercise Science Programs and The Division of Cardiology, The George Washington University Medical Center, Washington; the Department of Neurobiology and Behavior, Walter Reed Army Institute of Research, Washington; and the Division of Hematology-Oncology, Georgetown University Medical Center, Washington, DC. Dr. Fernhall’s address is: Exercise Science Department, Syracuse University, 820 Comstock Avenue, Room 201, Syracuse, New York 13244. Manuscript received January 17, 2000; revised manuscript received and accepted June 29, 2000.
1398
©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 December 15, 2000
MD,
randomized, crossover fashion. They received the medication for 3 days and were tested on day 3, 1 hour after taking the medication. Subjects reported to the laboratory in a fasted state (12 hours) between 7 and 9 A.M. to control for the influence of diurnal variations. After 1-hour supine rest, subjects were moved to a seated position for 5 minutes followed by measurements of resting heart rate and blood pressure. Subjects completed a maximal exercise test performed to volitional fatigue on an electronically braked cycle ergometer (SensorMedics, Yorba Linda, California) with oxygen uptake measurements (SensorMedics Vmax). Resting blood samples were obtained after 5 minutes of seated rest. Postexercise samples were obtained in a seated position within 1 minute of exercise termination. Blood was collected via venipuncture with minimal stasis from an antecubital vein. Tubes were immediately placed on ice and subsequently centrifuged at 2,600 g for 25 minutes. Plasma was aliquoted and stored at ⫺80°C until analyzed. Hematocrit and hemoglobin were measured using an automated cell counter (Baker System 9000 Series; Biochem Immunosystems, Allentown, Pennsylvania). Plasma volume changes were estimated from the hematocrit and hemoglobin values.12 Tissue plasminogen activator activity (t-PA) was determined by measuring the amidolytic activity of plasmin on a chromogenic substrate (S-2251) using commercially available kits (Coatest t-PA; Chromogenix, Mo¨lndal, Sweden). Plasminogen activator inhibitor (PAI-1) activity was determined by measuring the amidolytic activity of plasmin on a chromogenic substrate (S2403) performed in the presence of excess t-PA (Coatest PAI). t-PA and PAI-1 antigen levels were determined using commercially available enzyme-linked immunoassay kits (IMUBIND Total tPA, and IMUBIND PAI-1; American Diagnostica, Inc., Greenwich, Connecticut). Prothrombin fragment 1 ⫹ 2 (F 1 ⫹ 2) was measured using an enzyme-linked immunoassay (Thrombonostika F1.2, Organon Teknika, Durham, North Carolina). Epinephrine and norepinephrine were isolated using alumina extraction kits (Chromsystems, Munich, Germany) and high-performance liquid chromatography with electrochemical detection was used to determine their plasma concentration as described by Schneider et al.13 All samples from each subject were analyzed at one time to control for potential interassay variations. Descriptive statistics were calculated for all variables. A 3 ⫻ 2 (drug condition by rest and exercise) analysis of variance with repeated measures was used to evaluate t-PA and PAI-1 activities and antigens, 0002-9149/00/$–see front matter PII S0002-9149(00)01242-X
TABLE 1 Mean (⫾ SD) Resting and Maximal Cardiorespiratory, Hematologic, and Catecholamine Responses During Treatments
•••
This study demonstrates that neither selective (atenolol) nor nonseVariable Atenolol Propanolol Placebo lective (propranolol)  blockade significantly altered fibrinolytic activity Resting heart rate (beats/min) 53 ⫾ 5 55 ⫾ 11 62 ⫾ 12* Resting systolic blood pressure 110 ⫾ 12 114 ⫾ 11 120 ⫾ 14* at rest as measured by t-PA and (mm Hg) PAI-1 activity and antigen levels. Resting diastolic blood pressure 72 ⫾ 11 74 ⫾ 8 78 ⫾ 8* However, in response to maximal ex(mm Hg) † ercise, atenolol and propranolol atMaximal heart rate (beats/min) 139 ⫾ 14 127 ⫾ 11 186 ⫾ 13 Maximal systolic blood pressure 193 ⫾ 36 182 ⫾ 34 218 ⫾ 33† tenuated the fibrinolytic response, as (mm Hg) evidenced by a lesser increase in Maximal diastolic blood pressure 76 ⫾ 13 78 ⫾ 8 82 ⫾ 7* t-PA activity and a lesser reduction (mm Hg) in PAI-1 activity than responses with Maximal oxygen uptake 38.4 ⫾ 7 37.1 ⫾ 7 37.5 ⫾ 6 placebo. Activation of coagulation at (ml 䡠 kg⫺1 䡠 min⫺1) Resting t-PA activity (IU 䡠 ml⫺1) 1.9 ⫾ 0.5 2.0 ⫾ 0.6 1.9 ⫾ 0.5 rest and during exercise was unalMaximal t-PA activity (IU 䡠 ml⫺1) 6.3 ⫾ 2.5‡ 6.6 ⫾ 2.3‡ 8.0 ⫾ 2.5§ tered by  blockade in this study. To ⫺1 Resting t-PA antigen (ng 䡠 ml ) 6.8 ⫾ 1.7 6.6 ⫾ 1.7 6.3 ⫾ 1.4 our knowledge, the present study is ⫺1 ‡ ‡ ‡ Maximal t-PA antigen (ng 䡠 ml ) 16.6 ⫾ 6.1 15.8 ⫾ 5.3 17.2 ⫾ 7.8 the first to evaluate the various fiResting PAI-1 activity (AU 䡠 ml⫺1) 14.0 ⫾ 11 10.3 ⫾ 10.4 12.5 ⫾ 7.9 Maximal PAI-1 activity (AU 䡠 ml⫺1) 8.0 ⫾ 8.8‡ 6.8 ⫾ 7.9‡ 4.3 ⫾ 5.5§ brinolytic system components as Resting PAI-1 antigen (ng 䡠 ml⫺1) 44.7 ⫾ 26 44.4 ⫾ 20 42.4 ⫾ 20 well as coagulation activation during ⫺1 Maximal PAI-1 antigen (ng 䡠 ml ) 38.7 ⫾ 21 37.6 ⫾ 13 42.2 ⫾ 20 the interaction of  blockade and exResting F 1⫹ 2 (nM) 0.62 ⫾ 0.2 0.75 ⫾ 0.2 0.64 ⫾ 0.25 ercise. Maximal F 1⫹ 2 (nM) 0.55 ⫾ 0.1 2.7 ⫾ 5.7 0.59 ⫾ 0.2 Our findings are in agreement Resting epinephrine (pg 䡠 ml⫺1) 129 ⫾ 104 110 ⫾ 74 129 ⫾ 87 ⫺1 § ‡ Maximal epinephrine (pg 䡠 ml ) 172 ⫾ 77 287 ⫾ 113 200 ⫾ 101‡ with other investigators who have reResting norepinephrine (pg 䡠 ml⫺1) 565 ⫾ 152 681 ⫾ 361 668 ⫾ 377 ported no change in fibrinolytic variMaximal norepinephrine (pg 䡠 ml⫺1) 1,846 ⫾ 821§ 2,523 ⫾ 1,493‡ 2,348 ⫾ 942‡ ables at rest after nonselective  *Placebo significantly different from atenolol (p ⬍0.05). blockade.11 Teger-Nilsson et al14 † Placebo significantly different from both atenolol and propranolol (p ⬍0.05). suggested that fibrinolysis may be ‡ Significant change from rest (p ⬍0.05). controlled by 2 stimulation, espe§ Significant change from rest to exercise between placebo and both atenolol and propranolol (p cially under conditions of enhanced ⬍0.05). adrenergic stimulation, such as stress or catecholamine infusion. The restand F 1 ⫹ 2 levels before and after exercise. A Tukey ing conditions in our study cannot be described as post hoc analysis was used if statistical significance stressful. Furthermore, circulating catecholamine levwas found. The level of significance was set at p els did not differ among patients taking drugs in the resting state. Consequently, in the absence of adren⬍0.05. The results are displayed in Table 1. Heart rate and ergic stimulation,  blockade may not influence fibriblood pressure attained during maximal exercise were nolysis. Atenolol did not alter resting fibrinolytic acsignificantly lower during therapy with both atenolol tivity, which is in agreement with existing data.15 and propranolol compared with placebo. There was no The increase in fibrinolytic activity after a bout of difference in maximal oxygen consumption among physical exercise4 –7 is at least partially mediated by therapies. Beta blockade had no effect on t-PA activity adrenergic stimulation.14,16 Consequently, nonselecat rest. Exercise increased t-PA activity during all tive  blockade can significantly decrease the fibrinodrug conditions. The increase with exercise was lytic response to exercise,11 and the fibrinolytic regreater during placebo than during atenolol and pro- sponse to adrenaline infusions can be blocked by pranolol administration. There was no difference be- nonselective  blockade.17 Our data show that protween results with atenolol and propranolol. The t-PA pranolol reduced the exercise-induced increase in antigen levels were similar among all patients at rest, t-PA activity, and attenuated the exercise-induced reand increased with exercise in all conditions. The duction in PAI-1 activity. However, attenuation in PAI-1 activity was also similar during rest and de- fibrinolytic activity occurred without differences in creased with exercise in all treatment conditions. The circulating catecholamines after exercise during proexercise-induced decrease in PAI-1 activity was pranolol administration compared with placebo adgreater during placebo than during therapy with either ministration. Although catecholamines have been atenolol or propranolol. The PAI-1 antigen levels did shown to be elevated during exercise after propranolol not differ between testing at rest, and they did not administration,18 this may simply be related to relative change with exercise. The F 1 ⫹ 2 did not change with exercise intensity, because exercise capacity deexercise and was not different between treatment con- creased with propranolol in that study, whereas it was ditions. Epinephrine or norepinephrine did not differ unchanged in our study. We also found that atenolol between conditions at rest. Both epinephrine and nor- attenuated the decrease in PAI-1 activity, significantly epinephrine levels increased with exercise, but the affecting the overall fibrinolytic response to exercise. increase was greater during therapy with placebo and This reduction also corresponded to a lower level of propranolol than with atenolol. circulating catecholamines after exercise with atenolol BRIEF REPORTS
1399
than with placebo. Similar findings were reported by Held et al8 in a large sample of patients with coronary artery disease. Neither  blockade nor exercise significantly affected coagulation activation. The lack of an exerciseinduced effect is not surprising. Existing data suggest that long duration, high-intensity exercise is needed to produce appreciable increases in F 1 ⫹ 2.19 Thus, the exercise stimulus in the present study may not have been sufficient to produce significant increases in F 1 ⫹ 2. Because  blockade decreases mortality and cardiac events, it seems paradoxical that it would also decrease fibrinolytic potential. It is possible that the overall effect of  blockade on blood pressure and autonomic activity overrides the relatively small effect of decreased fibrinolytic activity. Furthermore, at this time it is not known if the changes in fibrinolytic potential with exercise in our study actually translates to increased risk for thrombotic events, but this warrants further investigation. In summary, we found that atenolol and propranolol attenuated the fibrinolytic response to exercise, but neither medication altered resting fibrinolytic potential. 1. Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic
activity, clotting factors, and long term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993;342:1076 –1079. 2. Hamsten A, DeFaire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987;4:3–9. 3. Kienast J, Thompson SG, Raskino C, Pelzer H, Fechtrup C, Ostermann H, van de Loo J. Prothrombin activation fragment 1⫹2 and thrombin antithrombin III complexes in patients with angina pectoris: relation to the presence and severity of coronary atherosclerosis. Thromb Haemost 1993;70:550 –553.
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