Protective
Effects of Propranolol on the
Exercise-Induced Reduction of Blood Flow in Arteriopathic Patients Gregorio Brevetti, M.D., F.I.C.A., Massimo Chiariello, M.D., Franco Rengo, M.D., Giuseppe Lavecchia, M.D., Giampaolo Paudice, M.D., and Mario Condorelli, M.D., F.I.C.A.
NAPLES,
ITALY
A bstract
The vascular steal
phenomenow, that is, the shunting of blood from ischemic to normally perfused areas, is commonly observed during exercise in the affected limbs of patients with peripheral arterial insufficiency. Propranolol was administered to 18 arteriopathic patients before the exercise to ascertain whether the reverse situation can be induced. The results indicate that before propranolol administration, Jantsch’s index (used to quantify the plethysmographic waves) decreased from 0.53 ~ 0.05 to 0.33 ~ 0.04 (P < 0.001 ) at 1 minute, and to 0.38 (P < 0.001) at 5 minutes after the end of the exercise. When the exercise repeated after propranolol, Jantsch’s index did not change. These findings
~ 0.04 was
indicate that
propranolol
can
inhibit exercise-induced vascular steal.
Introduction
hyperemia is commonly observed
in the limbs of normal subjects as a consequence of arteriolar dilation induced by vasoactive substances released by the tissue during exercise itself.’,’ However, in most patients with preripheral arterial insufficiency exercise induces a reduction in blood flow in the affected limb, which is indicated by a reduction in the amplitude of the oscillographic recordings.3~4 This reduction is probably the result of the socalled blood steal phenomenon, that is, the shunting of blood from ischemic areas, under maximal dilation induced by hypoxia, toward normally perfused zones where dilation is possible.5,6 It has been suggested that interventions that cause arterial constriction in normal areas could improve the blood flow to the ischemic areas.’ Actually, a reverse coronary steal induced by methoxamine, a vasoconstrictor agent, has been described.’ Similarly, we have demonstrated that propranolol inhibits the blood steal during the postischemic period in arteriopathic patients.’
Postexercise
From the Istituto di
Facolta’ a Patologia Speciale Medica, 2
Napoli, Naples, Italy.
696
di Medicina
e
Chirurgia, Universita’
di
697 Therefore this study was designed to determine whether the abnormal response induced by exercise in artheriopathic patients could be modified by the block of beta receptors induced by propranolol. Materials and Methods
Eighteen hospitalized patients with obliterative arteriopathy of the lower extremities were included in the study. The diagnosis was established beforehand on the basis of history, physical examination, impedance plethysmography, oscillographic recordings, and arteriography. The angiographic location of lesions, the walking distance, and other information on each patient are shown in Table 1. All of the patients demonstrated a reduction of blood supply to the affected limbs during physical exercise, as shown by impedance plethysmographic tracings. The age of the patients ranged from 48 to 63. During the 12 hours before the study, they where not allowed to consume any alcohol, tea, coffee, or tobacco. The test was performed in a quiet room at a constant temperature of 22 ~ 0.5°C. Electrical
’
impedance plethysmographic tracings TABLE I
Characteristics of Patients
were
recorded in the af-
698
fected limb by a C3B OTE Montedel plethysmograph, to derive a noninvasive index of blood flow. This plethysmographic method, described elsewhere,lO,l1 was chosen because by surface impedance electrodes the segmental volume conditions can be best defined without abnormal segmental compression, and without the crude air or watertight encasement always required for mechanical plethysmography. While the subjects lay in the supine position on a comfortable examination bed, a control tracing was recorded. Subsequently, an exercise test was performed on a bicycle ergometer until pain was felt in the limb. Then new plethysmographic tracings were recorded in the supine position 1 and 5 minutes after the end of the exercise. The entire study was repeated 60 minutes later, after the intravenous administration of 10 mg of propranolol (Beta-Neg, Ellem ), and the patients performed the same workload as they did under control condition. Each recording was made for 30 seconds, and in order to quantify changes of the plethysmographic waves, Jantsch’s index was calculated in five consecutive waves and then averaged. This index is as accurate as othersll for the quantification of the pulse volumes, as previously demonstrated by Jantsch himself.12 It is calculated according to the following formula:
where A represents the amplitude in millimeters of the plethysmographic wave, Ew is a correcting factor expressed in Ohms to reduce the resistance of the explored segment, Ez is the height in millimeters of the calibration, and R is the resistance in Ohms of the segment. A and Ez are measured from the tracing, while Ew and R are obtained from the plethymsographic device. The value of Jantsch’s index remains constant for at least 40 minutes both in normal subjects and in arteriopathic patients, as previously demonstrated.’ Furthermore, to assess the reproducibility of the method, in 5 patients plethysmographic recordings were made and Jantsch’s index was calculated after the completion of three exercises performed at 30-minute interval. Arterial blood pressure (AP) was determined by cuff recordings, and the mean arterial pressure (MAP) was estimated. The heart rate (HR) was measured from the ECG tracings. Statistical analysis was performed by standard techniques.&dquo;
R results Under control conditions, the exercise significantly reduced Jantsch’s index in all of the examinated subjects. This index, which was 0.53 rb 0.05 before exercise, was reduced to 0.33 =b 0.04 (P < 0.001) at 1 minute and to 0.38 ~ 0.04 (P < 0.001 ) at 5 minutes after the end of the exercise (Figure 1). Meanwhile, HR increased significantly 1 and 5 minutes after the end of the
699 TABLE 2 Mean Arterial Pressure
(MAP) and Heart Rate (HR) Before and After Propranolol Administration
Arteriopathic
All
measurements are
postexercise
recorded
as
to
Patients
mean ± SEM. Statistical
analysis
was
performed betw,een
basal and
values.
MAP was significantly higher 1 minute after exercise, although it returned to the control value in 5 minutes (Table 2). Propranolol administration did not induce changes in the rest values of Jantsch’s index. However, this drug did abolish completely the abnormal response to exercise of the plethysmographic index, which was no longer reduced after bicycle stress. Actually, Jantsch’s index did not change after exercise and was 0.46 ~ 0.06 and 0.50 ~ 0.07 after 1 and 5 minutes respectively. These values did not differ significantly from what measured at rest after propranolol (0.47 ~ 0.05) (Figure 1 ). Table 3 indicates the values of Jantsch’s index in basal condition and during the postexercise period, before and after propranolol, for
exercise (Table 2).
Similarly,
individual
arteriopathic patients. Simultaneously, after betablock, HR and MAP were significantly higher only 1 minute after the exercise, while at 5 minutes no difference from rest values was observed (Table 2). The results of the reproducibility tests are reported in Table 4.
FIG. 1. Changes in Jantsch’s index before and after propranolol administration at 1 and 5 minutes after the end of the exercise. Asterisk: Different from the basal value (B). P < 0.001.
700 TABLE 3
JantsLh’s Index
Statistical analysis end of the exercise.
was
Before and After Propranolol Administration
performed between the
to
values obtained at rest
Arteriopathic
(B) and I and
Patients
5 minutes after the
Discussion In most patients affected by atherosclerotic peripheral vascular disease, the pressure in the muscle arterioles and collaterals of the affected limb is low, and when the perfusion pressure in the ischemic area falls below a critical level, the
intra-arteriolar pressure may be surpassed by the surrounding tissue pressure.14 The consequence of this is a passive compression of the arterioles with a further reduction in the muscular blood flow.15 This is probably the mechanism operTABLE 4
Changes
in Jantsch’s Index
After the Completion of Three
Reproducibility of the method. Changes in Jantsch’s index at rest exercise I and 5 minutes after the end of the exercise.
Consecutive Exercises
(B) and after the repetition of the
701
ating when blood flow decreases in patients with arterial occlusion while walking. In fact, as is well known, exercise induces a vasodilation in the nonischemic of the affected limb, and thus diverts blood from the ischemic tissue under maximal metabolic dilation.’,’ This borrowing-lending effect lowers the local blood pressure in the ischemic zone, allowing the collapse of the arterioles which determines a further decrease in blood flow. Therefore the blood steal phenomenon can be considered at least partially responsible for the claudication on effort in patients with limited circulatory capacity. The results of our investigation indicate that propranolol can prevent vascular steal in arteriopathic patients, as shown by the inhibition of the reduction in Jantsch’s index during the control exercise. This protective effect of propranolol was observed only during effort, since Jantsch’s index at rest was not affected by beta-receptor blockade. It should be noted that the beneficial effect of propranolol on the plethysmographic wave after exercise had its clinical equivalent in the complete abolition of the claudication during exercise induced by propranolol in all but 1 patient. The data produced by this study do not allow a definite explanation for the effect of the beta blockade on the exercise-induced ischemia. However, on the basis of previous studies,7,9 an hypothesis can be suggested. The blockade of beta receptors by propranolol favors, in the normal areas, a constriction of the arteriovenous connections due to the overwhelming action of alpha receptors. Therefore, before propranolol administration and after exercise, the amount of blood that was shunted through these connections away from the affected areas is at least partially forced to the post-stenotic area through collateral channels. In fact, the increase in vascular resistance in normal zones raises the pressure gradient between the normal and the affected areas, and therefore may increase the flow through open collateral channels. This hypothesis seems to be confirmed by studies showing that the greater the pressure gradient, the more rapid the collateral dilation, and that the dilation gradually declines as the gradient is reduced.’s-18 In contrast with the results indicating that beta blockers may be beneficial in arteriopathic patients, others reported previously that chronic treatment of these patients with propranolol resulted in increased evidence of peripheral arterial insufficiency.&dquo; They ascribed this deleterious effect to the propranololinduced inhibition of the beta-adrenergically-mediated vasodilation, and thus to the prevalence of the alpha-adrenergic-mediated vasoconstriction. It seems probable that these unfavorable results are related to the hemodynamic effects induced by chronic treatment with propranolol, in particular to its action of reducing blood pressure and thus perfusion pressure. In contrast, in our patients the systemic blood pressure was not modified by the acute administration of the drug. However, it should be emphasized that the aim of this study was not to areas
702
suggest that peripheral arterial insufficiency should be treated by chronic beta blockade. But the demonstration of the beneficial effects of propranolol in exercise-induced peripheral ischemia in arteriopathic patients suggests that a drug that has the same characteristics as propranolol on the arteriovenous connections, but without the undesirable side effects of beta-blocking agents, may represent a new approach to the treatment of peripheral arterial diseases.
Gregorio Brevetti, M.D., F.I.C.A. Istituto di Patologia Medica a Facoltà di Medicina e Chirurgia 2 Università di Napoli Via Sergio Pansini 5 80131 Naples, Italy
References 1.Haddy, F. J., Scott, J. B.: Bioassay and other evidence for partecipation of chemical factors in local regulation of blood flow. Circ. Res. 28: 86, 1971 (Suppl. 1 ). 2. Berne, R. M., Rubio, R., Dobson, J. G., et al.: Adenosine and adenine nucleotides as possible mediators of cardiac and skeletal muscle blood flow. Circ. Res. 28: 115, 1971. Suppl. 1. 3. Leary, W. V., Allen, E. V.: Intermittent claudication as a result of arterial spasm induced by walking. Am. Heart J., 22: 719, 1941. 4. Lindquist, T.: Intermittent claudication and vascular spasm. II. Can intermittent claudication be due to vascular spasm without accompanying structural disease of the arteries? Acta Med. Scand., 121: 32, 1945. 5. Winsor, T., Hyman, C., Payne, J. H.: Exercise and limb circulation in health and disease. Arch. Surg., 78: 184, 1959. 6. Zetterquist, S.: Muscle and skin clearance of antipyrine from exercising ischemic legs before and after vasodilating trials. Acta Med. Scand., 183: 487, 1968. 7. Lichtlen, P.: Coronary and left ventricular dynamics under nifedipine in comparison to nitrates, beta-blocking agents and dipyridamole. Second International Adalat Sym-
posium. Berlin-Heidelberg-New York, Springer-Verlag, 1975. 8. Chiariello, M., Ribeiro, L. G. T., Davis, M. A., et al.: "Reverse coronary steal" induced by coronary vasoconstriction following coronary artery occlusion in dogs. Circulation, 56: 809, 1977. 9. Brevetti, G., Rengo, F., Chiariello, M., et al.: Reduction of blood flow following ischemia
in
10.
arteriopathic patients:
Reversion of the
phenomenon induced by propranolol. Angiology,:2 687, 1977. 8 Nyober, J.: Electrical Impedance Plethysmography. Ed. 2. Springfield, IL, Charles C Thomas, 1970.
11.
12.
13. 14.
15.
16.
17.
J. A.: Blood-flow indices in amputee and control limbs by mutual electrical impedance plethysmography. Am. Heart J., 87: 704, 1974. Jantsch, M.: Zur Auswezjung des peripheren Rheogramms. Wien. Med. Wochenschr., 45: 1004,1958. Snedecor, G. W., Cochran, W. G.: Statistical Methods. Ames, Iowa University Press, 1967. Wezler, K.: Die Funktion der peripheren Strohmbahngebiete. Regensburg. JB. Ärztl. Fortbild., II/X: 462, 1954. Ashton, H.: Critical closing pressure in human peripheral vascular beds. Clin. Sci., 22: 79, 1962. Eckstein, R. W., Gregg, D. E., Pritchard, W. H.: The magnitude and time of development of the collateral circulation in occluded femoral, carotid and coronary arteries. Am. J. Physiol., 132: 351, 1941. John, H. T., Warren, R.: The stimulus to collateral circulation. Surgery, 59: 14, 1961.
Nyober J., Murray, P., Sedensky,
18. Winblad, J. N., Reemtsma, K., Vernhet, J., et al.: Etiologic mechanisms in the development of collateral circulation. Surgery, 45: 105, 1959. 19. Frohlich, E. D., Tarazi, R. C., Dustan, H. P.: Peripheral arterial insufficiency. A complication of beta-adrenergic blocking therapy. JAMA, 208: 2471, 1969.
Effects of Propranolol on the
Exercise-Induced Reduction of Blood Flow in Arteriopathic Patients Gregorio Brevetti, M.D., F.I.C.A., Massimo Chiariello, M.D., Franco Rengo, M.D., Giuseppe Lavecchia, M.D., Giampaolo Paudice, M.D., and Mario Condorelli, M.D., F.I.C.A.
NAPLES,
ITALY
A bstract
The vascular steal
phenomenow, that is, the shunting of blood from ischemic to normally perfused areas, is commonly observed during exercise in the affected limbs of patients with peripheral arterial insufficiency. Propranolol was administered to 18 arteriopathic patients before the exercise to ascertain whether the reverse situation can be induced. The results indicate that before propranolol administration, Jantsch’s index (used to quantify the plethysmographic waves) decreased from 0.53 ~ 0.05 to 0.33 ~ 0.04 (P < 0.001 ) at 1 minute, and to 0.38 (P < 0.001) at 5 minutes after the end of the exercise. When the exercise repeated after propranolol, Jantsch’s index did not change. These findings
~ 0.04 was
indicate that
propranolol
can
inhibit exercise-induced vascular steal.
Introduction
hyperemia is commonly observed
in the limbs of normal subjects as a consequence of arteriolar dilation induced by vasoactive substances released by the tissue during exercise itself.’,’ However, in most patients with preripheral arterial insufficiency exercise induces a reduction in blood flow in the affected limb, which is indicated by a reduction in the amplitude of the oscillographic recordings.3~4 This reduction is probably the result of the socalled blood steal phenomenon, that is, the shunting of blood from ischemic areas, under maximal dilation induced by hypoxia, toward normally perfused zones where dilation is possible.5,6 It has been suggested that interventions that cause arterial constriction in normal areas could improve the blood flow to the ischemic areas.’ Actually, a reverse coronary steal induced by methoxamine, a vasoconstrictor agent, has been described.’ Similarly, we have demonstrated that propranolol inhibits the blood steal during the postischemic period in arteriopathic patients.’
Postexercise
From the Istituto di
Facolta’ a Patologia Speciale Medica, 2
Napoli, Naples, Italy.
696
di Medicina
e
Chirurgia, Universita’
di
697 Therefore this study was designed to determine whether the abnormal response induced by exercise in artheriopathic patients could be modified by the block of beta receptors induced by propranolol. Materials and Methods
Eighteen hospitalized patients with obliterative arteriopathy of the lower extremities were included in the study. The diagnosis was established beforehand on the basis of history, physical examination, impedance plethysmography, oscillographic recordings, and arteriography. The angiographic location of lesions, the walking distance, and other information on each patient are shown in Table 1. All of the patients demonstrated a reduction of blood supply to the affected limbs during physical exercise, as shown by impedance plethysmographic tracings. The age of the patients ranged from 48 to 63. During the 12 hours before the study, they where not allowed to consume any alcohol, tea, coffee, or tobacco. The test was performed in a quiet room at a constant temperature of 22 ~ 0.5°C. Electrical
’
impedance plethysmographic tracings TABLE I
Characteristics of Patients
were
recorded in the af-
698
fected limb by a C3B OTE Montedel plethysmograph, to derive a noninvasive index of blood flow. This plethysmographic method, described elsewhere,lO,l1 was chosen because by surface impedance electrodes the segmental volume conditions can be best defined without abnormal segmental compression, and without the crude air or watertight encasement always required for mechanical plethysmography. While the subjects lay in the supine position on a comfortable examination bed, a control tracing was recorded. Subsequently, an exercise test was performed on a bicycle ergometer until pain was felt in the limb. Then new plethysmographic tracings were recorded in the supine position 1 and 5 minutes after the end of the exercise. The entire study was repeated 60 minutes later, after the intravenous administration of 10 mg of propranolol (Beta-Neg, Ellem ), and the patients performed the same workload as they did under control condition. Each recording was made for 30 seconds, and in order to quantify changes of the plethysmographic waves, Jantsch’s index was calculated in five consecutive waves and then averaged. This index is as accurate as othersll for the quantification of the pulse volumes, as previously demonstrated by Jantsch himself.12 It is calculated according to the following formula:
where A represents the amplitude in millimeters of the plethysmographic wave, Ew is a correcting factor expressed in Ohms to reduce the resistance of the explored segment, Ez is the height in millimeters of the calibration, and R is the resistance in Ohms of the segment. A and Ez are measured from the tracing, while Ew and R are obtained from the plethymsographic device. The value of Jantsch’s index remains constant for at least 40 minutes both in normal subjects and in arteriopathic patients, as previously demonstrated.’ Furthermore, to assess the reproducibility of the method, in 5 patients plethysmographic recordings were made and Jantsch’s index was calculated after the completion of three exercises performed at 30-minute interval. Arterial blood pressure (AP) was determined by cuff recordings, and the mean arterial pressure (MAP) was estimated. The heart rate (HR) was measured from the ECG tracings. Statistical analysis was performed by standard techniques.&dquo;
R results Under control conditions, the exercise significantly reduced Jantsch’s index in all of the examinated subjects. This index, which was 0.53 rb 0.05 before exercise, was reduced to 0.33 =b 0.04 (P < 0.001) at 1 minute and to 0.38 ~ 0.04 (P < 0.001 ) at 5 minutes after the end of the exercise (Figure 1). Meanwhile, HR increased significantly 1 and 5 minutes after the end of the
699 TABLE 2 Mean Arterial Pressure
(MAP) and Heart Rate (HR) Before and After Propranolol Administration
Arteriopathic
All
measurements are
postexercise
recorded
as
to
Patients
mean ± SEM. Statistical
analysis
was
performed betw,een
basal and
values.
MAP was significantly higher 1 minute after exercise, although it returned to the control value in 5 minutes (Table 2). Propranolol administration did not induce changes in the rest values of Jantsch’s index. However, this drug did abolish completely the abnormal response to exercise of the plethysmographic index, which was no longer reduced after bicycle stress. Actually, Jantsch’s index did not change after exercise and was 0.46 ~ 0.06 and 0.50 ~ 0.07 after 1 and 5 minutes respectively. These values did not differ significantly from what measured at rest after propranolol (0.47 ~ 0.05) (Figure 1 ). Table 3 indicates the values of Jantsch’s index in basal condition and during the postexercise period, before and after propranolol, for
exercise (Table 2).
Similarly,
individual
arteriopathic patients. Simultaneously, after betablock, HR and MAP were significantly higher only 1 minute after the exercise, while at 5 minutes no difference from rest values was observed (Table 2). The results of the reproducibility tests are reported in Table 4.
FIG. 1. Changes in Jantsch’s index before and after propranolol administration at 1 and 5 minutes after the end of the exercise. Asterisk: Different from the basal value (B). P < 0.001.
700 TABLE 3
JantsLh’s Index
Statistical analysis end of the exercise.
was
Before and After Propranolol Administration
performed between the
to
values obtained at rest
Arteriopathic
(B) and I and
Patients
5 minutes after the
Discussion In most patients affected by atherosclerotic peripheral vascular disease, the pressure in the muscle arterioles and collaterals of the affected limb is low, and when the perfusion pressure in the ischemic area falls below a critical level, the
intra-arteriolar pressure may be surpassed by the surrounding tissue pressure.14 The consequence of this is a passive compression of the arterioles with a further reduction in the muscular blood flow.15 This is probably the mechanism operTABLE 4
Changes
in Jantsch’s Index
After the Completion of Three
Reproducibility of the method. Changes in Jantsch’s index at rest exercise I and 5 minutes after the end of the exercise.
Consecutive Exercises
(B) and after the repetition of the
701
ating when blood flow decreases in patients with arterial occlusion while walking. In fact, as is well known, exercise induces a vasodilation in the nonischemic of the affected limb, and thus diverts blood from the ischemic tissue under maximal metabolic dilation.’,’ This borrowing-lending effect lowers the local blood pressure in the ischemic zone, allowing the collapse of the arterioles which determines a further decrease in blood flow. Therefore the blood steal phenomenon can be considered at least partially responsible for the claudication on effort in patients with limited circulatory capacity. The results of our investigation indicate that propranolol can prevent vascular steal in arteriopathic patients, as shown by the inhibition of the reduction in Jantsch’s index during the control exercise. This protective effect of propranolol was observed only during effort, since Jantsch’s index at rest was not affected by beta-receptor blockade. It should be noted that the beneficial effect of propranolol on the plethysmographic wave after exercise had its clinical equivalent in the complete abolition of the claudication during exercise induced by propranolol in all but 1 patient. The data produced by this study do not allow a definite explanation for the effect of the beta blockade on the exercise-induced ischemia. However, on the basis of previous studies,7,9 an hypothesis can be suggested. The blockade of beta receptors by propranolol favors, in the normal areas, a constriction of the arteriovenous connections due to the overwhelming action of alpha receptors. Therefore, before propranolol administration and after exercise, the amount of blood that was shunted through these connections away from the affected areas is at least partially forced to the post-stenotic area through collateral channels. In fact, the increase in vascular resistance in normal zones raises the pressure gradient between the normal and the affected areas, and therefore may increase the flow through open collateral channels. This hypothesis seems to be confirmed by studies showing that the greater the pressure gradient, the more rapid the collateral dilation, and that the dilation gradually declines as the gradient is reduced.’s-18 In contrast with the results indicating that beta blockers may be beneficial in arteriopathic patients, others reported previously that chronic treatment of these patients with propranolol resulted in increased evidence of peripheral arterial insufficiency.&dquo; They ascribed this deleterious effect to the propranololinduced inhibition of the beta-adrenergically-mediated vasodilation, and thus to the prevalence of the alpha-adrenergic-mediated vasoconstriction. It seems probable that these unfavorable results are related to the hemodynamic effects induced by chronic treatment with propranolol, in particular to its action of reducing blood pressure and thus perfusion pressure. In contrast, in our patients the systemic blood pressure was not modified by the acute administration of the drug. However, it should be emphasized that the aim of this study was not to areas
702
suggest that peripheral arterial insufficiency should be treated by chronic beta blockade. But the demonstration of the beneficial effects of propranolol in exercise-induced peripheral ischemia in arteriopathic patients suggests that a drug that has the same characteristics as propranolol on the arteriovenous connections, but without the undesirable side effects of beta-blocking agents, may represent a new approach to the treatment of peripheral arterial diseases.
Gregorio Brevetti, M.D., F.I.C.A. Istituto di Patologia Medica a Facoltà di Medicina e Chirurgia 2 Università di Napoli Via Sergio Pansini 5 80131 Naples, Italy
References 1.Haddy, F. J., Scott, J. B.: Bioassay and other evidence for partecipation of chemical factors in local regulation of blood flow. Circ. Res. 28: 86, 1971 (Suppl. 1 ). 2. Berne, R. M., Rubio, R., Dobson, J. G., et al.: Adenosine and adenine nucleotides as possible mediators of cardiac and skeletal muscle blood flow. Circ. Res. 28: 115, 1971. Suppl. 1. 3. Leary, W. V., Allen, E. V.: Intermittent claudication as a result of arterial spasm induced by walking. Am. Heart J., 22: 719, 1941. 4. Lindquist, T.: Intermittent claudication and vascular spasm. II. Can intermittent claudication be due to vascular spasm without accompanying structural disease of the arteries? Acta Med. Scand., 121: 32, 1945. 5. Winsor, T., Hyman, C., Payne, J. H.: Exercise and limb circulation in health and disease. Arch. Surg., 78: 184, 1959. 6. Zetterquist, S.: Muscle and skin clearance of antipyrine from exercising ischemic legs before and after vasodilating trials. Acta Med. Scand., 183: 487, 1968. 7. Lichtlen, P.: Coronary and left ventricular dynamics under nifedipine in comparison to nitrates, beta-blocking agents and dipyridamole. Second International Adalat Sym-
posium. Berlin-Heidelberg-New York, Springer-Verlag, 1975. 8. Chiariello, M., Ribeiro, L. G. T., Davis, M. A., et al.: "Reverse coronary steal" induced by coronary vasoconstriction following coronary artery occlusion in dogs. Circulation, 56: 809, 1977. 9. Brevetti, G., Rengo, F., Chiariello, M., et al.: Reduction of blood flow following ischemia
in
10.
arteriopathic patients:
Reversion of the
phenomenon induced by propranolol. Angiology,:2 687, 1977. 8 Nyober, J.: Electrical Impedance Plethysmography. Ed. 2. Springfield, IL, Charles C Thomas, 1970.
11.
12.
13. 14.
15.
16.
17.
J. A.: Blood-flow indices in amputee and control limbs by mutual electrical impedance plethysmography. Am. Heart J., 87: 704, 1974. Jantsch, M.: Zur Auswezjung des peripheren Rheogramms. Wien. Med. Wochenschr., 45: 1004,1958. Snedecor, G. W., Cochran, W. G.: Statistical Methods. Ames, Iowa University Press, 1967. Wezler, K.: Die Funktion der peripheren Strohmbahngebiete. Regensburg. JB. Ärztl. Fortbild., II/X: 462, 1954. Ashton, H.: Critical closing pressure in human peripheral vascular beds. Clin. Sci., 22: 79, 1962. Eckstein, R. W., Gregg, D. E., Pritchard, W. H.: The magnitude and time of development of the collateral circulation in occluded femoral, carotid and coronary arteries. Am. J. Physiol., 132: 351, 1941. John, H. T., Warren, R.: The stimulus to collateral circulation. Surgery, 59: 14, 1961.
Nyober J., Murray, P., Sedensky,
18. Winblad, J. N., Reemtsma, K., Vernhet, J., et al.: Etiologic mechanisms in the development of collateral circulation. Surgery, 45: 105, 1959. 19. Frohlich, E. D., Tarazi, R. C., Dustan, H. P.: Peripheral arterial insufficiency. A complication of beta-adrenergic blocking therapy. JAMA, 208: 2471, 1969.
