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Pulmonary hypertensive effects of bretylium tosylate in the dog
Pulmonary hypertensive effects of bretylium tosylate
in the dog
Charles J. McGaff, M.D.* Leonard Leight, M.D. Louisville, Ky.
B
retylium tosylate is a new hypotensive agent which inhibits the peripheral sympathetic nervous system and has little effect upon the ganglia. Since this compound was introduced in 1959, by Boura and his associates,l it has been shown to elevate the pulmonary arteriolar resistance of man2 and the total pulmonary vascular resistance of sheep .3 This report describes the pulmonary vascular effects of this drug in dogs. Methods
Fifteen fasting mongrel dogs were anesthetized with intravenous pentobarbital (28 mg. per kilogram). Cardiac catheters were inserted into the main pulmonary artery, pulmonary capillary wedge position, and femoral artery. The positions of the catheters were verified by fluoroscopy, pressures, and autopsy. A small polyethylene catheter (PE-SO) was placed in the left atrium by transbronchial left atria1 puncture. Respiration was maintained by positive pressure, and airway pressure was measured by needle puncture of the respirator tubing. Pressures were measured by strain-gauge transducers, and mean pressures were obtained by electronic integration. Zero level for pressures was Fran
one half of the anteroposterior diameter of the thorax in the supine position. Cardiac output was determined by the indicator-dilution method, using indocyanine green. Blood was sampled at a constant speed from the femoral artery through a Gilford densitometer which was calibrated by the pooled-sample method of McNeely and Gravallese.4 Because of electronic malfunction the Fick principle was used to calculate flow in one animal. Oxygen content of samples of femoral arterial blood was determined in the Van Slyke manometric apparatus. The pressures and dilution curves were recorded by a direct-writing Sanborn oscillograph. Pulmonary blood volume was calculated by the method of Milnor, Jose, and McGaff5j6 and was taken to be the difference between the dilution volumes calculated from rapidly consecutive injections of indicator into the pulmonary artery and left atrium. Thirty duplicate measurements of control pulmonary blood volumes in dogs yielded a standard deviation of 10.9 ml. per 10 Kg. and a standard error of the mean of 2.0 ml. per 10 Kg.6 Control observations of pressures, flow, and volumes were made in duplicate 5 minutes apart. Bretylium tosylatet was
the Department of Medicine and Cardiac Catheterization Laboratory, University of Louisville School of Medicine, Louisville, KY. Supported by Research Grant H-5419 from the United States Public Health Service. Presentedin part at the Annual Scientific Session, American Heart Association, Miami, Fla., October, 1961 Received for cubEcation Tune 11. 1962. *John and Mary R. Markle Scholar in Medical Science. tKindly furn&hed as Darenthin by Burroughs Wellcome 81 Co. (U.S..%) Inc., Tuckahoe, N, Y.
240
Pulmonary
241
hypertensive efects of bretylium tosylate in dog
then given intravenously by a slow infusion to 2 animals and as a 2-minute injection to the other 13. The dose was SO mg. per kilogram in 13 dogs. One animal was given 20 mg. per kilogram, and another was given 150 mg. per kilogram. Although these dosages are higher than those used by other investigators, they were used since they yielded the observed effects. Observations were again repeated in duplicate after an average interval of 45 minutes after administration of the drug. Nine paired measurements of pulmonary blood volume were made before and after the injection of bretylium in 6 dogs. In 4 dogs the spleen was removed before the control observations were made. Three animals were ventilated with 100 per cent oxygen after the effects of bretylium had been studied, and all measurements were again repeated in duplicate. Pulmonary vascular resistance was calculated by dividing the difference between mean pulmonary arterial and left atria1 pressures
by the cardiac output per 10 kilograms of dog and was expressed as resistance units (R.U./lO Kg.). Pulmonary arteriolar resistance was obtained by subtracting mean pulmonary capillary wedge pressure from the mean pulmonary arterial pressure and dividing by the cardiac output per 10 kilograms of dog. Systemic resistance was obtained by dividing mean femoral arterial pressure by the cardiac output per 10 kilograms. Results
The number of observations and the changes in paired measurements before and after the bretylium are shown in Table I. There was no difference between the results obtained from infusion and those from injection of the bretylium. The cardiac output and pulmonary blood volume did not change significantly. There was a significant decrease in heart rate and a significant increase in hematocrit. In the 4 splenectomized animals the hematocrit
Table I Number of Papameter
paired observaGons
Bretylium
26
1.428
1,412
-1
9
130
155
+19
Heart rate (beats/min.)
24
169
1.55
-8
Hematocrit (per cent)
17
47
51
+g
8
94.7
92.7
-2
28 29 18 27 3
117 11.9 5.6 4.0 4.5
140 17.0 5.3 3.3 4.3
+19 i-43 -5 -18 -4
26 16 2.5
7.2 7.7 110
13.4 13.1 1.54
+86 +70 +40
Cardiac output (L./min./l0 Pulmonary (ml./10
Oxygen (per
Kg.)
blood Kg.)
Per cent change
.%gn$can~ chunge (p value)
Conho
volume
saturation cent)
Mean pressure (mm. Femoral artery Pulmonary artery Pulmonary “wedge” Left atrium Airway
Hg)
Resistance Pulmonary Pulmonary Systemic
Kg.)
(R.U./lO vascular arteriohr vascular
242
McGaf
and Leight
Fig. 1. Change in mean pressure artery (ATPA) and left atrium (AFL*) tration of bretylium. The pulmonary pressure (w&&e) rose significantly paired observations. Left atria1 (ukkz) did not change significantly.
in pulmonary after adminisarterial mean in all but 5 mean pressure
did not change. There was no significant deviation in the arterial oxygen saturation. The pulmonary (Fig. 1) and femoral arterial mean pressures rose significantly, but the left atria1 (Fig. l), pulmonary capillary, and airway pressures did not change predictably. Thus, there was a significant elevation in calculated total pulmonary vascular, pulmonary arteriolar, and systemic vascular resistances. The administration of 100 per cent oxygen had no effect on the bretylium-induced elevation in pulmonary vascular resistance in the 3 animals studied. Discussion
In man, Taylor and Donald2 demonstrated that bretylium causes a rise in pulmonary arterial pressure and pulmonary arteriolar resistance. Halmagyi and Colebatch3 described increased total pulmonary vascular resistance in sheep. This study extends these observations to the dog and shows the same effects on the pulmonary vasculature. Pulmonary capillary pressure
was measured in 2 sheep by Hallnag) and was found to rise after administration of the drug. Whether this represented pulmonary venous consQiction or a rise in pressure in the left side of the heart is unknown. It is clear, however, that in man and in the dogs reported on here the elevation in pulmonary arterial pressure is the result of increased resistance to blood flow at the level of small vessels, presumably the arterioles. The lack of significant change in pulmonary blood volume is consonant with this hypothesis and against constriction of most of the vascular bed, such as may be seen when serotonin elevates pulmonary vascular resistance and reduces the pulmonary blood volume.6 The possibility exists that constriction of the pulmonary arteries and dilation of the pulmonary veins would decrease and increase pulmonary blood volume, respectively, and the volume of blood measured by this method would not change. This possibility cannot be ascertained by the method used. Gaffney’ has suggested that bretylium depletes the heart of catecholamines, yet Boural maintains that it has no influence on the catecholamine content of the adrenals or the sympathetic ganglia. It is possible that some of the effects which were observed were due to release of catecholamines into the circulation, as several authors have suggested.8,g The rise in systemic arterial pressure is probably due to the elevated level of catecholamines, and the slowing of the heart rate can be attributed to a reflex vagal effect that results from stimulation of the carotid sinus by the increased pressure. This was not studied in these experiments. The dog’s spleen is known to contract with sympathetic stimulation, and the rise in hematocrit with the spleen in place and the lack of any change in hematocrit in the splenectomized animals implicates the spleen as the source of this additional red cell mass. It is important to note that the elevated pulmonary resistance was not due alone to increased blood viscosity secondary to the elevated hematocrit, for in the splenectomized animals with no change in hematocrit a significant rise in resistance was still found after the bretylium had been given. The lack of any change in arterial oxygen
Pulmonary
hypertensive ej’ects of bretylium
saturation or airway pressure is good evidence that the observed changes were not secondary to anosia or bronchospasm. The exact mechanism whereby bretylium elevates the pulmonary arterial pressure and resistance remains obscure, but it seems to be a localized effect, at arteriolar level, and affects man, dogs, and possibly sheep. Further observations on other species with more reactive pulmonary vessels will be of interest.
A sympathetic-blocking agent, bretylium tosylate, was given intravenously in large dosage to 15 anesthetized mongrel dogs with closed chests. This drug caused a significant increase in mean pulmonary arterial pressure, total pulmonary vascular resistance, and pulmonary arteri,olar resistance. Pulmonary blood volume did not change significantly. These changes are compatible with constriction of a small segment of the pulmonary vascular bed, such as the arterioles. REFERENCES Boura, A. L. A., Green, A. F., McCoubrey, Laurence, D. R., Moulton, R., and Rosenheim,
3.
A.,
M. L.: Darenthin: hypotensive agent tvpe, Lancet 1:17,1959. Taylor, S. H., and Donald, K. W.: The latory effects of bretylium tosylate and thidine, Lancet 2:389, 1960. Halmagyi, D. F. J., and Colebatch, H. Effect of bretylium tosylate (Darenthin) pulmonary circulation, Circulation Res.
1961. 4. McNeely,
5.
Summary
1.
2.
6.
7.
8.
9.
tosylate in dog
243
of new circuguaneJ. H.: on 9:136,
W. F., and Gravallese, M. A.: Measurement of cardiac output by dye-dilution technique: use of an “integrated” sample collection in calibration of the photometric instrument, J. Appl. Physiol. 755, 1954. Milnor, W. R., Jose, A. D., and McGaff, C. J.: Pulmonary vascular volume, resistance and compliance in man, Circulation 22:130, 1960. McGaff, C. J., and Milnor, W. R.: Effects of serotonin on pulmonary blood volume in the dog, Am. J. Physiol. 202:957, 1962, Gaffney, T. E.: Effect of guanethidine and bretylium on the dog heart-lung preparation, Circulation Res. 9:83, 1961. Yelnosky, J., and Mortimer, L. C.: Brief study of the sympathomimetic cardiovascular effects of bretylium, Arch. internat. pharmacodyn. 130:200, 1961. Gilmore, J. P., and Siegel, J. A.: Mechanism of the myocardial effects of bretylium, Circulation Res. 10:347, 1962.
in the dog
Charles J. McGaff, M.D.* Leonard Leight, M.D. Louisville, Ky.
B
retylium tosylate is a new hypotensive agent which inhibits the peripheral sympathetic nervous system and has little effect upon the ganglia. Since this compound was introduced in 1959, by Boura and his associates,l it has been shown to elevate the pulmonary arteriolar resistance of man2 and the total pulmonary vascular resistance of sheep .3 This report describes the pulmonary vascular effects of this drug in dogs. Methods
Fifteen fasting mongrel dogs were anesthetized with intravenous pentobarbital (28 mg. per kilogram). Cardiac catheters were inserted into the main pulmonary artery, pulmonary capillary wedge position, and femoral artery. The positions of the catheters were verified by fluoroscopy, pressures, and autopsy. A small polyethylene catheter (PE-SO) was placed in the left atrium by transbronchial left atria1 puncture. Respiration was maintained by positive pressure, and airway pressure was measured by needle puncture of the respirator tubing. Pressures were measured by strain-gauge transducers, and mean pressures were obtained by electronic integration. Zero level for pressures was Fran
one half of the anteroposterior diameter of the thorax in the supine position. Cardiac output was determined by the indicator-dilution method, using indocyanine green. Blood was sampled at a constant speed from the femoral artery through a Gilford densitometer which was calibrated by the pooled-sample method of McNeely and Gravallese.4 Because of electronic malfunction the Fick principle was used to calculate flow in one animal. Oxygen content of samples of femoral arterial blood was determined in the Van Slyke manometric apparatus. The pressures and dilution curves were recorded by a direct-writing Sanborn oscillograph. Pulmonary blood volume was calculated by the method of Milnor, Jose, and McGaff5j6 and was taken to be the difference between the dilution volumes calculated from rapidly consecutive injections of indicator into the pulmonary artery and left atrium. Thirty duplicate measurements of control pulmonary blood volumes in dogs yielded a standard deviation of 10.9 ml. per 10 Kg. and a standard error of the mean of 2.0 ml. per 10 Kg.6 Control observations of pressures, flow, and volumes were made in duplicate 5 minutes apart. Bretylium tosylatet was
the Department of Medicine and Cardiac Catheterization Laboratory, University of Louisville School of Medicine, Louisville, KY. Supported by Research Grant H-5419 from the United States Public Health Service. Presentedin part at the Annual Scientific Session, American Heart Association, Miami, Fla., October, 1961 Received for cubEcation Tune 11. 1962. *John and Mary R. Markle Scholar in Medical Science. tKindly furn&hed as Darenthin by Burroughs Wellcome 81 Co. (U.S..%) Inc., Tuckahoe, N, Y.
240
Pulmonary
241
hypertensive efects of bretylium tosylate in dog
then given intravenously by a slow infusion to 2 animals and as a 2-minute injection to the other 13. The dose was SO mg. per kilogram in 13 dogs. One animal was given 20 mg. per kilogram, and another was given 150 mg. per kilogram. Although these dosages are higher than those used by other investigators, they were used since they yielded the observed effects. Observations were again repeated in duplicate after an average interval of 45 minutes after administration of the drug. Nine paired measurements of pulmonary blood volume were made before and after the injection of bretylium in 6 dogs. In 4 dogs the spleen was removed before the control observations were made. Three animals were ventilated with 100 per cent oxygen after the effects of bretylium had been studied, and all measurements were again repeated in duplicate. Pulmonary vascular resistance was calculated by dividing the difference between mean pulmonary arterial and left atria1 pressures
by the cardiac output per 10 kilograms of dog and was expressed as resistance units (R.U./lO Kg.). Pulmonary arteriolar resistance was obtained by subtracting mean pulmonary capillary wedge pressure from the mean pulmonary arterial pressure and dividing by the cardiac output per 10 kilograms of dog. Systemic resistance was obtained by dividing mean femoral arterial pressure by the cardiac output per 10 kilograms. Results
The number of observations and the changes in paired measurements before and after the bretylium are shown in Table I. There was no difference between the results obtained from infusion and those from injection of the bretylium. The cardiac output and pulmonary blood volume did not change significantly. There was a significant decrease in heart rate and a significant increase in hematocrit. In the 4 splenectomized animals the hematocrit
Table I Number of Papameter
paired observaGons
Bretylium
26
1.428
1,412
-1
9
130
155
+19
Heart rate (beats/min.)
24
169
1.55
-8
Hematocrit (per cent)
17
47
51
+g
8
94.7
92.7
-2
28 29 18 27 3
117 11.9 5.6 4.0 4.5
140 17.0 5.3 3.3 4.3
+19 i-43 -5 -18 -4
26 16 2.5
7.2 7.7 110
13.4 13.1 1.54
+86 +70 +40
Cardiac output (L./min./l0 Pulmonary (ml./10
Oxygen (per
Kg.)
blood Kg.)
Per cent change
.%gn$can~ chunge (p value)
Conho
volume
saturation cent)
Mean pressure (mm. Femoral artery Pulmonary artery Pulmonary “wedge” Left atrium Airway
Hg)
Resistance Pulmonary Pulmonary Systemic
Kg.)
(R.U./lO vascular arteriohr vascular
242
McGaf
and Leight
Fig. 1. Change in mean pressure artery (ATPA) and left atrium (AFL*) tration of bretylium. The pulmonary pressure (w&&e) rose significantly paired observations. Left atria1 (ukkz) did not change significantly.
in pulmonary after adminisarterial mean in all but 5 mean pressure
did not change. There was no significant deviation in the arterial oxygen saturation. The pulmonary (Fig. 1) and femoral arterial mean pressures rose significantly, but the left atria1 (Fig. l), pulmonary capillary, and airway pressures did not change predictably. Thus, there was a significant elevation in calculated total pulmonary vascular, pulmonary arteriolar, and systemic vascular resistances. The administration of 100 per cent oxygen had no effect on the bretylium-induced elevation in pulmonary vascular resistance in the 3 animals studied. Discussion
In man, Taylor and Donald2 demonstrated that bretylium causes a rise in pulmonary arterial pressure and pulmonary arteriolar resistance. Halmagyi and Colebatch3 described increased total pulmonary vascular resistance in sheep. This study extends these observations to the dog and shows the same effects on the pulmonary vasculature. Pulmonary capillary pressure
was measured in 2 sheep by Hallnag) and was found to rise after administration of the drug. Whether this represented pulmonary venous consQiction or a rise in pressure in the left side of the heart is unknown. It is clear, however, that in man and in the dogs reported on here the elevation in pulmonary arterial pressure is the result of increased resistance to blood flow at the level of small vessels, presumably the arterioles. The lack of significant change in pulmonary blood volume is consonant with this hypothesis and against constriction of most of the vascular bed, such as may be seen when serotonin elevates pulmonary vascular resistance and reduces the pulmonary blood volume.6 The possibility exists that constriction of the pulmonary arteries and dilation of the pulmonary veins would decrease and increase pulmonary blood volume, respectively, and the volume of blood measured by this method would not change. This possibility cannot be ascertained by the method used. Gaffney’ has suggested that bretylium depletes the heart of catecholamines, yet Boural maintains that it has no influence on the catecholamine content of the adrenals or the sympathetic ganglia. It is possible that some of the effects which were observed were due to release of catecholamines into the circulation, as several authors have suggested.8,g The rise in systemic arterial pressure is probably due to the elevated level of catecholamines, and the slowing of the heart rate can be attributed to a reflex vagal effect that results from stimulation of the carotid sinus by the increased pressure. This was not studied in these experiments. The dog’s spleen is known to contract with sympathetic stimulation, and the rise in hematocrit with the spleen in place and the lack of any change in hematocrit in the splenectomized animals implicates the spleen as the source of this additional red cell mass. It is important to note that the elevated pulmonary resistance was not due alone to increased blood viscosity secondary to the elevated hematocrit, for in the splenectomized animals with no change in hematocrit a significant rise in resistance was still found after the bretylium had been given. The lack of any change in arterial oxygen
Pulmonary
hypertensive ej’ects of bretylium
saturation or airway pressure is good evidence that the observed changes were not secondary to anosia or bronchospasm. The exact mechanism whereby bretylium elevates the pulmonary arterial pressure and resistance remains obscure, but it seems to be a localized effect, at arteriolar level, and affects man, dogs, and possibly sheep. Further observations on other species with more reactive pulmonary vessels will be of interest.
A sympathetic-blocking agent, bretylium tosylate, was given intravenously in large dosage to 15 anesthetized mongrel dogs with closed chests. This drug caused a significant increase in mean pulmonary arterial pressure, total pulmonary vascular resistance, and pulmonary arteri,olar resistance. Pulmonary blood volume did not change significantly. These changes are compatible with constriction of a small segment of the pulmonary vascular bed, such as the arterioles. REFERENCES Boura, A. L. A., Green, A. F., McCoubrey, Laurence, D. R., Moulton, R., and Rosenheim,
3.
A.,
M. L.: Darenthin: hypotensive agent tvpe, Lancet 1:17,1959. Taylor, S. H., and Donald, K. W.: The latory effects of bretylium tosylate and thidine, Lancet 2:389, 1960. Halmagyi, D. F. J., and Colebatch, H. Effect of bretylium tosylate (Darenthin) pulmonary circulation, Circulation Res.
1961. 4. McNeely,
5.
Summary
1.
2.
6.
7.
8.
9.
tosylate in dog
243
of new circuguaneJ. H.: on 9:136,
W. F., and Gravallese, M. A.: Measurement of cardiac output by dye-dilution technique: use of an “integrated” sample collection in calibration of the photometric instrument, J. Appl. Physiol. 755, 1954. Milnor, W. R., Jose, A. D., and McGaff, C. J.: Pulmonary vascular volume, resistance and compliance in man, Circulation 22:130, 1960. McGaff, C. J., and Milnor, W. R.: Effects of serotonin on pulmonary blood volume in the dog, Am. J. Physiol. 202:957, 1962, Gaffney, T. E.: Effect of guanethidine and bretylium on the dog heart-lung preparation, Circulation Res. 9:83, 1961. Yelnosky, J., and Mortimer, L. C.: Brief study of the sympathomimetic cardiovascular effects of bretylium, Arch. internat. pharmacodyn. 130:200, 1961. Gilmore, J. P., and Siegel, J. A.: Mechanism of the myocardial effects of bretylium, Circulation Res. 10:347, 1962.