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Effect of infusion of saline on response of blood pressure to intravenous tetraethylammonium chloride
Effect
of infusion
on response intravenous
of sa*line
of blood pressure tetraethylammonium
to chloride
Marvin M. McCall, M.D.* Elbert P. Tuttle, Jr., M.D.** Atlanta, Ga.
T
he normal response to the intravenous administration of the ganglionic blocking agent, tetraethylammonium chloride (TEAC), is complex; it involves a tachycardia and a transient and small pressor response, followed by a marked fall in blood pressure. In patients with acute glomerulonephritis,’ pheochromocytoma,2 and in some hypertensive patients with unilaterai renal vascular lesions,’ a marked, exclusively pressor response to TEAC has been demonstrated. Pressor responses have also been demonstrated in dogs made hypertensive by renin, angiotensin, or cellophane perinephritis, and in nonhypertensive nephrectomized dogs.3 Both dogs3 and human subjects4 receiving infusions of epinephrine and norepinephrine respond to TEAC with a rise in blood pressure. It has been suggested that the response of blood pressure to ganglionic blockade produced by TEAC might be useful in predicting the response to surgical procedures by patients who are known to have renal vascular lesions in association with hypertension.’ From
Since a pressor response to been demonstrated in a variety and experimental situations, was designed to test the effect variable, the acute administration on the response of blood pressure Materials
and
TEAC has of clinical this study of another of saline, to TEAC.
methods
Nine hospitalized patients and one house officer were studied. There was no evidence of cardiovascular or renal disease in any patient. The age of the subjects ranged from 13 to 30 years. Most of the patients had been admitted for minor surgical procedures not related to chronic or generalized illness. Under minimal local skin anesthesia, a 15gauge needle was introduced into an arm vein, a slow drip of 5 per cent dextrose and water was started, and blood pressure was allowed to stabilize before the test was continued. Control blood pressureswere recorded. Four hundred milligrams of TEAC were then introduced rapidly through the rubber tubing at the site of infusion, and blood pressure was measured with an ordinary
the Department of Medicine. Emory University School of Medicine, and the Medical Service, Grady Memorial Hospital, Atlanta. Ga. Supported by Grant H-4191 Cl from the National Heart Institute. National Institutes of Health, IJnited States Public Health Service. Received for publication Nov. 8, 1961. *Chief Resident, Medical Service, Grady Memorial Hospital, and Instructor in Medicine, Emory University School of Medicine. **Assistant Professor of Medicine, Georgia Heart Association Chair of Cardiovascular Research. Emory University School of Medicine.
659
Am. Heart
McCall and Tuttle
660
EFFECT
Mny,
OF
SALINE
INFUSION
ON
BP
RESPONSE
TO
J. 1962
TEAC
CHANGE OF BLOOD PRESSURE
MINUTES!20 AFTER
-213 -2’0-1: ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ -IO
INJECTION
NO. I
BEFORE
INJECTION
Fig. 1. Effect of infusion of saline on response of blood pressure to TEAC. pressure responses of 10 subjects plotted as per cent change from control standard deviation from the mean.
sphygmomanometer at intervals of 30 seconds for 6 minutes, and at intervals of 1 to 2 minutes throughout a period of 15 minutes. The response to this injection was considered to be basal for this individual. After the blood pressure returned to control levels, approximately 3,000 ml. of warmed normal saline was infused within a period of 30 minutes. In the first 2 patients, another 400 mg. of TEAC was given immediately at the end of the infusion. In the last 8 patients, however, a stabilization period of from 5 to 10 minutes elapsed before the second injection of 400 mg. of TEAC was given. The time for stabilization was introduced in order that the period of rapid redistribution of saline across capillary membranes might be completed. Results
The normal depressor response to TEAC was converted to a pressor response in all subjects by the infusion of normal saline. Fig. 1 shows a slight initial pressor response followed by an abrupt fall of 15 per cent in systolic and diastolic pressures. A gradual return to the base-line pressures occurred in approximately 15 minutes.
-5
NO. 2
0
2
AFTER
4
6
INJECTION
6
10
12
NO. 2
The solid line represents mean blood levels. The dashed line represents one
This is the expected response in normal individuals. During the infusion of saline there was a slight rise in blood pressure initially, but by the end of the infusion the pressures approached the original base line. Had the first 2 patients been allowed a period of stabilization at the end of the infusion, the mean blood pressure line would have approached the base line even more closely. The injection of TEAC after the infusion of saline produced a rise of 18 per cent in both systolic and diastolic pressures. The pressor response occurred within the first minute after injection and was not sustained, but no drop in pressure below the base line occurred. Discussion
In 1948, Brust and associates5reported the effects of the administration of TEAC in 2 groups of pregnant women; one group was considered to be normal, and the other group was considered to have toxemia of pregnancy. The authors found that in the normal pregnant patient the fall in blood pressure produced by TEAC was considerably greater than that in normal nonpregnant women, i.e., the
Volume Number
63 5
E$ect of saline on BP response to intravenous
“TEAC floor” was lower. In those with toxemia, however, the “TEAC floor” was consistently higher but returned to normal in the postpartum period. They suggested that the hypertension of toxemia was supported by an excessive degree of humoral tone, since neurogenic tone had been blocked with TEAC. They also concluded that in the normal pregnant patient the maintenance of blood pressure was due to increased neurogenic tone, since the administration of TEAC produced such a profound drop in blood pressure. Page and McCubbir? demonstrated that the usual depressor effect of TEAC could be reversed in dogs made hypertensive by the administration of renin, angiotensin, epinephrine, or norepinephrine. They also showed that a similar reversal occurred in dogs in the malignant phase of hypertension produced by cellophane perinephand in normotensive dogs after ritis, nephrectomy. Wilber and Brust4 later showed that the normal blood-pressure response to TEAC in man was reversed when the subjects were made hypertensive with epinephrine and norepinephrine. Brust and Ferris’ studied responses to TEAC in 14 patients who were considered for renal surgery for cure of hypertension. Nephrectomy was performed on 10 patients. Of the 5 patients who had “parenchymal” renal disease, none responded to operation. Four of the 5 patients who had vascular lesions were “cured.” The response of the “cured” group to TEAC was strikingly different from that of the “surgical failure” group. All patients who were “cured” exhibited a pressor response to TEAC, whereas the patients in the “surgical failure” group showed a depressor response. They concluded that no fall in blood pressure or a pressor response might be useful in characterizing the hypertension as being caused by a demonstrated renal vascular lesion, and might suggest potential reversibility of the process, In contrast to these abnormal responses to TEAC, which were thought to be a consequence of the etiological or pathogenetic agent which caused the hypertension, several patients have been seen at Grady Memorial Hospital in whom a pressor response became a depressor re-
TEAC
661
sponse within a matter of days after diuresis and other therapy. This suggested that expansion of plasma volume or content of sodium in the body might be other causes of a pressor response. Frye and Braunwald6 have recently reported upon the effects which acute hypervolemia has on circulatory dynamics in the presence and absence of ganglionic blockade. They found that an increase in blood pressure and cardiac output were minimized in the presence of an intact autonomic nervous system, but that, when ganglionic blockade was effected, there was a significant increase in arterial blood pressure and cardiac output with expansion of blood volume. These findings appear to indicate that the normal responses to hypervolemia are mediated throughout the autonomic ganglia and tend to prevent an increase in. cardiac output and blood pressure by reflex enlargement of the vascular bed and depression of myocardial contractility. The data presented here are compatible with this concept. It is apparent that a pressor response to TEAC is not specific for hypertension on the basis of unilateral renal disease, circulating humoral pressor agents, or hypervolemia, but it may occur with any one of them. In many of the situations in which a pressor response has been described (i.e., toxemia, acute glomerulonephritis), retention of water and salt and hypervolemia are present and contributory. One can infer from the available data that a pressor response occurs when the general autonomic activity is blocked at the time at which its net function is to minimize a rise in blood pressure. Summary
and
conclusions
1. The response of blood pressure to the intravenous administration of TEAC has been evaluated in 10 normal subjects before and after hypervolemia was induced by the infusion of saline. 2. A reversal in the normal depressor response to TEAC has been produced by the induction of hypervolemia. 3. These data and the data of others suggest that a pressor response to TEAC is not specific for renal hypertension, circulating pressor substances, or hypervolemia.
662
McCall and Tuttle
Ii E F IJ K E N C I’S Brust, ~1. ,4., and Ferris, E. II.: ‘l‘he diagnostic approach to hypertension due to unilateral kidney disease, i\nn. Int. Med. 47:1049, 19.57. La Due, J. S., Murison, P. J., and Pack, G. T.: The use of tetraethylammonium bromide as a diagnostic test for pheochromocytoma, .4nn. Int. Med. 29:914, 1948. Page, I. H., and McCubbin, J.: The pattern of vascular reactivity in experimental hypertension of varied origin, Circulation 4:70, 1951. Wilber, J. A., and Brust, A. A.: The circulatory and metabolic effects in man of histamine, Mecholyl, tetraethylammonium and atropine in the presence of circulating epinephrine and norpinephrine, J. Clin. Invest. 37:476, 19.58.
Hrust, ,\. :\., :&ah, A’. S., and Ferris, I:. 13.: Evaluation of neurogenic and humoral factors in blood pressure maintenance in normal and toxemic pregnancy using tetraethylammonium chloride, J. Clin. Invest. 27:717, 1948. Frye, Ii. L., and Braunwald, E.: Studies on Starlincr’s law of the heart. I. The circulatorv response to acute hypervolemia and its tnoditication by ganglionic blockade, J. Clin. Invest. 39:1043, 1960. 7. Acheson, G. H., and Moe, G. K.: The action of tetraethylammonium ion on the mammalian circulation, J. Pharmacol. & Exper. Therap. 87:220. 1946.
of infusion
on response intravenous
of sa*line
of blood pressure tetraethylammonium
to chloride
Marvin M. McCall, M.D.* Elbert P. Tuttle, Jr., M.D.** Atlanta, Ga.
T
he normal response to the intravenous administration of the ganglionic blocking agent, tetraethylammonium chloride (TEAC), is complex; it involves a tachycardia and a transient and small pressor response, followed by a marked fall in blood pressure. In patients with acute glomerulonephritis,’ pheochromocytoma,2 and in some hypertensive patients with unilaterai renal vascular lesions,’ a marked, exclusively pressor response to TEAC has been demonstrated. Pressor responses have also been demonstrated in dogs made hypertensive by renin, angiotensin, or cellophane perinephritis, and in nonhypertensive nephrectomized dogs.3 Both dogs3 and human subjects4 receiving infusions of epinephrine and norepinephrine respond to TEAC with a rise in blood pressure. It has been suggested that the response of blood pressure to ganglionic blockade produced by TEAC might be useful in predicting the response to surgical procedures by patients who are known to have renal vascular lesions in association with hypertension.’ From
Since a pressor response to been demonstrated in a variety and experimental situations, was designed to test the effect variable, the acute administration on the response of blood pressure Materials
and
TEAC has of clinical this study of another of saline, to TEAC.
methods
Nine hospitalized patients and one house officer were studied. There was no evidence of cardiovascular or renal disease in any patient. The age of the subjects ranged from 13 to 30 years. Most of the patients had been admitted for minor surgical procedures not related to chronic or generalized illness. Under minimal local skin anesthesia, a 15gauge needle was introduced into an arm vein, a slow drip of 5 per cent dextrose and water was started, and blood pressure was allowed to stabilize before the test was continued. Control blood pressureswere recorded. Four hundred milligrams of TEAC were then introduced rapidly through the rubber tubing at the site of infusion, and blood pressure was measured with an ordinary
the Department of Medicine. Emory University School of Medicine, and the Medical Service, Grady Memorial Hospital, Atlanta. Ga. Supported by Grant H-4191 Cl from the National Heart Institute. National Institutes of Health, IJnited States Public Health Service. Received for publication Nov. 8, 1961. *Chief Resident, Medical Service, Grady Memorial Hospital, and Instructor in Medicine, Emory University School of Medicine. **Assistant Professor of Medicine, Georgia Heart Association Chair of Cardiovascular Research. Emory University School of Medicine.
659
Am. Heart
McCall and Tuttle
660
EFFECT
Mny,
OF
SALINE
INFUSION
ON
BP
RESPONSE
TO
J. 1962
TEAC
CHANGE OF BLOOD PRESSURE
MINUTES!20 AFTER
-213 -2’0-1: ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ -IO
INJECTION
NO. I
BEFORE
INJECTION
Fig. 1. Effect of infusion of saline on response of blood pressure to TEAC. pressure responses of 10 subjects plotted as per cent change from control standard deviation from the mean.
sphygmomanometer at intervals of 30 seconds for 6 minutes, and at intervals of 1 to 2 minutes throughout a period of 15 minutes. The response to this injection was considered to be basal for this individual. After the blood pressure returned to control levels, approximately 3,000 ml. of warmed normal saline was infused within a period of 30 minutes. In the first 2 patients, another 400 mg. of TEAC was given immediately at the end of the infusion. In the last 8 patients, however, a stabilization period of from 5 to 10 minutes elapsed before the second injection of 400 mg. of TEAC was given. The time for stabilization was introduced in order that the period of rapid redistribution of saline across capillary membranes might be completed. Results
The normal depressor response to TEAC was converted to a pressor response in all subjects by the infusion of normal saline. Fig. 1 shows a slight initial pressor response followed by an abrupt fall of 15 per cent in systolic and diastolic pressures. A gradual return to the base-line pressures occurred in approximately 15 minutes.
-5
NO. 2
0
2
AFTER
4
6
INJECTION
6
10
12
NO. 2
The solid line represents mean blood levels. The dashed line represents one
This is the expected response in normal individuals. During the infusion of saline there was a slight rise in blood pressure initially, but by the end of the infusion the pressures approached the original base line. Had the first 2 patients been allowed a period of stabilization at the end of the infusion, the mean blood pressure line would have approached the base line even more closely. The injection of TEAC after the infusion of saline produced a rise of 18 per cent in both systolic and diastolic pressures. The pressor response occurred within the first minute after injection and was not sustained, but no drop in pressure below the base line occurred. Discussion
In 1948, Brust and associates5reported the effects of the administration of TEAC in 2 groups of pregnant women; one group was considered to be normal, and the other group was considered to have toxemia of pregnancy. The authors found that in the normal pregnant patient the fall in blood pressure produced by TEAC was considerably greater than that in normal nonpregnant women, i.e., the
Volume Number
63 5
E$ect of saline on BP response to intravenous
“TEAC floor” was lower. In those with toxemia, however, the “TEAC floor” was consistently higher but returned to normal in the postpartum period. They suggested that the hypertension of toxemia was supported by an excessive degree of humoral tone, since neurogenic tone had been blocked with TEAC. They also concluded that in the normal pregnant patient the maintenance of blood pressure was due to increased neurogenic tone, since the administration of TEAC produced such a profound drop in blood pressure. Page and McCubbir? demonstrated that the usual depressor effect of TEAC could be reversed in dogs made hypertensive by the administration of renin, angiotensin, epinephrine, or norepinephrine. They also showed that a similar reversal occurred in dogs in the malignant phase of hypertension produced by cellophane perinephand in normotensive dogs after ritis, nephrectomy. Wilber and Brust4 later showed that the normal blood-pressure response to TEAC in man was reversed when the subjects were made hypertensive with epinephrine and norepinephrine. Brust and Ferris’ studied responses to TEAC in 14 patients who were considered for renal surgery for cure of hypertension. Nephrectomy was performed on 10 patients. Of the 5 patients who had “parenchymal” renal disease, none responded to operation. Four of the 5 patients who had vascular lesions were “cured.” The response of the “cured” group to TEAC was strikingly different from that of the “surgical failure” group. All patients who were “cured” exhibited a pressor response to TEAC, whereas the patients in the “surgical failure” group showed a depressor response. They concluded that no fall in blood pressure or a pressor response might be useful in characterizing the hypertension as being caused by a demonstrated renal vascular lesion, and might suggest potential reversibility of the process, In contrast to these abnormal responses to TEAC, which were thought to be a consequence of the etiological or pathogenetic agent which caused the hypertension, several patients have been seen at Grady Memorial Hospital in whom a pressor response became a depressor re-
TEAC
661
sponse within a matter of days after diuresis and other therapy. This suggested that expansion of plasma volume or content of sodium in the body might be other causes of a pressor response. Frye and Braunwald6 have recently reported upon the effects which acute hypervolemia has on circulatory dynamics in the presence and absence of ganglionic blockade. They found that an increase in blood pressure and cardiac output were minimized in the presence of an intact autonomic nervous system, but that, when ganglionic blockade was effected, there was a significant increase in arterial blood pressure and cardiac output with expansion of blood volume. These findings appear to indicate that the normal responses to hypervolemia are mediated throughout the autonomic ganglia and tend to prevent an increase in. cardiac output and blood pressure by reflex enlargement of the vascular bed and depression of myocardial contractility. The data presented here are compatible with this concept. It is apparent that a pressor response to TEAC is not specific for hypertension on the basis of unilateral renal disease, circulating humoral pressor agents, or hypervolemia, but it may occur with any one of them. In many of the situations in which a pressor response has been described (i.e., toxemia, acute glomerulonephritis), retention of water and salt and hypervolemia are present and contributory. One can infer from the available data that a pressor response occurs when the general autonomic activity is blocked at the time at which its net function is to minimize a rise in blood pressure. Summary
and
conclusions
1. The response of blood pressure to the intravenous administration of TEAC has been evaluated in 10 normal subjects before and after hypervolemia was induced by the infusion of saline. 2. A reversal in the normal depressor response to TEAC has been produced by the induction of hypervolemia. 3. These data and the data of others suggest that a pressor response to TEAC is not specific for renal hypertension, circulating pressor substances, or hypervolemia.
662
McCall and Tuttle
Ii E F IJ K E N C I’S Brust, ~1. ,4., and Ferris, E. II.: ‘l‘he diagnostic approach to hypertension due to unilateral kidney disease, i\nn. Int. Med. 47:1049, 19.57. La Due, J. S., Murison, P. J., and Pack, G. T.: The use of tetraethylammonium bromide as a diagnostic test for pheochromocytoma, .4nn. Int. Med. 29:914, 1948. Page, I. H., and McCubbin, J.: The pattern of vascular reactivity in experimental hypertension of varied origin, Circulation 4:70, 1951. Wilber, J. A., and Brust, A. A.: The circulatory and metabolic effects in man of histamine, Mecholyl, tetraethylammonium and atropine in the presence of circulating epinephrine and norpinephrine, J. Clin. Invest. 37:476, 19.58.
Hrust, ,\. :\., :&ah, A’. S., and Ferris, I:. 13.: Evaluation of neurogenic and humoral factors in blood pressure maintenance in normal and toxemic pregnancy using tetraethylammonium chloride, J. Clin. Invest. 27:717, 1948. Frye, Ii. L., and Braunwald, E.: Studies on Starlincr’s law of the heart. I. The circulatorv response to acute hypervolemia and its tnoditication by ganglionic blockade, J. Clin. Invest. 39:1043, 1960. 7. Acheson, G. H., and Moe, G. K.: The action of tetraethylammonium ion on the mammalian circulation, J. Pharmacol. & Exper. Therap. 87:220. 1946.