- Email: [email protected]
Blood sugar responses to epinephrine in the dog in the presence of dual adrenergic blockade
EUROPEAN JOURNAL OF PHARMACOLOGY 17 (1972) 34-38. NORTH-HOLLAND PUBLISHING COMPANY
BLOOD SUGAR RESPONSES TO EPINEPHRINE IN THE PRESENCE OF DUAL ADRENERGIC
IN THE DOG BLOCKADE
Clinton B. NASH and Ronald D. SMITH Department of Pharmacology, University of Tennessee Medical Units, Memphis, Tennessee 38103, U.S.A.
Received 19 July 1971
Accepted 23 September 1971
C.B. NASH and R.D. SMITH, Blood sugar responses to epinephrine in the dog in the presence of dual adrenergic blockade, European J. Pharmacol. 17 (1972)34-38. The effects of c~-adrenergic blockade by phentolamine, #-adrenergic blockade by propranolol, and dual blockade by simultaneous use of these two agents were studied on the blood sugar response to increasing infusion rates of epinephrine in the dog. In control groups without epinephrine infusions, the blocking agents alone produced no important changes in blood sugar. In experimental groups the peak rise in blood sugar was unchanged by phentolamine, was partly blocked by propranolol, and was completely blocked by dual blockade. A possible explanation for this interaction is based on the concept that blood sugar elevations by epinephrine may involve both a- and fl-receptors. Epinephrine-induced hyperglycemia Dog blood glucose dose-response
1. INTRODUCTION The question of the involvement of specialized receptors in the metabolic responses to catecholamines still eludes a satisfactory answer. It seems clear that there may be great species differences both with regard to the effects of agonists and of antagonists (Himms-Hagen, 1967). Even with a single metabolic response in a single species, such as the blood sugar level in the dog, there are conflicting reports regarding the action of adrenergic blocking agents. There is fairly general agreement that t~-adrenergic blockers do not reduce the hyperglycemia produced by epinephrine (Havel and Goldfien, 1959; Ellis and Beckett, 1963); however, Mayer et al. (1961) reported that ergotamine was an effective blocker in the dog. In the case of/3-blockers, several reports indicate that these agents do prevent epinephrine-induced hyperglycemia in dogs (Mayer et al., 1961; Brown et al., 1968; Kvam et al., 1965), although Burns et al.
Dual adrenergic blockade
Phentolam ine Propranolol
(1964) found no blockade by pronethalol. In addition there are some agents which do not fit the classical description of either a- or 13-blocking agents, but which appear to block epinephrine-induced hyperglycemia (Mayer et al., 1961; Levy and Tozzi., 1963; Burns et al., 1964). In view of our previous finding that both a- and /3-adrenergic receptors are involved in the hyperlacticacidemic response to norepinephrine (Nash and Smith, 1969), it was of interest to determine the influence of dual adrenergic blockade on the blood glucose response to epinephrine in the dog.
2. MATERIALS AND METHODS Dogs of either sex weighing between 7 and 12 kg were fasted for 1 8 - 2 0 hr prior to the experiment. They were anesthetized with sodium pentobarbital, i.v., and prepared for the recording of blood pressure
35
C.B.Nash, R.D.Smith, Blood glucose and dual blockade
(Statham transducer), respiration (Grass PT-5 transducer) and EKG by a Grass Polygraph recorder. Blood samples were drawn from the exposed left femoral vein and epinephrine infusions were given by Harvard Syringe Pump into the cannulated right femoral vein. The infusion was given stepwise and the volumes were fixed at 0.025, 0.05, 0.125, 0.25, and 0.5 ml/min. These volumes corresponded to dose rates of epinephrine base of 0.15, 0.30, 0.75, 1.5, and 3.0 ktg/kg/min. Dose rates were maintained in a constant volume in each animal by adjustment of the concentration. Blood glucose was measured by the glucose oxidase method (Glucostat, Worthington Corp.). The animals were divided into 4 groups. Group I received only epinephrine bitartrate infusion in the dose rates described above. After control blood sampies, the infusion was begun at the lowest rate and increasedevery 20 min to the next higher level, a blood sample being taken just prior to each increase in rate. Following 20rain of infusion at 3.0/.tg/kg/min, the pump was turned off and a final blood sample taken 40 min later. Group II animals were given an a-adrenergic blocker, phentolamine, 7.5 mg/kg, i.v., 30 min prior to the epinephrine. Group III received propranolol, 2.0 mg/kg, i.v., 10 rain before the epinephrine infusion, and Group IV received both phentolamine and propranolol, as
described above, prior to the infusion. Additional control dogs corresponding to each of these 4 groups were given equivalent volumes of saline infusion without epinephrine.
3. RESULTS The fluctuations in blood levels of glucose in dogs receiving adrenergic blockers alone or in untreated dogs over a time period of 120 min are shown in fig. 1. Administration of phentolamine, propranolol, or both together did not cause a significant change from the untreated animals. In the case of proprano1ol, these results are in disagreement with both Berk et al. (1970) who found a decrease and with Grassi et al. (1969) who found an increase in blood glucose in the dog. Infusion of epinephrine at increasing rates resulted in a dose-effect curve with the peak level of blood glucose of 235 mg% occurring at the dose of 1.5/.tg/kg/min (fig. 2). When this rate was doubled, no further increase in blood glucose appeared. If t~-blockade (phentolamine) was established prior to epinephrine, the hyperglycemic effect of epinephrine was virtually unchanged. 13-blockade (propranolol) produced a significant reduction of approximately 50% in the blood sugar response to epinephrine. The
90 r~*~'~'°~
E
~ I
~
'
~-...>~..':.: .........~"~'~-
~
"[
............ : ~ '
_ 6o ~
~
~
~¢-:.-~"---~: . . . . . . .
f
"
..........
L ----"'-.---/
Phentolamine 7.5 mg/kg
k
Dual Block
30
..............
No Propranolol 20
0
//.
0
mg/kg i
40
80
120
Minutes Fig. 1. The fluctuations in blood sugar levels with time in dogs receiving saline infusion without epinephrine. The points are the means of 4 animals in each group. The first point was obtained before the administration of blocking agents. Time zero represents 30 rain after phentolamine and 10 rain after proptanolol. The vertical bars represent S.E.M. No R x = saline infusion without blocking agents.
C.B.Nash, R.D.Smith, Blood glucose and dual blockade
36
270o
•- - ,
Controls
....
Alpha
Block
E 210-
o,)
90-
o
%15
c~
30-
0 3 Epi
O
20
075 Infusion
1 5 , ~g/kg/min
3 0
60 Time-(minutes)
t
100
1,io
Fig. 2. Blood sugar responses to epinephrine infusions in dogs with and without adrenergic blockade, c~-Blockade produced by phentolamine, 7.5 mg/kg, 13-blockadeby propranolol, 2 mg/kg, and dual blockade by both agents. Phentolamine was given 30 min before and propranolo110 min before the epinephrine infusion began. Each point is the mean of 6-8 animals and the vertical bars represent S.E.M.
combination of a- plus 13-adrenergic blockade resulted in a full block of the hyperglycemic effect of epinephrine. Blood glucose levels in the dual blocked group were significantly different from the other experimental groups at each point, but they were not different from their own control at any point.
4. DISCUSSION The literature contains very little information regarding the blood glucose dose-effect curve resulting from epinephrine infusion in the dog. Most reports have dealt with the blood sugar response to a single dose of epinephrine given by various routes. Moreover, the usual study involved only one dose of the blocking agent. Since the efficacy of a fixed dose of a blocking agent may be quite different at the low end vs. the high end of a dose-effect curve of an agonist, it was necessary to construct a dose-effect curve to properly evaluate the effects of dual blockade. The interpretation of the effects of a-blockade by certain agents, such as dibenamine or phenoxybenzamine, on blood sugar changes is complicated by the actions of these agents themselves to cause an in-
crease in blood sugar (Mayer et al., 1961; Havel and Goldfien, 1959). This problem was avoided by the use of phentolamine which did not cause an increase in blood glucose (fig. 1). Although phentolamine alone, in toxic doses with repeated administration, has been reported to decrease blood glucose (Trapold et al., 1950), no decrease was noted with the dose used in the present study. The dose of phentolamine used, 7.5 mg/kg, is more than 7 times the minimal dose needed to reverse the effects of epinephrine on blood pressure in the dog (Trapold et al., 1950). The lack of effect on the epinephrine blood sugar d o s e effect curve seen in fig. 2 justifies the conclusion that a high degree of s-blockade alone does not prevent the usual hyperglycemic response to epinephrine, and is in agreement with the findings of Ellis and Beckett (1963). t3-Blockade with DCI was reported by Mayer et al. (1961) to block nearly completely epinephrine hyperglycemia, although the evaluation was complicated by the action of DCI itself in raising blood glucose; however, Burns et al. (1964), using pronethalol saw no blockade to epinephrine-induced hyperglycemia. Kvam et al. (1965) and Brown et al. (1968) found sotalol to be an effective blocking agent to the hyper-
CB.Nash, R.D.Smith, Blood glucose and dual blockade
glycemic response of epinephrine in the dog, but it is not entirely clear whether this response was completely suppressed. The dose of propranolol, 2 mg/kg, used in our study prevented only half of the control rise in blood glucose. The use of dual adrenergic blockade in the present study clearly shows that the addition of a dose of an c~-blocker which had no discernible effect, to a dose of/3-blocker which was only partly effective resulted in a complete blockade of the epinephrine-induced hyperglycemic response. Several possible mechanisms may be suggested to explain these results. The receptors involved may be undifferentiated and susceptible to blockade by both a- and/3-blocking agents. However, the results of many past investigations do not support this and the failure of large doses of phentolamine in our study to produce any change in blood sugar makes this very unlikely. For the same reason it is not likely that any changes in muscle glycogenolysis with resulting alterations in blood lactate levels were of any importance. We have previcusly shown that t~-adrenergic blockade alone does not reduce blood lactate increases produced by norepinephrine (Nash and Smith, 1969). A severe drop in blood flow through the liver could alter t ~ output of glucose. However, pharmacological doses of epinephrine are known to produce constriction of hepatic blood vessels and to decrease liver blood flow (Goodman and Gilman, 1965). In spite of this, a marked rise in blood glucose occurred with control epinephrine infusions. If dual blockade had any effect on hepatic blood flow, it would tend to increase rather than decrease flow. The effectiveness of dual blockade on blood sugar responses to epinephrine would seem to be more than a fortuitious event. In previous studies we reported a similar potentiation by use of dual blockade with respect to the hyperlacticacidemia, cardiac arrhythmias, and pH changes produced by norepinephrine (Nash and Smith, 1969) and myocardial hemorrhage by epinephrine (Nash, 1968). Although our data do not permit a definitive explanation, an additional possibility is based on the concept that certain responses to catecholamines may involve activation of both a- and /3-receptors. The two receptors may pass through a common junction where one or the other may be the dominant pathway. Blocking of the subdominant pathway may appear to produce little or no effect,
37
while blockade of the dominant pathway may greatly reduce or nearly block the end response. In such an arrangement blockade of both receptors simultaneously could produce a much greater inhibition than simple summation. This concept need not be in conflict with the well-known mechanism of action of catecholamines as put forward by Sutherland and coworkers (1968), since the proposed pathways could be located between the membrane receptors and the eventual activation of adenyl cyclase. This suggested mechanism would help to explain the species differences which exist in metabolic responses, in the actions of agonists, and in the effects of blocking agents, since the dominant receptor pathway could differ from one species to the next. Furthermore, the anomalous action of ergotamine and dihydroergotamine to block epinephrine-induced hyperglycemia might also be explained by our concept since these agents have been reported to have some degree of both a- and/3-blocking ability (Levy and Tozzi, 1963; Mayer et al., 1961).
ACKNOWLEDGMENT The technical assistance of Miss Betty Hall is gratefully acknowledged.
REFERENCES Berk, J.L., J.F. Hagen and W.H. Beyer, 1970, The hypoglycemic effect of propranolol, Hormone and Metabolic Res. 2, 277-281. Brown, J.H., D.A. Riggilo and K.W. Dungan, 1968, Oral effectiveness of beta adrenergic antagonists in preventing epinephrine-induced metabolic responses, J. Pharmacol. Exptl. Therap. 163, 25-35. Burns, J.J., K.I. Colville, L.A. Lindsay and R.A. Salvador, 1964, Blockade of some metabolic effects of catecholamines by N-isopropyl methoxamine (B.W. 61-43), J. Pharmacol. Exptl. Therap. 144, 163-171. Ellis, S.E. and S.B. Beckett, 1963, Mechanism of the potassium mobilizing action of epinephrine and glucagon, J. Pharmacol. Exptl. Therap. 142, 318-326. Goodman, L.S. and A. Gilman, 1965, The Pharmacological Basis of Therapeutics (Macmillan Co., New York) p. 488. Grassi, A.O., M.N.F. de Lew and H.E. Cingolani, 1969, Antilipolytic effect of propranolol in the dog, Life Sci. 8 (No.l), 1239-1245. Havel, R.J. and A. Goldfien, 1959, The role of the sympa-
38
C.B.Nash, R.D.Srnith, Blood glucose and dual blockade
thetic nervous system in the metabolism of free fatty acids, J. Lipid Res. 1,102-108. Himms-Hagen, J., 1967, Sympathetic regulation of metabolism, Pharmacol. Rev. 19,367-461. Kvam, D.C., D.A. Riggilo and P.M. Lish, 1965, Effect of some new beta-adrenergic blocking agents on certain metabolic responses to catecholamines, J. Pharmacol. Exptl. Therap. 149, 183-192. Levy, B. and S. Tozzi, 1963, The adrenergic receptive mechanism of the rat uterus, J. Pharmacol. Exptl. Therap. 142, 178-184. Mayer, S.N., N.C. Moran and J. Fain, 1961, The effect of adrenergic blocking agents on some metabolic agents of
catecholamines, J. Pharmacol. Exptl. Therap. 134, 18-27. Nash, C.B., 1968, Dual adrenergic blockade and epinephrine infusion, J. Pharmacol. Exptl. Therap. 162, 246-253. Nash, C.B. and R.D. Smith, 1969, Alteration of norepinephfine response in the dog by dual adrenergic blockade, European J. Pharmacol. 8, 310-314. Sutherland, E.W., G.A. Robinson and R.W. Butcher, 1968, Some aspects of the biologict,1 role of adenosine 3'5'-monophosphate (Cyclic AMP), Circulation 37,279-306. Trapold, J.H., M.R. Warren and R.A. Woodbury, 1950, Pharmacological and toxicological studies on 2-(N-p'-tolyl-N-(m'-hydroxyphenyl)-aminome thyl)-imidazoline (C-7337), a new adrenergic blocking agent, J. Pharmacol. Exptl. Therap. 100, 119-127.
BLOOD SUGAR RESPONSES TO EPINEPHRINE IN THE PRESENCE OF DUAL ADRENERGIC
IN THE DOG BLOCKADE
Clinton B. NASH and Ronald D. SMITH Department of Pharmacology, University of Tennessee Medical Units, Memphis, Tennessee 38103, U.S.A.
Received 19 July 1971
Accepted 23 September 1971
C.B. NASH and R.D. SMITH, Blood sugar responses to epinephrine in the dog in the presence of dual adrenergic blockade, European J. Pharmacol. 17 (1972)34-38. The effects of c~-adrenergic blockade by phentolamine, #-adrenergic blockade by propranolol, and dual blockade by simultaneous use of these two agents were studied on the blood sugar response to increasing infusion rates of epinephrine in the dog. In control groups without epinephrine infusions, the blocking agents alone produced no important changes in blood sugar. In experimental groups the peak rise in blood sugar was unchanged by phentolamine, was partly blocked by propranolol, and was completely blocked by dual blockade. A possible explanation for this interaction is based on the concept that blood sugar elevations by epinephrine may involve both a- and fl-receptors. Epinephrine-induced hyperglycemia Dog blood glucose dose-response
1. INTRODUCTION The question of the involvement of specialized receptors in the metabolic responses to catecholamines still eludes a satisfactory answer. It seems clear that there may be great species differences both with regard to the effects of agonists and of antagonists (Himms-Hagen, 1967). Even with a single metabolic response in a single species, such as the blood sugar level in the dog, there are conflicting reports regarding the action of adrenergic blocking agents. There is fairly general agreement that t~-adrenergic blockers do not reduce the hyperglycemia produced by epinephrine (Havel and Goldfien, 1959; Ellis and Beckett, 1963); however, Mayer et al. (1961) reported that ergotamine was an effective blocker in the dog. In the case of/3-blockers, several reports indicate that these agents do prevent epinephrine-induced hyperglycemia in dogs (Mayer et al., 1961; Brown et al., 1968; Kvam et al., 1965), although Burns et al.
Dual adrenergic blockade
Phentolam ine Propranolol
(1964) found no blockade by pronethalol. In addition there are some agents which do not fit the classical description of either a- or 13-blocking agents, but which appear to block epinephrine-induced hyperglycemia (Mayer et al., 1961; Levy and Tozzi., 1963; Burns et al., 1964). In view of our previous finding that both a- and /3-adrenergic receptors are involved in the hyperlacticacidemic response to norepinephrine (Nash and Smith, 1969), it was of interest to determine the influence of dual adrenergic blockade on the blood glucose response to epinephrine in the dog.
2. MATERIALS AND METHODS Dogs of either sex weighing between 7 and 12 kg were fasted for 1 8 - 2 0 hr prior to the experiment. They were anesthetized with sodium pentobarbital, i.v., and prepared for the recording of blood pressure
35
C.B.Nash, R.D.Smith, Blood glucose and dual blockade
(Statham transducer), respiration (Grass PT-5 transducer) and EKG by a Grass Polygraph recorder. Blood samples were drawn from the exposed left femoral vein and epinephrine infusions were given by Harvard Syringe Pump into the cannulated right femoral vein. The infusion was given stepwise and the volumes were fixed at 0.025, 0.05, 0.125, 0.25, and 0.5 ml/min. These volumes corresponded to dose rates of epinephrine base of 0.15, 0.30, 0.75, 1.5, and 3.0 ktg/kg/min. Dose rates were maintained in a constant volume in each animal by adjustment of the concentration. Blood glucose was measured by the glucose oxidase method (Glucostat, Worthington Corp.). The animals were divided into 4 groups. Group I received only epinephrine bitartrate infusion in the dose rates described above. After control blood sampies, the infusion was begun at the lowest rate and increasedevery 20 min to the next higher level, a blood sample being taken just prior to each increase in rate. Following 20rain of infusion at 3.0/.tg/kg/min, the pump was turned off and a final blood sample taken 40 min later. Group II animals were given an a-adrenergic blocker, phentolamine, 7.5 mg/kg, i.v., 30 min prior to the epinephrine. Group III received propranolol, 2.0 mg/kg, i.v., 10 rain before the epinephrine infusion, and Group IV received both phentolamine and propranolol, as
described above, prior to the infusion. Additional control dogs corresponding to each of these 4 groups were given equivalent volumes of saline infusion without epinephrine.
3. RESULTS The fluctuations in blood levels of glucose in dogs receiving adrenergic blockers alone or in untreated dogs over a time period of 120 min are shown in fig. 1. Administration of phentolamine, propranolol, or both together did not cause a significant change from the untreated animals. In the case of proprano1ol, these results are in disagreement with both Berk et al. (1970) who found a decrease and with Grassi et al. (1969) who found an increase in blood glucose in the dog. Infusion of epinephrine at increasing rates resulted in a dose-effect curve with the peak level of blood glucose of 235 mg% occurring at the dose of 1.5/.tg/kg/min (fig. 2). When this rate was doubled, no further increase in blood glucose appeared. If t~-blockade (phentolamine) was established prior to epinephrine, the hyperglycemic effect of epinephrine was virtually unchanged. 13-blockade (propranolol) produced a significant reduction of approximately 50% in the blood sugar response to epinephrine. The
90 r~*~'~'°~
E
~ I
~
'
~-...>~..':.: .........~"~'~-
~
"[
............ : ~ '
_ 6o ~
~
~
~¢-:.-~"---~: . . . . . . .
f
"
..........
L ----"'-.---/
Phentolamine 7.5 mg/kg
k
Dual Block
30
..............
No Propranolol 20
0
//.
0
mg/kg i
40
80
120
Minutes Fig. 1. The fluctuations in blood sugar levels with time in dogs receiving saline infusion without epinephrine. The points are the means of 4 animals in each group. The first point was obtained before the administration of blocking agents. Time zero represents 30 rain after phentolamine and 10 rain after proptanolol. The vertical bars represent S.E.M. No R x = saline infusion without blocking agents.
C.B.Nash, R.D.Smith, Blood glucose and dual blockade
36
270o
•- - ,
Controls
....
Alpha
Block
E 210-
o,)
90-
o
%15
c~
30-
0 3 Epi
O
20
075 Infusion
1 5 , ~g/kg/min
3 0
60 Time-(minutes)
t
100
1,io
Fig. 2. Blood sugar responses to epinephrine infusions in dogs with and without adrenergic blockade, c~-Blockade produced by phentolamine, 7.5 mg/kg, 13-blockadeby propranolol, 2 mg/kg, and dual blockade by both agents. Phentolamine was given 30 min before and propranolo110 min before the epinephrine infusion began. Each point is the mean of 6-8 animals and the vertical bars represent S.E.M.
combination of a- plus 13-adrenergic blockade resulted in a full block of the hyperglycemic effect of epinephrine. Blood glucose levels in the dual blocked group were significantly different from the other experimental groups at each point, but they were not different from their own control at any point.
4. DISCUSSION The literature contains very little information regarding the blood glucose dose-effect curve resulting from epinephrine infusion in the dog. Most reports have dealt with the blood sugar response to a single dose of epinephrine given by various routes. Moreover, the usual study involved only one dose of the blocking agent. Since the efficacy of a fixed dose of a blocking agent may be quite different at the low end vs. the high end of a dose-effect curve of an agonist, it was necessary to construct a dose-effect curve to properly evaluate the effects of dual blockade. The interpretation of the effects of a-blockade by certain agents, such as dibenamine or phenoxybenzamine, on blood sugar changes is complicated by the actions of these agents themselves to cause an in-
crease in blood sugar (Mayer et al., 1961; Havel and Goldfien, 1959). This problem was avoided by the use of phentolamine which did not cause an increase in blood glucose (fig. 1). Although phentolamine alone, in toxic doses with repeated administration, has been reported to decrease blood glucose (Trapold et al., 1950), no decrease was noted with the dose used in the present study. The dose of phentolamine used, 7.5 mg/kg, is more than 7 times the minimal dose needed to reverse the effects of epinephrine on blood pressure in the dog (Trapold et al., 1950). The lack of effect on the epinephrine blood sugar d o s e effect curve seen in fig. 2 justifies the conclusion that a high degree of s-blockade alone does not prevent the usual hyperglycemic response to epinephrine, and is in agreement with the findings of Ellis and Beckett (1963). t3-Blockade with DCI was reported by Mayer et al. (1961) to block nearly completely epinephrine hyperglycemia, although the evaluation was complicated by the action of DCI itself in raising blood glucose; however, Burns et al. (1964), using pronethalol saw no blockade to epinephrine-induced hyperglycemia. Kvam et al. (1965) and Brown et al. (1968) found sotalol to be an effective blocking agent to the hyper-
CB.Nash, R.D.Smith, Blood glucose and dual blockade
glycemic response of epinephrine in the dog, but it is not entirely clear whether this response was completely suppressed. The dose of propranolol, 2 mg/kg, used in our study prevented only half of the control rise in blood glucose. The use of dual adrenergic blockade in the present study clearly shows that the addition of a dose of an c~-blocker which had no discernible effect, to a dose of/3-blocker which was only partly effective resulted in a complete blockade of the epinephrine-induced hyperglycemic response. Several possible mechanisms may be suggested to explain these results. The receptors involved may be undifferentiated and susceptible to blockade by both a- and/3-blocking agents. However, the results of many past investigations do not support this and the failure of large doses of phentolamine in our study to produce any change in blood sugar makes this very unlikely. For the same reason it is not likely that any changes in muscle glycogenolysis with resulting alterations in blood lactate levels were of any importance. We have previcusly shown that t~-adrenergic blockade alone does not reduce blood lactate increases produced by norepinephrine (Nash and Smith, 1969). A severe drop in blood flow through the liver could alter t ~ output of glucose. However, pharmacological doses of epinephrine are known to produce constriction of hepatic blood vessels and to decrease liver blood flow (Goodman and Gilman, 1965). In spite of this, a marked rise in blood glucose occurred with control epinephrine infusions. If dual blockade had any effect on hepatic blood flow, it would tend to increase rather than decrease flow. The effectiveness of dual blockade on blood sugar responses to epinephrine would seem to be more than a fortuitious event. In previous studies we reported a similar potentiation by use of dual blockade with respect to the hyperlacticacidemia, cardiac arrhythmias, and pH changes produced by norepinephrine (Nash and Smith, 1969) and myocardial hemorrhage by epinephrine (Nash, 1968). Although our data do not permit a definitive explanation, an additional possibility is based on the concept that certain responses to catecholamines may involve activation of both a- and /3-receptors. The two receptors may pass through a common junction where one or the other may be the dominant pathway. Blocking of the subdominant pathway may appear to produce little or no effect,
37
while blockade of the dominant pathway may greatly reduce or nearly block the end response. In such an arrangement blockade of both receptors simultaneously could produce a much greater inhibition than simple summation. This concept need not be in conflict with the well-known mechanism of action of catecholamines as put forward by Sutherland and coworkers (1968), since the proposed pathways could be located between the membrane receptors and the eventual activation of adenyl cyclase. This suggested mechanism would help to explain the species differences which exist in metabolic responses, in the actions of agonists, and in the effects of blocking agents, since the dominant receptor pathway could differ from one species to the next. Furthermore, the anomalous action of ergotamine and dihydroergotamine to block epinephrine-induced hyperglycemia might also be explained by our concept since these agents have been reported to have some degree of both a- and/3-blocking ability (Levy and Tozzi, 1963; Mayer et al., 1961).
ACKNOWLEDGMENT The technical assistance of Miss Betty Hall is gratefully acknowledged.
REFERENCES Berk, J.L., J.F. Hagen and W.H. Beyer, 1970, The hypoglycemic effect of propranolol, Hormone and Metabolic Res. 2, 277-281. Brown, J.H., D.A. Riggilo and K.W. Dungan, 1968, Oral effectiveness of beta adrenergic antagonists in preventing epinephrine-induced metabolic responses, J. Pharmacol. Exptl. Therap. 163, 25-35. Burns, J.J., K.I. Colville, L.A. Lindsay and R.A. Salvador, 1964, Blockade of some metabolic effects of catecholamines by N-isopropyl methoxamine (B.W. 61-43), J. Pharmacol. Exptl. Therap. 144, 163-171. Ellis, S.E. and S.B. Beckett, 1963, Mechanism of the potassium mobilizing action of epinephrine and glucagon, J. Pharmacol. Exptl. Therap. 142, 318-326. Goodman, L.S. and A. Gilman, 1965, The Pharmacological Basis of Therapeutics (Macmillan Co., New York) p. 488. Grassi, A.O., M.N.F. de Lew and H.E. Cingolani, 1969, Antilipolytic effect of propranolol in the dog, Life Sci. 8 (No.l), 1239-1245. Havel, R.J. and A. Goldfien, 1959, The role of the sympa-
38
C.B.Nash, R.D.Srnith, Blood glucose and dual blockade
thetic nervous system in the metabolism of free fatty acids, J. Lipid Res. 1,102-108. Himms-Hagen, J., 1967, Sympathetic regulation of metabolism, Pharmacol. Rev. 19,367-461. Kvam, D.C., D.A. Riggilo and P.M. Lish, 1965, Effect of some new beta-adrenergic blocking agents on certain metabolic responses to catecholamines, J. Pharmacol. Exptl. Therap. 149, 183-192. Levy, B. and S. Tozzi, 1963, The adrenergic receptive mechanism of the rat uterus, J. Pharmacol. Exptl. Therap. 142, 178-184. Mayer, S.N., N.C. Moran and J. Fain, 1961, The effect of adrenergic blocking agents on some metabolic agents of
catecholamines, J. Pharmacol. Exptl. Therap. 134, 18-27. Nash, C.B., 1968, Dual adrenergic blockade and epinephrine infusion, J. Pharmacol. Exptl. Therap. 162, 246-253. Nash, C.B. and R.D. Smith, 1969, Alteration of norepinephfine response in the dog by dual adrenergic blockade, European J. Pharmacol. 8, 310-314. Sutherland, E.W., G.A. Robinson and R.W. Butcher, 1968, Some aspects of the biologict,1 role of adenosine 3'5'-monophosphate (Cyclic AMP), Circulation 37,279-306. Trapold, J.H., M.R. Warren and R.A. Woodbury, 1950, Pharmacological and toxicological studies on 2-(N-p'-tolyl-N-(m'-hydroxyphenyl)-aminome thyl)-imidazoline (C-7337), a new adrenergic blocking agent, J. Pharmacol. Exptl. Therap. 100, 119-127.