Acta physiol. scand. 1977. 99. 457-461 From the Zoophysiological Laboratory, Institute of Biology, University of Turku, and the Department of Physiology, University of Kuopio, Finland
Alpha-Receptor Subsensitivity of Isolated Atria from Rats Following Physical Training or Repeated ACTH-Injections BY ANNELISILTOVUORI, RAUNOTIRRIand MIKKON. E. HARRI Received 29 September 1976
Abstract SILTOVUORI, A., R. TIRRIand M. N. E. HARRI.Alpha-receptor subsensitivity of isolated atria from rats following physical training of repeated ACTH-injections. Acta physiol. scand. 1977. 99. 457-461. Decreased chronotropic and inotropic sensitivity of isolated atria to phenylephrine but not to isoprenaline was found in rats following repeated physical training by swimming or repeated ACTH-injections. These changes were induced within a week of subjection of animals to these treatments. It is concluded, that these effects are mediated by increased adrenergic activity which results in this subsensitivity of alphareceptors.
Lowered sensitivity of cardiac a-receptors is induced in rats by cold-exposure (Harri et al. 1974) and by repeated injections of phenylephrine or isoprenaline (Tirri et al. 1976), as estimated by lowered atrial chronotropic response to an a-adrenergic drug phenylephrine. On the contrary, an increased sensitivity of cardiac a-receptors is found to be induced in frog and/or mammals by several conditions associated with low physiological activity of the animal. Such conditions are the inactivity of skeletal muscles (Szentivanyi et al. 1970 a), propylthiouracyl treatment (Nakashima el al. 1971), hypothyroidism (Kunos et al. 1974), increased vagal influences on heart (Szentivanyi et al. 1970 b) and low experimental temperature of the heart (Kunos and Szentivanyi 1968, Buckley and Jordan 1970, Harri 1973). These effects are usually associated with a lowered j?’-receptor sensitivity shown in inotropic and/or metabolic activity of the heart. Supersensitivity to the chronotropic effects of noradrenaline has been shown to appear in the dog heart in 1 to 3 days of treatment with reserpine (Fleming and Trendelenburg 1961, Westfall and Fleming 1968). This supersensitivity seemed to be nonspecific because it occurred also using calcium. To find out a possible common physiological condition, we further studied the effect of physical stress conditions and repeated ACTH-injections on the adrenergic response of isolated atria. 457
4.58
ANNELI SILTOVUORI, RAUNO TIRRI A N D MlKKO N. E. HARRl
Material and methods A total of 112 adult male Sprague-Dawley rats, 200-300 g in weight, were used in these expts. 48 of them were daily exercised by swimming for 20 min in water a t 30 C for 6 or 20 days. A weight of 7 g was attached at the base of the tail. An equal number of intact rats served as the control group. A group of 14 animals received once daily S.C. injection of adrenocorticotropic hormone (3 1U/kg) for a week. An
equal group of rats received injections of NaCI-solution. The cumulative concentration-response curves for the response to isoprenaline (ISO) and phenylephrine ( P H E ) were determined using isolated atria at 37'C in Tyrode's solution. The number of animals in each group I S presented in the graphs. To measure the chronotropic response to PHE and ISO, the animals were killed by decapitation. The atria were dissected from the hearts and suspended horizontally with a tension of 600 mg in 30 ml of Tyrode's solution gassed with 95 0, - 5 O U CO,. The rate of spontaneous contractions was recorded on a Mingograph 24 jet recorder by means of a suction electrode as described earlier (Harri ef al. 1974). For measuring the inotropic responses to P H E and I S 0 the cranial tip of the left atrium was suspended in Tlrode's solution by means of the pins with platinum electrodes on them. The caudal end was fixed into position with a hook connected to the force transducer on the Grass polygraph recorder. The contractions of the atrium were driben electrically from the stimulator at a steady rate of 120 heats per min. Square wave pulses hith double thrrshold intensity (about 2.5 V) and a duration of 3 ms were used. The resting tension applied was 600 mg, otherwise the conditions were the same as in the measurement of chronotropic response. A single concentration-response curve was determined with each atrial preparation. The following drugs were used: isoprenaline hydrochloride (Isuprels, Winthrop), phenylephrine hbdrochloride (Neo-slnephrine'. Winthrop) and adrenocorticotropic hormone (Isactid'"', Ferring).
Results The graphs in Fig. 1 show that after 6 and 20 days of physical training by swimming, the positive chronotropic sensitivity to PHE was lowered. This can be seen in the concentrationresponse curves shifted to the right. Because the maximum responses were strongly reduced ( p :.0.01), the EC,,-values did not differ significantly in any of the treated groups. The basic contraction frequency of rat atria was not changed after the swimming exercise as compared to the controls being 233 6 and 226 : 7 beats per min respectively. The results of the inotropic responses to PHE and I S 0 are presented in Fig. 2. The graphs show that physical training by daily swimming for 6 days reduced the sensitivity to PHE but did not change the response to KO. The results are thus similar to those in chronotropic response. The basic contractile force was slightly, but not significantly greater in rats after training by swimming than in controls ( I 76 k 16 mg and 147 i 14 mg, respectively, p ~0.20). The results in Fig. 3 indicate the effects of repeated ACTH-injections for 7 days on adrenergic atrial response. The chronotropic sensitivity to PHE was lowered after this treatment. The maximum response to PHE was reduced to about 50% after ACTH-injections as compared to the control values and it was statistically significant (p -< 0.05). The responses to IS0 were the same in the control and experimental group. ACTH-treatment did not cause any changes in the basic contraction frequency.
+
Discussion The results of the present study are similar to those found in isolated atria from cold-exposed rats (Harri et a/. 1974) and from rats injected chronically with PHE or I S 0 (Tirri et a/. 1976). In all these studies the lowered chronotropic sensitivity to the cr-adrenergic drug, PHE. wa5 observed in isolated atria, but there was no change in response to the b-adrenergic
459
a-RECEPTOR SUBSENSITIVITY IN RAT ATRIA
B
180. A
160
-
140
6days
20days
-
.c
E 120
JI u
-4
60
-
40
I0 9
I
I
I
I
I
I ,
8
7
6
5
4
9
I
I
8
7
phenylephrine
I
I
6
5
- log
I
4
B 1
1
0
9
8
7
6
1
1
1
0
9
8
7
6
5
m o l a r concentration of isoprenaline
Fig. 1. Log concentration-response curves for the chronotropic responses to phenylephrine (A) and isoprenaline (B) in atria from control rats (continuous lines) and rats trained by daily swimming for 6 or 20 days (broken lines). The number of animals in each group is in brackets and vertical bars indicate or - S.E.
+
drug, ISO. It could be assumed that the enhanced adrenergic activity in all these experimental conditions was responsible for the subsensitivity of cr-receptors observed (Harri et al. 1974, Tirri et al. 1976). The higher level of noradrenaline, as produced by cold, repeated injections of adrenergic drugs or physical training, could thus account for this lowered sensitivity of a-receptors. The subsensitivity induced by ACTH-injections may be a compensatory action of the stimulating effect of corticosteroids on the adrenergic action in heart muscle as shown in vitro by Kaumann (1972). On the other hand, the decreased sympathetic activity in rats resulting from decentralization or 6-hydroxydopamine treatment causes supersensitivity to noradrenaline but not to I S 0 (Trendelenburg 1963, Johansson 1973). This may also suggest a role of a-receptors in this supersensitivity. Kunos et al. (1973) have suggested that cardiac a- and b-receptors represent allosteric conformations of the same structure. They further suggest (Kunos et al. 1974) that changes in the thyroid hormone level result in an interconversion of myocardial a- and P-receptors. Our present and previous results indicate that the subsensitivity of a-receptors was not associated with a simultaneous increase in /%receptor response. This indicated that there was no interconversion of these receptors; thus giving support to Benfey (1975) who has also reported an opposing suggestion to the adrenoreceptor transformation hypothesis.
460
ANNELI SILTOVUORI, RAUNO TIRRI AND MIKKO N. E. HARRI
2401 200
160
-
1 120
-
z
0
: C
80.
Fig. 2. Log concentration-response curves for the inotropic responses to phenylephrine and isoprenaline in atria from control rats (continuous lines) and rats trained by swimming for 6 days (broken lines). Th e number of animals is in brackets and vertical bars indicate + or - S.E.
C
f
40-
E C
x
0 -
9
8 7 6 5 4 1 1 1 O Q 8 7 - l o g molar concentrotion o f phenylephrine isoprenoline
6
5
160
140
120
100
a0
60
40
'
20
II
0
(6,
T I $-dLJ
Fig. 3. Log concentration-response curves for the chronotropic responses t o phenylephrine and isoprenaline in atria from control rats (continuous lines) and rats injected with ACTH (3 IU/kg) for a week (broken lines). The number of animals is in brackets and vertical bars indicate
U-RECEPTOR SUBSENSITIVITY IN RAT ATRIA
46 1
The role of thyroxine as an inducer of changes in receptor sensitivity cannot be excluded. It has been shown that cold-exposure (Heroux 1960) and B-adrenergic stimulation by I S 0 (Melander et al. 1975) induce thyroid hormone secretion. Thus a change in sympathetic activity reflects changes in thyroxine levels (Melander et al. 1972). On the other hand, the increased adrenergic action can be induced by an increase of thyroxine hormone level, especially in hypothyroid or young animals (Swanson 1956, Lagerspetz et al. 1966). Thus, the changed adrenergic sensitivity, even when caused by altered thyroxine level, could also be explained by a changed adrenergic action. This study was supported by The Academy of Finland.
References BENFEY, B. G., Temperature dependence of phenoxybenzamine effects and the adrenoceptor transformation hypothesis. Nature (Lond.) 1975. 256. 745-747. G. A. and C. C . JORDAN, Temperature modulation of alpha- and beta-receptors in the isolated BUCKLEY, frog heart. Brit. J. Pharmacol. 1970. 38. 394-398. The development of supersensitivity to norepinephrine after FLEMING,W. W. and U. TRENDELENBURG, pretreatment with reserpine. J. Pharmacol. exp. Ther. 1961. 133. 41-51. HARRI,M. N. E., Temperature dependent sensitivity of adrenoreceptors in the toad’s heart. Acta Pharmacol. (Kbh.) 1973. 33. 273-279. and R. TIRRI,Changed chronotropic sensitivity to sympathomimetic amines HARRI,M. N. E., L. MELENDER in isolated atria from rats following cold acclimation. Exgerientia (Basel) 1974. 30. 1041-1043. O . , Adjustment of the adrenal cortex and thyroid during cold acclimation. Fed. Proc. 1960. 19. HEROUX, 82-85. JOHANSSON, B., Effects of propranolol and a new cardioselective beta-blocker, H 93/26, on responses of isolated rat atria to isoprenaline and noradrenaline. Europ. J. Pharmacol. 1973. 24. 194-204. KAUMANN, A. J., Potentiation of the effects of isoprenaline and noradrenaline by hydrocortisone in cat heart muscle. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 1972. 273. 134-153. Evidence favouring the existence of a single adrenergic receptor. Nature KUNOS,G. and M. SZENTIVANYI, (Lond.) 1968. 217. 1077-1078. Transformation of adrenergic receptors in the myocardium. KUNOS,G., M. S. YONGand M. NICKERSON, Nature New Biol. 1973. 241. 119-120. and M. NICKERSON, Effects of thyroid state on adrenoceptor properties. KUNOS,G., I. VERMES-KUNOS Nature (Lond.) 1974. 250. 779-781. LAGERSPETZ, K. Y. H., L. AUVINEN and R. TIRRI,The postnatal development of the metabolic response to adrenaline in mice. Ann. Med. exp. Fenn. 1966. 44. 67-70. Sympathetic activation of thyroid secretion. Endocrinology MELANDER, A,, E. NILSSONand F. SUNDLER, 1972. 90. 194-199. A,, E. RANKLEV, F. SUNDLER and U. WESTGREN,Beta,-adrenergic stimulation of thyroid MELANDER, hormone secretion. Endocrinology 1975. 97. 332-336. NAKASHIMA, M., K. MAEDA,A. SEKIYAand Y. HAGNIO,Effect of hypothyroid status on myocardial responses to sympathomimetic drugs. Jap. J. Pharmacol. 1971. 21. 819-825. SWANSON, H. E., The effect o r temperature on the potentiation of adrenalin by thyroxine in the albino rat. Endocrinology 1956. 60. 205-213. SZENTIVANYI, M., G. KUNOSand A. JUHASZ-NAGY, Modulator theory of adrenergic receptor mechanism : vessels of the dog hindlimb. Amer. J. Physiol. 1970 a. 218. 869-875. and A. JUHASZ-NAGY, The adrenergic reactions of the coronaries in view of a SZENTIVANYI, M., G. KLINOS new hypothesis of receptors. Acta physiol. Acad. hung. 1970 b. 37. 427-428. TIRRI,R., A. SILTOVUORI and M. N. E. HARRI,Alpha-receptor subsensitivity of isolated atria from rats following repeated injections of phenylephrine or isoprenaline. Experientiu (Basel) 1976.32. 1283-1285. TR~NDELENBURG, U., Supersensitivity and subsensitivity to sympathomimetic amines. Pharmacol. Rec. 1963. 15. 225-276. D. P. and W. W. FLEMING,Sensitivity changes in the dog heart to norepinephrine, calcium and WESTFALL, aminophylline resulting from pretreatment with reserpine. J. Pharmacol. exp. Ther. 1968. 159. 98-106.
Alpha-Receptor Subsensitivity of Isolated Atria from Rats Following Physical Training or Repeated ACTH-Injections BY ANNELISILTOVUORI, RAUNOTIRRIand MIKKON. E. HARRI Received 29 September 1976
Abstract SILTOVUORI, A., R. TIRRIand M. N. E. HARRI.Alpha-receptor subsensitivity of isolated atria from rats following physical training of repeated ACTH-injections. Acta physiol. scand. 1977. 99. 457-461. Decreased chronotropic and inotropic sensitivity of isolated atria to phenylephrine but not to isoprenaline was found in rats following repeated physical training by swimming or repeated ACTH-injections. These changes were induced within a week of subjection of animals to these treatments. It is concluded, that these effects are mediated by increased adrenergic activity which results in this subsensitivity of alphareceptors.
Lowered sensitivity of cardiac a-receptors is induced in rats by cold-exposure (Harri et al. 1974) and by repeated injections of phenylephrine or isoprenaline (Tirri et al. 1976), as estimated by lowered atrial chronotropic response to an a-adrenergic drug phenylephrine. On the contrary, an increased sensitivity of cardiac a-receptors is found to be induced in frog and/or mammals by several conditions associated with low physiological activity of the animal. Such conditions are the inactivity of skeletal muscles (Szentivanyi et al. 1970 a), propylthiouracyl treatment (Nakashima el al. 1971), hypothyroidism (Kunos et al. 1974), increased vagal influences on heart (Szentivanyi et al. 1970 b) and low experimental temperature of the heart (Kunos and Szentivanyi 1968, Buckley and Jordan 1970, Harri 1973). These effects are usually associated with a lowered j?’-receptor sensitivity shown in inotropic and/or metabolic activity of the heart. Supersensitivity to the chronotropic effects of noradrenaline has been shown to appear in the dog heart in 1 to 3 days of treatment with reserpine (Fleming and Trendelenburg 1961, Westfall and Fleming 1968). This supersensitivity seemed to be nonspecific because it occurred also using calcium. To find out a possible common physiological condition, we further studied the effect of physical stress conditions and repeated ACTH-injections on the adrenergic response of isolated atria. 457
4.58
ANNELI SILTOVUORI, RAUNO TIRRI A N D MlKKO N. E. HARRl
Material and methods A total of 112 adult male Sprague-Dawley rats, 200-300 g in weight, were used in these expts. 48 of them were daily exercised by swimming for 20 min in water a t 30 C for 6 or 20 days. A weight of 7 g was attached at the base of the tail. An equal number of intact rats served as the control group. A group of 14 animals received once daily S.C. injection of adrenocorticotropic hormone (3 1U/kg) for a week. An
equal group of rats received injections of NaCI-solution. The cumulative concentration-response curves for the response to isoprenaline (ISO) and phenylephrine ( P H E ) were determined using isolated atria at 37'C in Tyrode's solution. The number of animals in each group I S presented in the graphs. To measure the chronotropic response to PHE and ISO, the animals were killed by decapitation. The atria were dissected from the hearts and suspended horizontally with a tension of 600 mg in 30 ml of Tyrode's solution gassed with 95 0, - 5 O U CO,. The rate of spontaneous contractions was recorded on a Mingograph 24 jet recorder by means of a suction electrode as described earlier (Harri ef al. 1974). For measuring the inotropic responses to P H E and I S 0 the cranial tip of the left atrium was suspended in Tlrode's solution by means of the pins with platinum electrodes on them. The caudal end was fixed into position with a hook connected to the force transducer on the Grass polygraph recorder. The contractions of the atrium were driben electrically from the stimulator at a steady rate of 120 heats per min. Square wave pulses hith double thrrshold intensity (about 2.5 V) and a duration of 3 ms were used. The resting tension applied was 600 mg, otherwise the conditions were the same as in the measurement of chronotropic response. A single concentration-response curve was determined with each atrial preparation. The following drugs were used: isoprenaline hydrochloride (Isuprels, Winthrop), phenylephrine hbdrochloride (Neo-slnephrine'. Winthrop) and adrenocorticotropic hormone (Isactid'"', Ferring).
Results The graphs in Fig. 1 show that after 6 and 20 days of physical training by swimming, the positive chronotropic sensitivity to PHE was lowered. This can be seen in the concentrationresponse curves shifted to the right. Because the maximum responses were strongly reduced ( p :.0.01), the EC,,-values did not differ significantly in any of the treated groups. The basic contraction frequency of rat atria was not changed after the swimming exercise as compared to the controls being 233 6 and 226 : 7 beats per min respectively. The results of the inotropic responses to PHE and I S 0 are presented in Fig. 2. The graphs show that physical training by daily swimming for 6 days reduced the sensitivity to PHE but did not change the response to KO. The results are thus similar to those in chronotropic response. The basic contractile force was slightly, but not significantly greater in rats after training by swimming than in controls ( I 76 k 16 mg and 147 i 14 mg, respectively, p ~0.20). The results in Fig. 3 indicate the effects of repeated ACTH-injections for 7 days on adrenergic atrial response. The chronotropic sensitivity to PHE was lowered after this treatment. The maximum response to PHE was reduced to about 50% after ACTH-injections as compared to the control values and it was statistically significant (p -< 0.05). The responses to IS0 were the same in the control and experimental group. ACTH-treatment did not cause any changes in the basic contraction frequency.
+
Discussion The results of the present study are similar to those found in isolated atria from cold-exposed rats (Harri et a/. 1974) and from rats injected chronically with PHE or I S 0 (Tirri et a/. 1976). In all these studies the lowered chronotropic sensitivity to the cr-adrenergic drug, PHE. wa5 observed in isolated atria, but there was no change in response to the b-adrenergic
459
a-RECEPTOR SUBSENSITIVITY IN RAT ATRIA
B
180. A
160
-
140
6days
20days
-
.c
E 120
JI u
-4
60
-
40
I0 9
I
I
I
I
I
I ,
8
7
6
5
4
9
I
I
8
7
phenylephrine
I
I
6
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- log
I
4
B 1
1
0
9
8
7
6
1
1
1
0
9
8
7
6
5
m o l a r concentration of isoprenaline
Fig. 1. Log concentration-response curves for the chronotropic responses to phenylephrine (A) and isoprenaline (B) in atria from control rats (continuous lines) and rats trained by daily swimming for 6 or 20 days (broken lines). The number of animals in each group is in brackets and vertical bars indicate or - S.E.
+
drug, ISO. It could be assumed that the enhanced adrenergic activity in all these experimental conditions was responsible for the subsensitivity of cr-receptors observed (Harri et al. 1974, Tirri et al. 1976). The higher level of noradrenaline, as produced by cold, repeated injections of adrenergic drugs or physical training, could thus account for this lowered sensitivity of a-receptors. The subsensitivity induced by ACTH-injections may be a compensatory action of the stimulating effect of corticosteroids on the adrenergic action in heart muscle as shown in vitro by Kaumann (1972). On the other hand, the decreased sympathetic activity in rats resulting from decentralization or 6-hydroxydopamine treatment causes supersensitivity to noradrenaline but not to I S 0 (Trendelenburg 1963, Johansson 1973). This may also suggest a role of a-receptors in this supersensitivity. Kunos et al. (1973) have suggested that cardiac a- and b-receptors represent allosteric conformations of the same structure. They further suggest (Kunos et al. 1974) that changes in the thyroid hormone level result in an interconversion of myocardial a- and P-receptors. Our present and previous results indicate that the subsensitivity of a-receptors was not associated with a simultaneous increase in /%receptor response. This indicated that there was no interconversion of these receptors; thus giving support to Benfey (1975) who has also reported an opposing suggestion to the adrenoreceptor transformation hypothesis.
460
ANNELI SILTOVUORI, RAUNO TIRRI AND MIKKO N. E. HARRI
2401 200
160
-
1 120
-
z
0
: C
80.
Fig. 2. Log concentration-response curves for the inotropic responses to phenylephrine and isoprenaline in atria from control rats (continuous lines) and rats trained by swimming for 6 days (broken lines). Th e number of animals is in brackets and vertical bars indicate + or - S.E.
C
f
40-
E C
x
0 -
9
8 7 6 5 4 1 1 1 O Q 8 7 - l o g molar concentrotion o f phenylephrine isoprenoline
6
5
160
140
120
100
a0
60
40
'
20
II
0
(6,
T I $-dLJ
Fig. 3. Log concentration-response curves for the chronotropic responses t o phenylephrine and isoprenaline in atria from control rats (continuous lines) and rats injected with ACTH (3 IU/kg) for a week (broken lines). The number of animals is in brackets and vertical bars indicate
U-RECEPTOR SUBSENSITIVITY IN RAT ATRIA
46 1
The role of thyroxine as an inducer of changes in receptor sensitivity cannot be excluded. It has been shown that cold-exposure (Heroux 1960) and B-adrenergic stimulation by I S 0 (Melander et al. 1975) induce thyroid hormone secretion. Thus a change in sympathetic activity reflects changes in thyroxine levels (Melander et al. 1972). On the other hand, the increased adrenergic action can be induced by an increase of thyroxine hormone level, especially in hypothyroid or young animals (Swanson 1956, Lagerspetz et al. 1966). Thus, the changed adrenergic sensitivity, even when caused by altered thyroxine level, could also be explained by a changed adrenergic action. This study was supported by The Academy of Finland.
References BENFEY, B. G., Temperature dependence of phenoxybenzamine effects and the adrenoceptor transformation hypothesis. Nature (Lond.) 1975. 256. 745-747. G. A. and C. C . JORDAN, Temperature modulation of alpha- and beta-receptors in the isolated BUCKLEY, frog heart. Brit. J. Pharmacol. 1970. 38. 394-398. The development of supersensitivity to norepinephrine after FLEMING,W. W. and U. TRENDELENBURG, pretreatment with reserpine. J. Pharmacol. exp. Ther. 1961. 133. 41-51. HARRI,M. N. E., Temperature dependent sensitivity of adrenoreceptors in the toad’s heart. Acta Pharmacol. (Kbh.) 1973. 33. 273-279. and R. TIRRI,Changed chronotropic sensitivity to sympathomimetic amines HARRI,M. N. E., L. MELENDER in isolated atria from rats following cold acclimation. Exgerientia (Basel) 1974. 30. 1041-1043. O . , Adjustment of the adrenal cortex and thyroid during cold acclimation. Fed. Proc. 1960. 19. HEROUX, 82-85. JOHANSSON, B., Effects of propranolol and a new cardioselective beta-blocker, H 93/26, on responses of isolated rat atria to isoprenaline and noradrenaline. Europ. J. Pharmacol. 1973. 24. 194-204. KAUMANN, A. J., Potentiation of the effects of isoprenaline and noradrenaline by hydrocortisone in cat heart muscle. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 1972. 273. 134-153. Evidence favouring the existence of a single adrenergic receptor. Nature KUNOS,G. and M. SZENTIVANYI, (Lond.) 1968. 217. 1077-1078. Transformation of adrenergic receptors in the myocardium. KUNOS,G., M. S. YONGand M. NICKERSON, Nature New Biol. 1973. 241. 119-120. and M. NICKERSON, Effects of thyroid state on adrenoceptor properties. KUNOS,G., I. VERMES-KUNOS Nature (Lond.) 1974. 250. 779-781. LAGERSPETZ, K. Y. H., L. AUVINEN and R. TIRRI,The postnatal development of the metabolic response to adrenaline in mice. Ann. Med. exp. Fenn. 1966. 44. 67-70. Sympathetic activation of thyroid secretion. Endocrinology MELANDER, A,, E. NILSSONand F. SUNDLER, 1972. 90. 194-199. A,, E. RANKLEV, F. SUNDLER and U. WESTGREN,Beta,-adrenergic stimulation of thyroid MELANDER, hormone secretion. Endocrinology 1975. 97. 332-336. NAKASHIMA, M., K. MAEDA,A. SEKIYAand Y. HAGNIO,Effect of hypothyroid status on myocardial responses to sympathomimetic drugs. Jap. J. Pharmacol. 1971. 21. 819-825. SWANSON, H. E., The effect o r temperature on the potentiation of adrenalin by thyroxine in the albino rat. Endocrinology 1956. 60. 205-213. SZENTIVANYI, M., G. KUNOSand A. JUHASZ-NAGY, Modulator theory of adrenergic receptor mechanism : vessels of the dog hindlimb. Amer. J. Physiol. 1970 a. 218. 869-875. and A. JUHASZ-NAGY, The adrenergic reactions of the coronaries in view of a SZENTIVANYI, M., G. KLINOS new hypothesis of receptors. Acta physiol. Acad. hung. 1970 b. 37. 427-428. TIRRI,R., A. SILTOVUORI and M. N. E. HARRI,Alpha-receptor subsensitivity of isolated atria from rats following repeated injections of phenylephrine or isoprenaline. Experientiu (Basel) 1976.32. 1283-1285. TR~NDELENBURG, U., Supersensitivity and subsensitivity to sympathomimetic amines. Pharmacol. Rec. 1963. 15. 225-276. D. P. and W. W. FLEMING,Sensitivity changes in the dog heart to norepinephrine, calcium and WESTFALL, aminophylline resulting from pretreatment with reserpine. J. Pharmacol. exp. Ther. 1968. 159. 98-106.
