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Endogenous prostaglandins modulate adrenal catecholamine secretion
489
European Journal of Pharmacology, 58 (1979) 489--492 © Elsevier/North-Holland Biomedical Press
Short communication ENDOGENOUS PROSTAGLANDINS MODULATE ADRENAL CATECHOLAMINE SECRETION NILI FEUERSTEIN *, GIORA FEUERSTEIN and YEHUDA GUTMAN **,§
Department of Pharmacology, The Hebrew University --Hadassah, School of Medicine, Jerusalem, Israel Received 7 August 1979, accepted 10 August 1979
N. FEUERSTEIN, G. FEUERSTEIN and Y. GUTMAN, Endogenous prostaglandins modulate adrenal catecholamine secretion, European J. Pharmacol. 58 (1979) 489--492. Adrenal catecholamine secretion induced by haemorrhage in the cat was increased by administration of indomethacin to intact or to bilaterally nephrectomized animals. Infusion of PGE2 (but aot of PGF2~ ) suppressed the increased catecholamine secretion caused by indomethacin. Catecholamines
Indomethacin
PGE:
Adrenal
1. Introduction
We have previously described the suppression of catecholamine (CA) secretion from the rat adrenal medulla in vitro by PGE, (Boonyaviroj and Gutman, 1975). This was later confirmed for the human adrenal medulla (Boonyaviroj and Gutman, 1977). However, it is not clear from these experiments whether endogenous prostaglandins play a role in the modulation of CA secretion from the adrenal medulla in vivo. The secretion of CA from the adrenal medulla can be induced in vivo by various stimuli. We have recently studied the release of CA into the adrenolumbar vein of the cat in vivo, following haemorrhage (Feuerstein and Gutman, 1971). The increased secretion of CA induced by this stimulus in the cat is composed preferentially of noradrenaline (NA) and is mediated to a
* This report is part of a thesis for the MSc in Medical Science (Pharmacology) of N.F. ** Established investigator of the Chief Scientist's Bureau, Israeli Minister of Health. § Please send all correspondence to: Dr. Y. Gutman, Dept. Pharmacology, School of Medicine, Jerusalem, Israel.
large extent by renin-angiotensin (Feuerstein and Gutman 1971; Feuerstein et al., 1977). To assess whether prostaglandins (PG) play a modulating role in adrenal CA secretion in vivo, we have studied the effect of an inhibitor of prostaglandin synthesis, indomethacin, on the adrenal CA secretion induced by haemorrhage in the cat. The results presented in this report suggest that endogenous prostaglandins modulate the stimulated secretion of CA from the adrenal medulla.
2. Materials and methods 2.1. Animals
Cats of either sex, weighing 2.5--4 kg were used throughout. The experiments were carried out under pentobarbital anesthesia (50 mg/kg i.m.). The left adrenolumbar vein was cannulated, as described previously (Feuerstein and Gutman, 1971) and adrenal vein blood was collected into ice-cooled tubes. Each tube contained 0.5 ml of 1% EDTA and 1% ascorbic acid, to suppress oxidation of the catecholamines.
490
2.2. Procedures
Bilateral nephrectomy was performed under pentobarbital anesthesia after ligation of the kidney stalk, on the morning of the experiment. Haemorrhage was induced by withdrawing 14 ml/kg of blood from the femoral artery, over a period of 10 min. Indomethacin was dissolved in 0.2 M Na2CO3. The concentration of the indomethacin solution was 7 mg/ml. A total dose of 15 mg/kg was infused over a period of 1 h starting 75 min before the onset of haemorrhage. PGF2~ and PGE2, at a concentration of 10 mg/ml, were infused at the rate of 0.3 pg/ kg R min for 70 min, starting with the onset of haemorrhage. Adrenolumbar vein blood was collected over consecutive 10-min periods up to 70 min after haemorrhage. The average secretion rate of adrenal catecholamines during the t w o periods preceding haemorrhage was taken as control value. 2.3. Catecholamine isolation and assay
The blood samples were centrifuged to separate plasma from erythrocytes. The plasma samples were then acidified with trichloroacetic acid (TCA) to a final concentration of 0.4 M. The denatured proteins were sedimented and the supernatant was treated with K~CO3 to adjust the pH to 5.5 (to precipitate KC104). After separation of the precipitate, the pH was adjusted to 8.4 and the samples were passed through alumina columns. The CA were eluted and passed through columns of Bio-ttex 70 (Feuerstein et al., 1977). Assay of adrenaline (A) and noradrenaline (NA) was carried o u t using a modified trihydroxyindole method, as described previously (Feuerstein et al., 1977). The total CA were calculated from the amounts of A and NA and the results expressed as adrenal CA secretion/kg b o d y weight Xl0 min. The results are given as mean
N. FEUERSTEIN ET AL.
+- S.E. and statistical analysis was done using Student's t-test. 2.4. Chemicals
Indomethacin was kindly supplied by Assia-Riesel, Ramat Gan, Israel. PGE2 and PGF2~ were generously provided b y Dr. John Pike of Upjohn Co. Inc. Kalamozoo, Mi., U.S.A.
3. Results The response of adrenal CA to haemorrhage as previously described (Feuerstein and Gutman, 1971) was confirmed (fig. 1A). CA secretion into the adrenal lumbar vein increased seven-fold following heamorrhage, as compared to the secretion rate before haemorrhage. Our previous observation of a preferential increase in NA secretion following haemorrhage in the cat was also confirmed: while during the control period NA constituted only 35 + 7% of the total CA secreted, this proportion increased to 68 + 5% 1 h after haemorrhage. The continuous rise of CA secretion following haemorrhage was probably due to the fact that hypovolemia and blood pressure did not return to control levels throughout the experiment (not shown in figure) and thus constituted a continuous drive for further secretion of CA. When indomethacin, an inhibitor of prostaglandin synthesis was infused following haemorrhage there was a substantial increase of the rate of CA secretion from the adrenal medulla {fig. 1A). The increase by indomethacin of the CA secretion induced by haemorrhage was approximately four times the secretion induced by haemorrhage alone. During the control period, before induction of haemorrhage, the adrenal CA secretion rate in indomethacin-treated animals did n o t differ from that of control animals, although the rate tended to increase (50 + 5 as compared to 35 + 7 ng/kg × 10 min in indomethacintreated and control animals, respectively; dif-
PROSTAGLANDINS AND ADRENAL CATECHOLAMINES
C.
Indometh. Ind~.oPGF2o(
1000
•=E
XI
500
o
1 o
~ v c .O
0
Indomet°hPGE2 '
¢-E ' °E moo A
a
'
'
H ~ :
Jndometh.
B
500
Indometh,
Control 0
20
40
60
0~
20
40
60
minutes Fig. 1. Effect of i n d o m e t h a c i n and of PGE 2 and PGF2~ on adrenal c a t e c h o l a m i n e secretion in response to haemorrhage in the cat. J'H, haemorrhage induced by withdrawal of 14 m l / k g blood from the femoral artery. Results given as mean + S.E. A, control: adrenal catecholamine secretion following haemorrhage ( n = 8). I n d o m e t h . : adrenal catecholamine secretion following haemorrhage in cats given i n d o m e t h a c i n 0.25 mg/kg × min for 60 min, starting 75 min before the onset of haemorrhage (n = 8). B, E x p e r i m e n t s in bilaterally n e p h r e c t o m i z e d cats; control: adrenal catecholamine secretion following haemorrhage (n = 7). I n d o m e t h . : adrenal catecholamine secretion following haemorrhage in cats pretreated with i n d o m e t h a c i n , as in fig. 1A (n = 8). C, I n d o m e t h . : adrenal c a t e c h o l a m i n e secretion following haemorrhage in cats pretreated with i n d o m e t h a c i n (as in 1A and 1B) (n = 8). I n d o m e t h . + PGF2~: adrenal c a t e c h o l a m i n e secretion following haemorrhage in cats pretreated with i n d o m e t h a c i n and infused with PGF2a 0.3 pg/kg × min for 70 rain, starting with onset of haemorrhage (n = 5). I n d o m e t h . + PGE2: adrenal catecholamine secretion following haemorrhage in cats pretreated with i n d o m e t h a c i n and infused with PGE2 0.3 pg/kg × min for 70 min, starting with onset of haemorrhage (n = 8). * P < 0.05; • *P<0.025; ***P<0.02; ~P<0.01; /x/~p< 0.005; • P < 0.001. In A and B P was calculated for the difference b e t w e e n i n d o m e t h a c i n - t r e a t e d and control groups. In C P was calculated for the difference b e t w e e n i n d o m e t h a c i n + PGE2 and indomethacin alone.
491
ference not statistically significant}. Since we have previously shown that a major part of the adrenal CA response to haemorrhage depends on the increased release of renin from the kidney (Feuerstein et al., 1977) and since indomethacin could affect secretion of renin, it was of importance to establish whether the e~fect on adrenal CA secretion by indomethacin was secondary to an effect on the kidney or a primary one. To this end, the experiment was performed in cats after acute bilateral nephrectomy. Bilateral nephrectomy caused a considerable attenuation of the adrenal CA response to haemorrhage (fig. 1B) thus supporting our previous report (Feuerstein et al., 1977): 69 + 13 as compared to 243 + 83 ng CA/kg × 10 min following haemorrhage, in nephrectomized and control cats, respectively. Since angiotensin can directly release CA from adrenal medulla, whether injected into the adrenal circulation or added to adrenals in vitro (to be published} it would seem plausible that the effect of angiotensin is not exerted by sensitization of a reflex arc but by direct stimulation of the adrenal medulla. However, even in the nephrectomized cats, administration of indomethacin caused a substantial increase of the adrenal CA response to haemorrhage, a seven-fold increase in the indomethacin-treated cats as compared to control nephrectomized cats (fig. 1B). Thus, the presence of the kidney is not essential for the effect of indomethacin on the CA response. Here, again, it should be noted that the secretion rate of CA from the adrenal gland during the control period was n o t significantly different in the indomethacintreated and control groups {53 + 8 and 33 + 6 ng/kg X 10 min in indomethacin and control groups, respectively}, although a tendency to increased secretion was noted. To assess whether the effect of indomethacin was due to suppression of prostaglandin synthesis and not to a different mechanism, a third type of experiment was performed: in addition to the infusion of indomethacin, two types of prostaglandins were administered,
492
PGE2 and PGF2~, as seen in fig. 1C. The marked increase of the rate of adrenal CA secretion following haemorrhage in indomethacin-treated cats was substantially suppressed b y PGE: to levels even lower than in untreated cats following haemorrhage. A striking difference between the two prostaglandins was observed, i.e., PGF2~ had no significant effect on the increased CA secretion caused by indomethacin.
4. Discussion
The experiments reported here indicate that suppression of prostaglandin synthesis caused an increased adrenal CA response to haemorrhage. This could fit the assumption that prostaglandins suppress the response of adrenal CA secretion and that the secretion observed in intact cats is already the net result of stimulation and (partial) suppression by endogenous prostaglandins. The nature of the prostaglandin involved may be indicated by the preferential effect of PGE2 as compared to the ineffectiveness of PGF2~ in suppressing the adrenal CA secretion rate. We have previously observed in both rat and human adrenal medulla i n c u b a t e d i n vitro that PGE2 could inhibit the secretion of CA into the medium while P G F ~ had no effect (Boonyaviroj and Gutman, 1975). Conflicting reports on stimulation of CA release b y PGE1 (Kayaalp and Tfirker, 1967) may have been due to species differences (dog rather than cat) and to the rather large dose used (1--4 pg/kg of PGE1 injected into the aorta, close to the origin of the blood supply to the adrenal). The finding that suppression of PG synthesis was particularly effective during intensive stimulation of CA secretion (haemorrhage) but n o t during the control period may suggest that increased PG synthesis occurs during or as a result of increased sympathetic stimulation. This is supported by direct evidence for increased PG release following sympathetic stimulation (Hedqvist, 1970).
N. FEUERSTEIN ET AL.
Furthermore, an increased urinary excretion of CA during indomethacin treatment has been reported with a different type of stimulation of CA release, i.e., exposure to cold in the rat (Stj~irne, 1971). It is suggested, therefore, that PG, probably of type E, play a physiological role in the control of adrenal CA secretion, similar to that suggested for adrenergic nerve endings (Hedqvist, 1970). As for the origin of PG which affect CA secretion from the adrenal gland, the present experiments cannot clarify whether they are produced in the adrenal gland or transported to the gland through the circulation. However, the kidneys can be ruled o u t as the sole site of origin for these PG since the effect of indomethacin was evident even in nephrectomized cats. The nature of the PG involved (PGE or another PG) is also n o t shown by the present experiments; the efficacy of infusion of PGE may suggest that this is one of the PG involved.
References Boonyaviroj, P. and Y. Gutman 1975, Adrenergie stimulants, prostaglandins and catecholamine release from the adrenal gland in vitro, Prostaglandins 10, 109. Boonyaviroj, P. and Y. Gutman, 1975, Inhibition by PGE 2 and phenylephrine of catecholamine release from human adrenal in vitro, European J. Pharmacol. 41, 73. Feuerstein, G., P. Boonyaviroj and Y. Gutman, 1977, Renin angiotensin mediation of adrenal catecholamine secretion induced by haemorrhage, European J. Pharmacol. 4 4 , 1 3 1 . Feuerstein, G. and Y. Gutman, 1971, Preferential secretion of adrenaline or noradrenaline by the cat adrenal in vivo in response to different stimuli, Brit. J. Pharmacol. 4 3 , 1 6 4 . Hedqvist, P., 1970, Studies on the effect of prostaglandins E 1 and E 2 on the sympathetic neuromuscular transmission in some animal tissues, Acta Physiol. Scand. 79, Suppl. 345, 1. Kayaalp, S.O. and P.K. Tiirker, 1967, Release of catecholamines from the adrenal medulla by prostaglandin El, European J. Pharmacol. 2, 175. Stj~irne, L., 1971, Hyperexcretion of catecholamines induced by indomethacin, Acta Physiol. Scand. 83,574.
European Journal of Pharmacology, 58 (1979) 489--492 © Elsevier/North-Holland Biomedical Press
Short communication ENDOGENOUS PROSTAGLANDINS MODULATE ADRENAL CATECHOLAMINE SECRETION NILI FEUERSTEIN *, GIORA FEUERSTEIN and YEHUDA GUTMAN **,§
Department of Pharmacology, The Hebrew University --Hadassah, School of Medicine, Jerusalem, Israel Received 7 August 1979, accepted 10 August 1979
N. FEUERSTEIN, G. FEUERSTEIN and Y. GUTMAN, Endogenous prostaglandins modulate adrenal catecholamine secretion, European J. Pharmacol. 58 (1979) 489--492. Adrenal catecholamine secretion induced by haemorrhage in the cat was increased by administration of indomethacin to intact or to bilaterally nephrectomized animals. Infusion of PGE2 (but aot of PGF2~ ) suppressed the increased catecholamine secretion caused by indomethacin. Catecholamines
Indomethacin
PGE:
Adrenal
1. Introduction
We have previously described the suppression of catecholamine (CA) secretion from the rat adrenal medulla in vitro by PGE, (Boonyaviroj and Gutman, 1975). This was later confirmed for the human adrenal medulla (Boonyaviroj and Gutman, 1977). However, it is not clear from these experiments whether endogenous prostaglandins play a role in the modulation of CA secretion from the adrenal medulla in vivo. The secretion of CA from the adrenal medulla can be induced in vivo by various stimuli. We have recently studied the release of CA into the adrenolumbar vein of the cat in vivo, following haemorrhage (Feuerstein and Gutman, 1971). The increased secretion of CA induced by this stimulus in the cat is composed preferentially of noradrenaline (NA) and is mediated to a
* This report is part of a thesis for the MSc in Medical Science (Pharmacology) of N.F. ** Established investigator of the Chief Scientist's Bureau, Israeli Minister of Health. § Please send all correspondence to: Dr. Y. Gutman, Dept. Pharmacology, School of Medicine, Jerusalem, Israel.
large extent by renin-angiotensin (Feuerstein and Gutman 1971; Feuerstein et al., 1977). To assess whether prostaglandins (PG) play a modulating role in adrenal CA secretion in vivo, we have studied the effect of an inhibitor of prostaglandin synthesis, indomethacin, on the adrenal CA secretion induced by haemorrhage in the cat. The results presented in this report suggest that endogenous prostaglandins modulate the stimulated secretion of CA from the adrenal medulla.
2. Materials and methods 2.1. Animals
Cats of either sex, weighing 2.5--4 kg were used throughout. The experiments were carried out under pentobarbital anesthesia (50 mg/kg i.m.). The left adrenolumbar vein was cannulated, as described previously (Feuerstein and Gutman, 1971) and adrenal vein blood was collected into ice-cooled tubes. Each tube contained 0.5 ml of 1% EDTA and 1% ascorbic acid, to suppress oxidation of the catecholamines.
490
2.2. Procedures
Bilateral nephrectomy was performed under pentobarbital anesthesia after ligation of the kidney stalk, on the morning of the experiment. Haemorrhage was induced by withdrawing 14 ml/kg of blood from the femoral artery, over a period of 10 min. Indomethacin was dissolved in 0.2 M Na2CO3. The concentration of the indomethacin solution was 7 mg/ml. A total dose of 15 mg/kg was infused over a period of 1 h starting 75 min before the onset of haemorrhage. PGF2~ and PGE2, at a concentration of 10 mg/ml, were infused at the rate of 0.3 pg/ kg R min for 70 min, starting with the onset of haemorrhage. Adrenolumbar vein blood was collected over consecutive 10-min periods up to 70 min after haemorrhage. The average secretion rate of adrenal catecholamines during the t w o periods preceding haemorrhage was taken as control value. 2.3. Catecholamine isolation and assay
The blood samples were centrifuged to separate plasma from erythrocytes. The plasma samples were then acidified with trichloroacetic acid (TCA) to a final concentration of 0.4 M. The denatured proteins were sedimented and the supernatant was treated with K~CO3 to adjust the pH to 5.5 (to precipitate KC104). After separation of the precipitate, the pH was adjusted to 8.4 and the samples were passed through alumina columns. The CA were eluted and passed through columns of Bio-ttex 70 (Feuerstein et al., 1977). Assay of adrenaline (A) and noradrenaline (NA) was carried o u t using a modified trihydroxyindole method, as described previously (Feuerstein et al., 1977). The total CA were calculated from the amounts of A and NA and the results expressed as adrenal CA secretion/kg b o d y weight Xl0 min. The results are given as mean
N. FEUERSTEIN ET AL.
+- S.E. and statistical analysis was done using Student's t-test. 2.4. Chemicals
Indomethacin was kindly supplied by Assia-Riesel, Ramat Gan, Israel. PGE2 and PGF2~ were generously provided b y Dr. John Pike of Upjohn Co. Inc. Kalamozoo, Mi., U.S.A.
3. Results The response of adrenal CA to haemorrhage as previously described (Feuerstein and Gutman, 1971) was confirmed (fig. 1A). CA secretion into the adrenal lumbar vein increased seven-fold following heamorrhage, as compared to the secretion rate before haemorrhage. Our previous observation of a preferential increase in NA secretion following haemorrhage in the cat was also confirmed: while during the control period NA constituted only 35 + 7% of the total CA secreted, this proportion increased to 68 + 5% 1 h after haemorrhage. The continuous rise of CA secretion following haemorrhage was probably due to the fact that hypovolemia and blood pressure did not return to control levels throughout the experiment (not shown in figure) and thus constituted a continuous drive for further secretion of CA. When indomethacin, an inhibitor of prostaglandin synthesis was infused following haemorrhage there was a substantial increase of the rate of CA secretion from the adrenal medulla {fig. 1A). The increase by indomethacin of the CA secretion induced by haemorrhage was approximately four times the secretion induced by haemorrhage alone. During the control period, before induction of haemorrhage, the adrenal CA secretion rate in indomethacin-treated animals did n o t differ from that of control animals, although the rate tended to increase (50 + 5 as compared to 35 + 7 ng/kg × 10 min in indomethacintreated and control animals, respectively; dif-
PROSTAGLANDINS AND ADRENAL CATECHOLAMINES
C.
Indometh. Ind~.oPGF2o(
1000
•=E
XI
500
o
1 o
~ v c .O
0
Indomet°hPGE2 '
¢-E ' °E moo A
a
'
'
H ~ :
Jndometh.
B
500
Indometh,
Control 0
20
40
60
0~
20
40
60
minutes Fig. 1. Effect of i n d o m e t h a c i n and of PGE 2 and PGF2~ on adrenal c a t e c h o l a m i n e secretion in response to haemorrhage in the cat. J'H, haemorrhage induced by withdrawal of 14 m l / k g blood from the femoral artery. Results given as mean + S.E. A, control: adrenal catecholamine secretion following haemorrhage ( n = 8). I n d o m e t h . : adrenal catecholamine secretion following haemorrhage in cats given i n d o m e t h a c i n 0.25 mg/kg × min for 60 min, starting 75 min before the onset of haemorrhage (n = 8). B, E x p e r i m e n t s in bilaterally n e p h r e c t o m i z e d cats; control: adrenal catecholamine secretion following haemorrhage (n = 7). I n d o m e t h . : adrenal catecholamine secretion following haemorrhage in cats pretreated with i n d o m e t h a c i n , as in fig. 1A (n = 8). C, I n d o m e t h . : adrenal c a t e c h o l a m i n e secretion following haemorrhage in cats pretreated with i n d o m e t h a c i n (as in 1A and 1B) (n = 8). I n d o m e t h . + PGF2~: adrenal c a t e c h o l a m i n e secretion following haemorrhage in cats pretreated with i n d o m e t h a c i n and infused with PGF2a 0.3 pg/kg × min for 70 rain, starting with onset of haemorrhage (n = 5). I n d o m e t h . + PGE2: adrenal catecholamine secretion following haemorrhage in cats pretreated with i n d o m e t h a c i n and infused with PGE2 0.3 pg/kg × min for 70 min, starting with onset of haemorrhage (n = 8). * P < 0.05; • *P<0.025; ***P<0.02; ~P<0.01; /x/~p< 0.005; • P < 0.001. In A and B P was calculated for the difference b e t w e e n i n d o m e t h a c i n - t r e a t e d and control groups. In C P was calculated for the difference b e t w e e n i n d o m e t h a c i n + PGE2 and indomethacin alone.
491
ference not statistically significant}. Since we have previously shown that a major part of the adrenal CA response to haemorrhage depends on the increased release of renin from the kidney (Feuerstein et al., 1977) and since indomethacin could affect secretion of renin, it was of importance to establish whether the e~fect on adrenal CA secretion by indomethacin was secondary to an effect on the kidney or a primary one. To this end, the experiment was performed in cats after acute bilateral nephrectomy. Bilateral nephrectomy caused a considerable attenuation of the adrenal CA response to haemorrhage (fig. 1B) thus supporting our previous report (Feuerstein et al., 1977): 69 + 13 as compared to 243 + 83 ng CA/kg × 10 min following haemorrhage, in nephrectomized and control cats, respectively. Since angiotensin can directly release CA from adrenal medulla, whether injected into the adrenal circulation or added to adrenals in vitro (to be published} it would seem plausible that the effect of angiotensin is not exerted by sensitization of a reflex arc but by direct stimulation of the adrenal medulla. However, even in the nephrectomized cats, administration of indomethacin caused a substantial increase of the adrenal CA response to haemorrhage, a seven-fold increase in the indomethacin-treated cats as compared to control nephrectomized cats (fig. 1B). Thus, the presence of the kidney is not essential for the effect of indomethacin on the CA response. Here, again, it should be noted that the secretion rate of CA from the adrenal gland during the control period was n o t significantly different in the indomethacintreated and control groups {53 + 8 and 33 + 6 ng/kg X 10 min in indomethacin and control groups, respectively}, although a tendency to increased secretion was noted. To assess whether the effect of indomethacin was due to suppression of prostaglandin synthesis and not to a different mechanism, a third type of experiment was performed: in addition to the infusion of indomethacin, two types of prostaglandins were administered,
492
PGE2 and PGF2~, as seen in fig. 1C. The marked increase of the rate of adrenal CA secretion following haemorrhage in indomethacin-treated cats was substantially suppressed b y PGE: to levels even lower than in untreated cats following haemorrhage. A striking difference between the two prostaglandins was observed, i.e., PGF2~ had no significant effect on the increased CA secretion caused by indomethacin.
4. Discussion
The experiments reported here indicate that suppression of prostaglandin synthesis caused an increased adrenal CA response to haemorrhage. This could fit the assumption that prostaglandins suppress the response of adrenal CA secretion and that the secretion observed in intact cats is already the net result of stimulation and (partial) suppression by endogenous prostaglandins. The nature of the prostaglandin involved may be indicated by the preferential effect of PGE2 as compared to the ineffectiveness of PGF2~ in suppressing the adrenal CA secretion rate. We have previously observed in both rat and human adrenal medulla i n c u b a t e d i n vitro that PGE2 could inhibit the secretion of CA into the medium while P G F ~ had no effect (Boonyaviroj and Gutman, 1975). Conflicting reports on stimulation of CA release b y PGE1 (Kayaalp and Tfirker, 1967) may have been due to species differences (dog rather than cat) and to the rather large dose used (1--4 pg/kg of PGE1 injected into the aorta, close to the origin of the blood supply to the adrenal). The finding that suppression of PG synthesis was particularly effective during intensive stimulation of CA secretion (haemorrhage) but n o t during the control period may suggest that increased PG synthesis occurs during or as a result of increased sympathetic stimulation. This is supported by direct evidence for increased PG release following sympathetic stimulation (Hedqvist, 1970).
N. FEUERSTEIN ET AL.
Furthermore, an increased urinary excretion of CA during indomethacin treatment has been reported with a different type of stimulation of CA release, i.e., exposure to cold in the rat (Stj~irne, 1971). It is suggested, therefore, that PG, probably of type E, play a physiological role in the control of adrenal CA secretion, similar to that suggested for adrenergic nerve endings (Hedqvist, 1970). As for the origin of PG which affect CA secretion from the adrenal gland, the present experiments cannot clarify whether they are produced in the adrenal gland or transported to the gland through the circulation. However, the kidneys can be ruled o u t as the sole site of origin for these PG since the effect of indomethacin was evident even in nephrectomized cats. The nature of the PG involved (PGE or another PG) is also n o t shown by the present experiments; the efficacy of infusion of PGE may suggest that this is one of the PG involved.
References Boonyaviroj, P. and Y. Gutman 1975, Adrenergie stimulants, prostaglandins and catecholamine release from the adrenal gland in vitro, Prostaglandins 10, 109. Boonyaviroj, P. and Y. Gutman, 1975, Inhibition by PGE 2 and phenylephrine of catecholamine release from human adrenal in vitro, European J. Pharmacol. 41, 73. Feuerstein, G., P. Boonyaviroj and Y. Gutman, 1977, Renin angiotensin mediation of adrenal catecholamine secretion induced by haemorrhage, European J. Pharmacol. 4 4 , 1 3 1 . Feuerstein, G. and Y. Gutman, 1971, Preferential secretion of adrenaline or noradrenaline by the cat adrenal in vivo in response to different stimuli, Brit. J. Pharmacol. 4 3 , 1 6 4 . Hedqvist, P., 1970, Studies on the effect of prostaglandins E 1 and E 2 on the sympathetic neuromuscular transmission in some animal tissues, Acta Physiol. Scand. 79, Suppl. 345, 1. Kayaalp, S.O. and P.K. Tiirker, 1967, Release of catecholamines from the adrenal medulla by prostaglandin El, European J. Pharmacol. 2, 175. Stj~irne, L., 1971, Hyperexcretion of catecholamines induced by indomethacin, Acta Physiol. Scand. 83,574.