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Adrenal catecholamine response to haemorrhage abolished by an angiotensin antagonist
European Journal of Pharmacology, 41 (1977) 85--86
85
© Elsevier/North-Holland Biomedical Press, Amsterdam -- Printed in The Netherlands
Rapid communication A D R E N A L CATECHOLAMINE RESPONSE TO H A E M O R R H A G E ABOLISHED BY AN ANGIOTENSIN ANTAGONIST
G. FEUERSTEIN, P. BOONYAVIROJ, Y. GUTMAN*, M.C. KHOSLA** and F.M. BUMPUS**
Department Pharmacology, School of Medicine, Jerusalem, Israel, and **Research Division, Cleveland Clinic, Cleveland, Ohio, U.S.A. Received 3 November 1976, accepted 4 November 1976
Haemorrhage is accompanied by the simultaneous activation of the renin--angiotensin system and the sympathetic nervous system. Angiotensin can stimulate adrenergic mechanisms (Yu and Dickinson, 1971). On the other hand, sympathetic activation can stimulate release of renin and a rise in angiotensin II (Johnson et al., 1971). In many experiments where angiotensin II effects on the sympathetic nervous system have been shown, isolated, in vitro preparations were used or pharmacological doses of angiotensin II were applied. Therefore, in vivo, physiological stimulation, affecting both the renin--angiotensin system and the sympathetic nervous system, would be more important to establish whether these systems are interdependent. We have used acute haemorrhage in the cat to study which was the primary and which was the secondary response: is renin responsible for adrenal catecholamine (CA) secretion or is catecholamine the cause for increased renin release. To asses the role of angiotensin II we have used Sar ~-IleS-angiotensin II, which had been reported to be a specific and competitive antagonist of angiotensin II (Sweet et al., 1973). Male cats weighing 2.5--3.4 kg were anesthetized with pentobarbitone sodium (50 *Established Investigator, Chief Scientist's Bureau, Israeli Ministry of Health.
mg/kg, i.m.) and the femoral artery and vein were cannulated. Left adrenal vein blood samples were collected through a polyethylene cannula which was inserted into the adrenolumbar vein. Haemorrhage was induced by withdrawal of 13.3 ml/kg of arterial blood, over a 10 min period. Adrenaline and noradrenaline in the adrenal vein blood were assayed with the trihydroxyindole method, after isolation on aluminium oxide columns followed by passage through Bio-Rex 70 columns. Infusion of Sat 1 -Ile s -angiotensin II: 50 ~g of Sat 1-IleS-angiotensin II were dissolved in 10 ml of 0.9% NaC1. Intravenous infusion (0.4 ~g/kg/min) was started 2 min before the induction of haemorrhage, and continued over a 40 min period. Haemorrhage induced an immediate increase of CA o u t p u t from the adrenal gland of the intact anaesthetized cat. The peak secretion rate following haemorrhage was 164.3 + 38.5 ng/kg/10 min, in comparison to 52.8 + 7.8 ng/kg/10 min, during the control period (p < 0.01, n = 8). Furthermore, there was a significant change in adrenaline/noradrenaline ratio: while during the control period adrenaline comprised 79.3 + 5.5% of total CA in adrenal vein plasma, this percentage decreased after haemorrhage to 55.4 -+ 5.8% (p < 0.01). Thus, haemorrhage elicited in the cat a relatively noradrenalinergic response, as we
86
have previously reported (Feuerstein and Gutman, 1971). Fig. 1 shows that during infusion of the angiotensin II antagonist, Sarl-IleS-angio tensin II, the increase of catecholamine secretion from the adrenal gland was completely abolished. When the infusion of the antagonist was discontinued, adrenal CA secretion rate increased gradually to the level found in cats not infused with the antagonist. CA-% o f c o n t r o l 4O0
-
m
•
200
0
i
~
I
-20
0
20
l
I 60
I rni n
Fig. 1. The effect of Sarl-IleS-angiotensin II on catecholamine release from the adrenal gland of cats exposed to haemorrhage. Ordinate: Catecholamine as percent of secretion rate during control period, preceding haemorrhage. ¢>---o: Intact cats exposed to haemorrhage (n = 8). • e: Sar 1-Iles-angiotensin II infusion in cats exposed to haemorrhage (n = 7). H: Arrow indicates time of bleeding induction. Vertical bars: S.E.M. [_Sarl-IleS-AII_J: infusion of antagonist (40 min) at the rate of 0.4 /.tg/kg/min. *p < 0.02; **p < 0.01; ***p < 0.001 for difference between antagonist-infused cats and control cats.
During the infusion of the angiotensin antagonist following haemorrhage, the composition of CA (i.e. % adrenaline) did not differ from that found in control cats w i t h o u t haemorrhage (80.0 + 6.5%). However, after cessation of Sat 1 -Ile s -angiotensin II infusion,
simultaneously with the increased rate of CA secretion, the percentage of adrenaline decreased significantly to 54.9 + 8.5% (p < 0.05). Thus, the typical 'noradrenalinergic' response has emerged once the angiotensin II antagonist infusion was discontinued. The experiments reported in this communication demonstrate the dependence of the adrenal catecholamine response to haemorrhage on circulating angiotensin. Since in previous experiments {unpublished data) we had noticed that denervated adrenal glands do not respond to haemorrhage even in the presence of increased concentrations of plasma angiotensin II, a central site of angiotensin action may be postulated. Since Sat 1-Ile 8angiotensin II has been shown to pass the blood-brain-barrier in a manner similar to angiotensin II (Hoffman and Philips, 1976), its observed effect may result from an action in the central nervous system. These experiments indicate that renin generation of angiotensin II is the mediator for increased release from the adrenal medulla following haemorrhage. References Feuerstein, G. and Y. Gutman, 1971, Preferential secretion of adrenaline and noradrenaline by the cat adrenal in vivo, in response to different stimuli, Brit. J. Pharmacol. 4 3 , 7 6 4 . Hoffman, W.E. and M.I. Philips, 1976, Evidence for Sar 1-Iles-angiotensin II crossing the blood brain barrier to antagonize central effects of angiotensin II, Brain Res. 109,541. Johnson, Y.A., J.O. Davis and R.T. Whitty, 1971, Effect of catecholamines and renal nerve stimulation on renin release in the non-filtering kidney, Circulation Res. 29,646. Sweet, C.S., C.M. Ferrario, M.C. Khosla and F.M. Bumpus, 1973, Antagonism of peripheral and central effects of angiotensin II by [1-sarcosine, 8-Ileucine]-angiotensin II, J. Pharmacol. Exptl. Therap. 185, 35. Yu, R. and C.J. Dickinson, 1971, Progressive pressor response to angiotensin II in the rabbit: role of sympathetic nervous system, Arch. Intern. Pharmacoldyn. Therap. 191, 24.
85
© Elsevier/North-Holland Biomedical Press, Amsterdam -- Printed in The Netherlands
Rapid communication A D R E N A L CATECHOLAMINE RESPONSE TO H A E M O R R H A G E ABOLISHED BY AN ANGIOTENSIN ANTAGONIST
G. FEUERSTEIN, P. BOONYAVIROJ, Y. GUTMAN*, M.C. KHOSLA** and F.M. BUMPUS**
Department Pharmacology, School of Medicine, Jerusalem, Israel, and **Research Division, Cleveland Clinic, Cleveland, Ohio, U.S.A. Received 3 November 1976, accepted 4 November 1976
Haemorrhage is accompanied by the simultaneous activation of the renin--angiotensin system and the sympathetic nervous system. Angiotensin can stimulate adrenergic mechanisms (Yu and Dickinson, 1971). On the other hand, sympathetic activation can stimulate release of renin and a rise in angiotensin II (Johnson et al., 1971). In many experiments where angiotensin II effects on the sympathetic nervous system have been shown, isolated, in vitro preparations were used or pharmacological doses of angiotensin II were applied. Therefore, in vivo, physiological stimulation, affecting both the renin--angiotensin system and the sympathetic nervous system, would be more important to establish whether these systems are interdependent. We have used acute haemorrhage in the cat to study which was the primary and which was the secondary response: is renin responsible for adrenal catecholamine (CA) secretion or is catecholamine the cause for increased renin release. To asses the role of angiotensin II we have used Sar ~-IleS-angiotensin II, which had been reported to be a specific and competitive antagonist of angiotensin II (Sweet et al., 1973). Male cats weighing 2.5--3.4 kg were anesthetized with pentobarbitone sodium (50 *Established Investigator, Chief Scientist's Bureau, Israeli Ministry of Health.
mg/kg, i.m.) and the femoral artery and vein were cannulated. Left adrenal vein blood samples were collected through a polyethylene cannula which was inserted into the adrenolumbar vein. Haemorrhage was induced by withdrawal of 13.3 ml/kg of arterial blood, over a 10 min period. Adrenaline and noradrenaline in the adrenal vein blood were assayed with the trihydroxyindole method, after isolation on aluminium oxide columns followed by passage through Bio-Rex 70 columns. Infusion of Sat 1 -Ile s -angiotensin II: 50 ~g of Sat 1-IleS-angiotensin II were dissolved in 10 ml of 0.9% NaC1. Intravenous infusion (0.4 ~g/kg/min) was started 2 min before the induction of haemorrhage, and continued over a 40 min period. Haemorrhage induced an immediate increase of CA o u t p u t from the adrenal gland of the intact anaesthetized cat. The peak secretion rate following haemorrhage was 164.3 + 38.5 ng/kg/10 min, in comparison to 52.8 + 7.8 ng/kg/10 min, during the control period (p < 0.01, n = 8). Furthermore, there was a significant change in adrenaline/noradrenaline ratio: while during the control period adrenaline comprised 79.3 + 5.5% of total CA in adrenal vein plasma, this percentage decreased after haemorrhage to 55.4 -+ 5.8% (p < 0.01). Thus, haemorrhage elicited in the cat a relatively noradrenalinergic response, as we
86
have previously reported (Feuerstein and Gutman, 1971). Fig. 1 shows that during infusion of the angiotensin II antagonist, Sarl-IleS-angio tensin II, the increase of catecholamine secretion from the adrenal gland was completely abolished. When the infusion of the antagonist was discontinued, adrenal CA secretion rate increased gradually to the level found in cats not infused with the antagonist. CA-% o f c o n t r o l 4O0
-
m
•
200
0
i
~
I
-20
0
20
l
I 60
I rni n
Fig. 1. The effect of Sarl-IleS-angiotensin II on catecholamine release from the adrenal gland of cats exposed to haemorrhage. Ordinate: Catecholamine as percent of secretion rate during control period, preceding haemorrhage. ¢>---o: Intact cats exposed to haemorrhage (n = 8). • e: Sar 1-Iles-angiotensin II infusion in cats exposed to haemorrhage (n = 7). H: Arrow indicates time of bleeding induction. Vertical bars: S.E.M. [_Sarl-IleS-AII_J: infusion of antagonist (40 min) at the rate of 0.4 /.tg/kg/min. *p < 0.02; **p < 0.01; ***p < 0.001 for difference between antagonist-infused cats and control cats.
During the infusion of the angiotensin antagonist following haemorrhage, the composition of CA (i.e. % adrenaline) did not differ from that found in control cats w i t h o u t haemorrhage (80.0 + 6.5%). However, after cessation of Sat 1 -Ile s -angiotensin II infusion,
simultaneously with the increased rate of CA secretion, the percentage of adrenaline decreased significantly to 54.9 + 8.5% (p < 0.05). Thus, the typical 'noradrenalinergic' response has emerged once the angiotensin II antagonist infusion was discontinued. The experiments reported in this communication demonstrate the dependence of the adrenal catecholamine response to haemorrhage on circulating angiotensin. Since in previous experiments {unpublished data) we had noticed that denervated adrenal glands do not respond to haemorrhage even in the presence of increased concentrations of plasma angiotensin II, a central site of angiotensin action may be postulated. Since Sat 1-Ile 8angiotensin II has been shown to pass the blood-brain-barrier in a manner similar to angiotensin II (Hoffman and Philips, 1976), its observed effect may result from an action in the central nervous system. These experiments indicate that renin generation of angiotensin II is the mediator for increased release from the adrenal medulla following haemorrhage. References Feuerstein, G. and Y. Gutman, 1971, Preferential secretion of adrenaline and noradrenaline by the cat adrenal in vivo, in response to different stimuli, Brit. J. Pharmacol. 4 3 , 7 6 4 . Hoffman, W.E. and M.I. Philips, 1976, Evidence for Sar 1-Iles-angiotensin II crossing the blood brain barrier to antagonize central effects of angiotensin II, Brain Res. 109,541. Johnson, Y.A., J.O. Davis and R.T. Whitty, 1971, Effect of catecholamines and renal nerve stimulation on renin release in the non-filtering kidney, Circulation Res. 29,646. Sweet, C.S., C.M. Ferrario, M.C. Khosla and F.M. Bumpus, 1973, Antagonism of peripheral and central effects of angiotensin II by [1-sarcosine, 8-Ileucine]-angiotensin II, J. Pharmacol. Exptl. Therap. 185, 35. Yu, R. and C.J. Dickinson, 1971, Progressive pressor response to angiotensin II in the rabbit: role of sympathetic nervous system, Arch. Intern. Pharmacoldyn. Therap. 191, 24.