European Journal of Pharmacology, 52 (1978) 375--377
375
© Elsevier/North-Holland Biomedical Press
Short communication ANGIOTENSIN II MEDIATION OF A D R E N A L CATECHOLAMINE SECRETION INDUCED BY I N T R A R E N A L ISOPRENALINE INFUSION GIORA FEUERSTEIN t , MICHAEL KRAUSZ *, SILVIA COHEN, YEHUDA GUTMAN t t , MAHESH C. KHOSLA ** and MERLIN F. BUMPUS
Department of Pharmacology, Hebrew University-Hadassah Medical School, and * Department of Surgery, Hadassah University Hospital, Jerusalem, Israel, and ** Research Division, Cleveland Clinic, Cleveland, Ohio, U.S.A. Received 26 September 1978, accepted 28 September 1978
G. FEUERSTEIN, M. KRAUSZ, S. COHEN, Y. GUTMAN, M.C. KHOSLA and M.F. BUMPUS, Angiotensin H mediation of adrenal catecholamine secretion induced by intrarenal isoprenaline infusion, European J. Pharmacol. 52 (1978) 375--377. Isoprenaline infusion into the renal artery of the cat induced an increase in the catecholamine (CA) secretion rate from the adrenal gland. CA release by isoprenaline was preferentially noradrenaline. Intravenous infusion of an angiotensin II ( A I I ) antagonist abolished adrenal CA response to intrarenal isoprenaline injection. It is suggested that intrarenal isoprenaline infusion stimulates renal renin release and A I I production which, in turn, stimulates adrenal CA secretion. Catecholamines
Angiotensin II
Adrenal medulla
1. Introduction
Multiple sites of interaction between the renal renin--angiotensin system and the adrenergic nervous system are known to exist (Buckley and Jandhyala, 1977; Starke et al., 1977). However, there is still controversy as to the role o f A II in regulation of adrenergic functions, since in many experiments, isolated in vitro preparations and pharmacological doses of A I I were used (Hughes and Roth, 1969; Boadle-Biber and Roth, 1972). Moreover, it remains uncertain whether endogenous A II is generated at rates that suffice for activation of adrenomedullar CA secretion. The following in vivo experit Address for correspondence: Dr. G. Feuerstein, Department of Pharmacology, Hebrew UniversityHadassah Medical School, Ein Kerem, Jerusalem, Israel tt Established Investigator of the Chief Scientist's Office, Ministry of Health, Israel.
Isoprenaline
ments were aimed at elucidating the effect of A II, endogenously produced through direct renal renin release, on adrenal gland adrenaline and noradrenaline secretion. To assess the role of A II, Sarl-IleuS-A II was used, which is a specific and competitive A II antagonist (Sweet et al., 1973).
2. Materials and methods Male cats weighing 2.5--4.5 kg were anesthetized with pentobarbitone sodium (45 mg/ kg, i.m.) and the left femoral artery and vein were cannulated. The right kidney was removed through a midabdominal incision and its renal artery stump cannulated with a specially prepared polyethylene cannula (19 G Intracath®; O.D. 0.4 mm). The cannula was inserted through the aorta into the left renal artery, with the tip 0.5 cm distal to the aorta. Infusion of 0.9% NaC1 (0.05 ml/min)
376 i n t o t h e renal a r t e r y was started i m m e d i a t e l y u p o n c a n n u l a t i o n . T h e left a d r e n o l u m b a r vein was c a n n u l a t e d as p r e v i o u s l y described (Feuerstein and Gutman, 1971). I s o p r e n a l i n e s u l p h a t e (Teva Ltd., Jerusalem, Israel) was dissolved in 6.0 ml 0.9% NaC1 and i n f u s e d at a rate o f 0.1 pg/kg/min for 30 min, either intrarenally or i n t r a v e n o u s l y . Sar lIleuS-A II was dissolved in 6.0 ml 0.9% NaC1. I n f u s i o n o f t h e A I I a n t a g o n i s t (at a rate o f 0.4 pg/kg/min) was started at the same t i m e as t h e isoprenaline i n f u s i o n and c o n t i n u e d t h r o u g h o u t t h e rest o f the e x p e r i m e n t . A d r e n a l i n e and n o r a d r e n a l i n e in the adrenal vein b l o o d were assayed with the t r i h y d r o x y i n d o l e m e t h o d a f t e r isolation o n a l u m i n u m o x i d e c o l u m n s f o l l o w e d b y passage t h r o u g h Bio-Rex 70 c o l u m n s ( F e u e r s t e i n et al., 1977).
3. Results Basal c a t e c h o l a m i n e secretion rates o f all f o u r e x p e r i m e n t a l g r o u p s -- controls, intrarenal isoprenaline, i n t r a v e n o u s isoprenaline and angiotensin II a n t a g o n i s t t r e a t e d - - w e r e 4 3 . 8 -+ 4.0, 38.0 + 6.3, 46.2 + 6.3 and 43.4 + 6.3 pg/kg/lO min, respectively. I n t r a v e n o u s isoprenaline infusion h a d n o e f f e c t on t h e adrenomedullary catecholamine secretion, w h i c h was f o u n d t o be 50.2 +- 19.8 pg/kg/lO min as c o m p a r e d t o 39.4 + 12.5 pg/kg/lO min o f the c o n t r o l i n t a c t cats, at the end o f the e x p e r i m e n t . I n t r a r e n a l isoprenaline infusion elicited a significant increase o f adrenal c a t e c h o l a m i n e secretion, u p to 186 + 44 pg/ k g / 1 0 min (fig. 1). It also i n d u c e d a preferential n o r a d r e n a l i n e release since t h e p e r c e n t a g e o f adrenaline ( o f the t o t a l CA secretion) was Fig. 2. Catecholamine composition in adrenal vein blood of control cats and cats infused intrarenally with isoprenaline. Ordinate: percent adrenaline of total catecholamine secreted. Abscissa: time (min). • • control intact cats (n = 7); A A intrarenal infusion of isoprenaline (0.1 pg/kg/min; n = 9); l l period of isoprenaline infusion. * P < 0.05; ** P < 0.01, for differences between isoprenaline-infused and control cats.
G. FEUERSTEIN ET AL.
600
400
200
0
Isoprenali~e ~ Sat i- $leuS- Angiotensm]I I
I
J
10
30
50
70
Fig. I. Effect of Sar I -IleuS-angiotensin II on catecho!a m i n e release from the adrenal gland of intrarenally isoprenaline infused cats. Ordinate: catecholamine as percent of secretion rate during control period, preceding isoprenaline. Abscissa." time (min). ~. :.
control intact cats (n = 7); A ~ intrarenal infusion of isoprenaline (0.1 pg/kg/min; n = 9); o o Sar 1-Illeus-Angiotensin II infusion (0.4 pg/kg/min) in cats stimulated by intrarenal infusion of isoprenaline (n = 8); 1 1 period of drug infusion. *P < 0.05; ** P < 0.02; *** P < 0.001, for differences between isoprenaline-infused cats and cats infused with both isoprenaline and Sar]-IleuS-angiotensin II. Vertical bar: S.E.M. in all figures.
o l0
100
50
I
I Isopreno[ine
I
[
lO
30
I 50
70
ADRENAL CATECHOLAMINES AND ANGIOTENSIN II ANTAGONIST 36.6-+ 10% at t h e end o f t h e e x p e r i m e n t as c o m p a r e d t o 77.4 + 8.5% during t h e c o n t r o l p e r i o d {fig. 2). I n t r a v e n o u s a d m i n i s t r a t i o n o f Sar a-Ileu 8-A II c o m p l e t e l y abolished the adrenal CA response t o intrarenal isoprenaline infusion. T h e AI]: a n t a g o n i s t - t r e a t e d animals n e i t h e r d e m o n s t r a t e d a significant deviation o f CA secretion f r o m their basal rate t h r o u g h o u t the entire e x p e r i m e n t a l period, n o r was t h e r e a n y d i f f e r e n c e in CA secretion at t h e end o f t h e e x p e r i m e n t (78.8 + 16.4) as compared t o t h e c o n t r o l i n t a c t group.
4. Discussion T h e e x p e r i m e n t s r e p o r t e d in this comm u n i c a t i o n show t h a t in vivo A I I generation t h r o u g h d i r e c t renal renin release stimulates adrenal CA secretion. T h e e f f e c t o f A I I o n the adrenal m e d u l l a is p r e f e r e n t i a l l y noradrenalinergic, in c o n t r a s t t o a p r i m a r y adrenalinergic response seen in in vitro e x p e r i m e n t s o n p e r f u s e d cat adrenals (Staszewska-Barczak and Vane, 1 9 6 7 ; A c k e r l y et al., 1977). Since central A I I pressor responses were s h o w n t o be m e d i a t e d t h r o u g h t h e s y m p a t h e tic nervous s y s t e m (Keim and Sigg, 1971), a central origin o f t h e adrenal m e d u l l a response t o circulating A I I is n o t unconceivable. As a m a t t e r o f fact, we have r e c e n t l y d e m o n s t r a t e d t h a t t h e d e n e r v a t e d adrenal gland (splanchnic nerve resection) failed to r e s p o n d t o stress stimuli, in spite o f an i n t a c t renin--angiotensin s y s t e m ( F e u e r s t e i n et al., 1977). A central origin for t h e in vivo stimulation o f t h e adrenal m e d u l l a b y A I I m i g h t also a c c o u n t f o r t h e differences in CA c o m p o s i t i o n o f in vitro s t i m u l a t e d adrenal gland. These possibilities are n o w u n d e r investigation b y central application o f an A I I antagonist.
377
Acknowledgement
This study was supported by the Joint Research Fund of the Hebrew University and Hadassah (No. 015-9999).
References Ackerly, J.A., C.A. Sarstedt and M.J. Peach, 1977, Peptide antagonists of angiotensin induced arterial catecholamine release, European J. Pharmacol. 42, 391. Boadle-Biber, M.C. and R.H. Roth, 1972, Effects of drugs on the synthesis of noradrenaline in guinea pig vas deferens, Brit. J. Pharmacol. 46,696. Buckley, J.P. and B.S. Jandhyala, 1977, Central cardiovascular effects of angiotensin, Life Sci.
20, 1485. Feurstein, 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. 43, 764. Feuerstein, G., P. Boonyaviroj and Y. Gutman, 1977, Renin--angiotensin mediation of adrenal catecholamine secretion induced by hemorrhage, European J. Pharmacol. 44, 131. Hughes, J. and R.H. Roth, 1969, Enhanced release of transmitter during sympathetic nerve stimulation in the presence of angiotensin, Brit. J. Pharmacol. 37,516. Keim, K.L. and E.B. Sigg, 1971, Activation of central sympathetic neurons by angiotensin II, Life Sci. 10, 565. Staszewska-Barczak, J. and J.R. Vane, 1967, The release of catecholamine from the adrenal medulla by peptides, Brit. J. Pharmacol. Chemotherap. 30, 655. Starke, K., H.D. Taube and E. Borowski, 1977, Presynaptic receptor system in catecholaminergic transmission, Biochem. Pharmacol. 26, 259. Sweet, C.S., C.M. Ferrario, M.C. Khosla and M.F. Bumpus, 1973, Antagonism of peripheral and central effects of angiotensin II by [1-sarcosine, 8 Ileucine]-angiotensin II, J. Pharmacol. Exptl. Therap. 185, 35.
375
© Elsevier/North-Holland Biomedical Press
Short communication ANGIOTENSIN II MEDIATION OF A D R E N A L CATECHOLAMINE SECRETION INDUCED BY I N T R A R E N A L ISOPRENALINE INFUSION GIORA FEUERSTEIN t , MICHAEL KRAUSZ *, SILVIA COHEN, YEHUDA GUTMAN t t , MAHESH C. KHOSLA ** and MERLIN F. BUMPUS
Department of Pharmacology, Hebrew University-Hadassah Medical School, and * Department of Surgery, Hadassah University Hospital, Jerusalem, Israel, and ** Research Division, Cleveland Clinic, Cleveland, Ohio, U.S.A. Received 26 September 1978, accepted 28 September 1978
G. FEUERSTEIN, M. KRAUSZ, S. COHEN, Y. GUTMAN, M.C. KHOSLA and M.F. BUMPUS, Angiotensin H mediation of adrenal catecholamine secretion induced by intrarenal isoprenaline infusion, European J. Pharmacol. 52 (1978) 375--377. Isoprenaline infusion into the renal artery of the cat induced an increase in the catecholamine (CA) secretion rate from the adrenal gland. CA release by isoprenaline was preferentially noradrenaline. Intravenous infusion of an angiotensin II ( A I I ) antagonist abolished adrenal CA response to intrarenal isoprenaline injection. It is suggested that intrarenal isoprenaline infusion stimulates renal renin release and A I I production which, in turn, stimulates adrenal CA secretion. Catecholamines
Angiotensin II
Adrenal medulla
1. Introduction
Multiple sites of interaction between the renal renin--angiotensin system and the adrenergic nervous system are known to exist (Buckley and Jandhyala, 1977; Starke et al., 1977). However, there is still controversy as to the role o f A II in regulation of adrenergic functions, since in many experiments, isolated in vitro preparations and pharmacological doses of A I I were used (Hughes and Roth, 1969; Boadle-Biber and Roth, 1972). Moreover, it remains uncertain whether endogenous A II is generated at rates that suffice for activation of adrenomedullar CA secretion. The following in vivo experit Address for correspondence: Dr. G. Feuerstein, Department of Pharmacology, Hebrew UniversityHadassah Medical School, Ein Kerem, Jerusalem, Israel tt Established Investigator of the Chief Scientist's Office, Ministry of Health, Israel.
Isoprenaline
ments were aimed at elucidating the effect of A II, endogenously produced through direct renal renin release, on adrenal gland adrenaline and noradrenaline secretion. To assess the role of A II, Sarl-IleuS-A II was used, which is a specific and competitive A II antagonist (Sweet et al., 1973).
2. Materials and methods Male cats weighing 2.5--4.5 kg were anesthetized with pentobarbitone sodium (45 mg/ kg, i.m.) and the left femoral artery and vein were cannulated. The right kidney was removed through a midabdominal incision and its renal artery stump cannulated with a specially prepared polyethylene cannula (19 G Intracath®; O.D. 0.4 mm). The cannula was inserted through the aorta into the left renal artery, with the tip 0.5 cm distal to the aorta. Infusion of 0.9% NaC1 (0.05 ml/min)
376 i n t o t h e renal a r t e r y was started i m m e d i a t e l y u p o n c a n n u l a t i o n . T h e left a d r e n o l u m b a r vein was c a n n u l a t e d as p r e v i o u s l y described (Feuerstein and Gutman, 1971). I s o p r e n a l i n e s u l p h a t e (Teva Ltd., Jerusalem, Israel) was dissolved in 6.0 ml 0.9% NaC1 and i n f u s e d at a rate o f 0.1 pg/kg/min for 30 min, either intrarenally or i n t r a v e n o u s l y . Sar lIleuS-A II was dissolved in 6.0 ml 0.9% NaC1. I n f u s i o n o f t h e A I I a n t a g o n i s t (at a rate o f 0.4 pg/kg/min) was started at the same t i m e as t h e isoprenaline i n f u s i o n and c o n t i n u e d t h r o u g h o u t t h e rest o f the e x p e r i m e n t . A d r e n a l i n e and n o r a d r e n a l i n e in the adrenal vein b l o o d were assayed with the t r i h y d r o x y i n d o l e m e t h o d a f t e r isolation o n a l u m i n u m o x i d e c o l u m n s f o l l o w e d b y passage t h r o u g h Bio-Rex 70 c o l u m n s ( F e u e r s t e i n et al., 1977).
3. Results Basal c a t e c h o l a m i n e secretion rates o f all f o u r e x p e r i m e n t a l g r o u p s -- controls, intrarenal isoprenaline, i n t r a v e n o u s isoprenaline and angiotensin II a n t a g o n i s t t r e a t e d - - w e r e 4 3 . 8 -+ 4.0, 38.0 + 6.3, 46.2 + 6.3 and 43.4 + 6.3 pg/kg/lO min, respectively. I n t r a v e n o u s isoprenaline infusion h a d n o e f f e c t on t h e adrenomedullary catecholamine secretion, w h i c h was f o u n d t o be 50.2 +- 19.8 pg/kg/lO min as c o m p a r e d t o 39.4 + 12.5 pg/kg/lO min o f the c o n t r o l i n t a c t cats, at the end o f the e x p e r i m e n t . I n t r a r e n a l isoprenaline infusion elicited a significant increase o f adrenal c a t e c h o l a m i n e secretion, u p to 186 + 44 pg/ k g / 1 0 min (fig. 1). It also i n d u c e d a preferential n o r a d r e n a l i n e release since t h e p e r c e n t a g e o f adrenaline ( o f the t o t a l CA secretion) was Fig. 2. Catecholamine composition in adrenal vein blood of control cats and cats infused intrarenally with isoprenaline. Ordinate: percent adrenaline of total catecholamine secreted. Abscissa: time (min). • • control intact cats (n = 7); A A intrarenal infusion of isoprenaline (0.1 pg/kg/min; n = 9); l l period of isoprenaline infusion. * P < 0.05; ** P < 0.01, for differences between isoprenaline-infused and control cats.
G. FEUERSTEIN ET AL.
600
400
200
0
Isoprenali~e ~ Sat i- $leuS- Angiotensm]I I
I
J
10
30
50
70
Fig. I. Effect of Sar I -IleuS-angiotensin II on catecho!a m i n e release from the adrenal gland of intrarenally isoprenaline infused cats. Ordinate: catecholamine as percent of secretion rate during control period, preceding isoprenaline. Abscissa." time (min). ~. :.
control intact cats (n = 7); A ~ intrarenal infusion of isoprenaline (0.1 pg/kg/min; n = 9); o o Sar 1-Illeus-Angiotensin II infusion (0.4 pg/kg/min) in cats stimulated by intrarenal infusion of isoprenaline (n = 8); 1 1 period of drug infusion. *P < 0.05; ** P < 0.02; *** P < 0.001, for differences between isoprenaline-infused cats and cats infused with both isoprenaline and Sar]-IleuS-angiotensin II. Vertical bar: S.E.M. in all figures.
o l0
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50
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I Isopreno[ine
I
[
lO
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I 50
70
ADRENAL CATECHOLAMINES AND ANGIOTENSIN II ANTAGONIST 36.6-+ 10% at t h e end o f t h e e x p e r i m e n t as c o m p a r e d t o 77.4 + 8.5% during t h e c o n t r o l p e r i o d {fig. 2). I n t r a v e n o u s a d m i n i s t r a t i o n o f Sar a-Ileu 8-A II c o m p l e t e l y abolished the adrenal CA response t o intrarenal isoprenaline infusion. T h e AI]: a n t a g o n i s t - t r e a t e d animals n e i t h e r d e m o n s t r a t e d a significant deviation o f CA secretion f r o m their basal rate t h r o u g h o u t the entire e x p e r i m e n t a l period, n o r was t h e r e a n y d i f f e r e n c e in CA secretion at t h e end o f t h e e x p e r i m e n t (78.8 + 16.4) as compared t o t h e c o n t r o l i n t a c t group.
4. Discussion T h e e x p e r i m e n t s r e p o r t e d in this comm u n i c a t i o n show t h a t in vivo A I I generation t h r o u g h d i r e c t renal renin release stimulates adrenal CA secretion. T h e e f f e c t o f A I I o n the adrenal m e d u l l a is p r e f e r e n t i a l l y noradrenalinergic, in c o n t r a s t t o a p r i m a r y adrenalinergic response seen in in vitro e x p e r i m e n t s o n p e r f u s e d cat adrenals (Staszewska-Barczak and Vane, 1 9 6 7 ; A c k e r l y et al., 1977). Since central A I I pressor responses were s h o w n t o be m e d i a t e d t h r o u g h t h e s y m p a t h e tic nervous s y s t e m (Keim and Sigg, 1971), a central origin o f t h e adrenal m e d u l l a response t o circulating A I I is n o t unconceivable. As a m a t t e r o f fact, we have r e c e n t l y d e m o n s t r a t e d t h a t t h e d e n e r v a t e d adrenal gland (splanchnic nerve resection) failed to r e s p o n d t o stress stimuli, in spite o f an i n t a c t renin--angiotensin s y s t e m ( F e u e r s t e i n et al., 1977). A central origin for t h e in vivo stimulation o f t h e adrenal m e d u l l a b y A I I m i g h t also a c c o u n t f o r t h e differences in CA c o m p o s i t i o n o f in vitro s t i m u l a t e d adrenal gland. These possibilities are n o w u n d e r investigation b y central application o f an A I I antagonist.
377
Acknowledgement
This study was supported by the Joint Research Fund of the Hebrew University and Hadassah (No. 015-9999).
References Ackerly, J.A., C.A. Sarstedt and M.J. Peach, 1977, Peptide antagonists of angiotensin induced arterial catecholamine release, European J. Pharmacol. 42, 391. Boadle-Biber, M.C. and R.H. Roth, 1972, Effects of drugs on the synthesis of noradrenaline in guinea pig vas deferens, Brit. J. Pharmacol. 46,696. Buckley, J.P. and B.S. Jandhyala, 1977, Central cardiovascular effects of angiotensin, Life Sci.
20, 1485. Feurstein, 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. 43, 764. Feuerstein, G., P. Boonyaviroj and Y. Gutman, 1977, Renin--angiotensin mediation of adrenal catecholamine secretion induced by hemorrhage, European J. Pharmacol. 44, 131. Hughes, J. and R.H. Roth, 1969, Enhanced release of transmitter during sympathetic nerve stimulation in the presence of angiotensin, Brit. J. Pharmacol. 37,516. Keim, K.L. and E.B. Sigg, 1971, Activation of central sympathetic neurons by angiotensin II, Life Sci. 10, 565. Staszewska-Barczak, J. and J.R. Vane, 1967, The release of catecholamine from the adrenal medulla by peptides, Brit. J. Pharmacol. Chemotherap. 30, 655. Starke, K., H.D. Taube and E. Borowski, 1977, Presynaptic receptor system in catecholaminergic transmission, Biochem. Pharmacol. 26, 259. Sweet, C.S., C.M. Ferrario, M.C. Khosla and M.F. Bumpus, 1973, Antagonism of peripheral and central effects of angiotensin II by [1-sarcosine, 8 Ileucine]-angiotensin II, J. Pharmacol. Exptl. Therap. 185, 35.
