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Central alpha-activation by clonidine reduces plasma level of beta-endorphin in patients with essential hypertension
Life Sciences, Vol. 37, pp. 1461-1467 Printed in the U.S.A.
Pergamon Press
CENTRAL ALPHA-ACTIVATION BY CLONIDINE REDUCES PLASMA LEVEL OF BETA-ENDORPHIN IN PATIENTS WITH ESSENTIAL HYPERTENSION K. Yasunari*, Y. Kanayama*, M. Kohno*, K. Murakawa*, T. Kawarabayashi*, T. Takeda*, N. Kotsuga1**, K. Sato** *First Department of Internal Mediclne, Osaka City University Medical School, 1-5-7, Asahi-machi Abeno-ku Osaka 545 Japan **RI Research Unit, Special Reference Laboratory Co. 5 1 K o m i y a - c h o Hachioji-shi Tokyo 192 Japan (Received in final form August 12, 1985) SUMMARY Whether peripheral B-endorphin contributes to the antlhypertensive action of clonidine was examined by measurlng plasma levels of B-endorphin-like immunoreactivity (BEpLI) after acute administration of clonldine in patlents wlth essentlal hypertension. Administratlon of clonldine (0.225 mg) in one dose significantly lowered blood pressure, decreased heart rate and reduced the plasma level of BEpLI and ACTH, while the placebo had no effect on blood pressure, heart rate or plasma level of ~EpLI suggesting that peripheral B-endorphin does not play a major role in the antihypertensive action of acute clonidlne admlnlstratlon. Clonidine is an antihypertensive drug which acts on the central ~-receptor. Recently, the posslble involvement of B-endorphin in the antlhypertensive action of clonldine has been proposed(1). Subacute admlnlstration of clonldine significantly increased plasma level of BEpLI in hypertensive patlents(2), and acute administration of clonidine resulted in a signiflcant decrease of plasma ACTH level in patients wlth essential hypertension(3) and in dogs(4,5). Since current evidence suggests that ACTH and ~-endorphin exist withln the same hypophyseal cells and are secreted together from the pltultary gland in response to secretagogues(6,7,8,9~10,11), these reports seem to be conflictlng. We examined the plasma level of BEpLI and ACTH slmultaneously after administratlon of clonidlne and Investlgated the relationshlp between blood pressure and plsma ~-endorphln level.
Adress reprint requests to: Kenichi Yasunari M.D., First Department of Internal Mediclne, Osaka Clth University Medlcal School, I-5-7 Asahi-machi Abeno-ku Osaka 545 Japan.
0024-3205/85 $3.00 + .00 Copyright (c) 1985 Pergamon Press Ltd.
1462
Clonldine and Plasma ~-endorphln
Vol. 37, No. 16, 1985
METHODS Patients
and Protocol
Seventeen patlents, I0 men and 7 women, with mild to moderate essentlal hypertension particlpated in the study. Age range was between 29 and 69 years, with a mean of 47.7 years. All patlents had dlscontinued antihypertenslve medicatlon at least one week before the study. An intravenous line was inserted into an antecubital veln for blood sampling. After 30 min recumbent rest blood samples were collected for determination of plasma levels of ~EpLI and ACTH. Then, 12 patients were given clonidine in one oral dose of 0.225 mg and 5 patients were glven placebo at about 1 p.m. to avoid interference by circadian v a r l a t l o n o f plasma BEpLI levels. Blood pressure and pulse rate were determlned as the average of three readings and measured before and 30 min, 60 min, 90 mln, 120 min, and 180 min after adminlstration of clonidine or placebo. Blood samples were withdrawn into chilled plastic syrlnges before and 60 min, 120 min, and 180 min after admlnistration of clonldine or placebo. All blood samples were immediately transferred to chilled, siliconize~ disposable glass tubes that contained Aprotinin (Trasylol~300 Kallikrein inactivation units/ml) and EDTA (img/ml). Plasma was separated by centrlfugation at 4°C and plasma samples were kept in -80~C untll assay. Plasma Extractlon BEpLI (Wako Pure eluted by containing
and Radioimmunoassay
was extracted from human plasma using a sillca gel Chemical Industries., Osaka, Japan). Then, it was 0.i N HCL-acetone. Extraction efficiency for plasma human B-endorphin was 81.3 ! 3.0%.
~EpLI was measured by radiolmmunoassay, uslng human ~-endorphln standards (Proteln Research Foundatlon, Osaka, Japan). Antibody was made in rabblts by weekly immunlzation of synthetlc human B-endorphin, whlch was not conjugated to any carrier proteln, in complete Freund's adjunant. The assay showed 3.3 % corssreactivity wlth human B-llpotropin but no tracer displacement by ~ a n d ~-endorphin, ACTH (1~39)(1410)(18~39), or methionlne and leucine enkephalin. The minimal detectable dose of human BEpLI was 3 pg/ml of plasma. The intra- and inter-assay coefficients of variation were 7.8 % and 6.5 %, respectively. Plasma ACTH was measured by ACTH Radioimmunoassay Kit (Commissariat A L'Energie Atomique, Paris, France). Statistlcal
Analysis
Statistical analyses were performed by multiple measures ANOVA(22). A ~ value less than 0.05 was considered a signiflcant level. RESULTS As shown in Table I, a signlficant r e d u c t i o n l n b l o o d p r e s s u r e , and heart rate was observed 30 mln, 60 min, 90 min, 120 min,150 min and 180 min after adminlstration of clonidine. The plasma
Vol. 37, No. 16, 1985
Clonidine and Plasma B-endorphin
1463
level of BEpLI was d e c r e a s e d s l g n l f l c a n t l y 120 m i n after administration, w h i l e p l a c e b o had no effect on b l o o d pressure, h e a r t rate, or the p l a s m a level of BEpLI in p a t i e n t s w i t h e s s e n t i a l h y p e r t e n sion. Table
I
C h a n g e s in m e a n b l o o d pressure, h e a r t rate B - e n d o r p h i n - l i k e i m m u n o r e a c t i v i t y (BEpLI) after c l o n i d i n e (0.225 mg) or p l a c e b o in one dose.
M e a n Blood P r e s s u r e (mmHg)
Control
group
(Placebo
H e a r t Rate (beats/min)
BEpLI (pg/ml)
37.2 + 5.6
admlnstratlon)
PRE
112.8 + 7.6
67.6 +7.6
30 M I N
ii0.0 + 9.9
67.2 + 7.0
60 M I N
109.2
+ 10.5
67.2
+ 6.6
90 M I N
110.2
+ 7.2
68.8
+ 7.4
120 M I N
109.4 + 9.1
67.2
+ 7.3
150 M I N
106.6
69.6
+ 7.7
180 M I N
109.4 + 8.5
Clonidine
+ 8.4
administration
39.0 + I0.9 NS
37.2 + 13.5 NS
71.2 + 7.6
35.6 + 11.7
group
113.8
30 M I N
107.3 + 14.4"
60 M I N
99.4 + 14.7 °
62.7
90 M I N
94.4 + 14.8 °
60.9 + 7.7 °
120 MIN
93.4 + 12.6 °
60.3 + 6.2
150 M I N
92.0 + 11.5 °
57.6 + 6.5 °
180 MIN
96.4 + 13.3 °
61.5 + 8.6 °
g~ven
32.4 + 8.8 NS
68.8 + 8.3
PRE
Values
and p l a s m a level of a d m i n i s t r a t i o n of
+ 12.6
are the m e a n ! S.D.
66.3 + 7.2 ° + 7.3 °
28.5 + 14.6 NS
26.6
+ 7.9*
28.5 + 15.5
o p(0.01 * pi0.05 NS not s i g n i f i c a n t
NS
1464
Clonldine and Plasma 6-endorphln
Vol. 37, No. 16, 1985
plasma /3EpL I I pg/m~)
60 50
40 _
-.,,.
30 20
10
Fzg.
1
I
I
I
I
PRE
1 HR
2HR
3HR
Changes placebo
in plasma ~EpLI level after admznistration of (above) and clonzdlne (below) for each patzent.
Figure 1 shows the changes zn plasma BEpLI level after admznistration of clonzdine or placebo for each patient. The plasma level of 6EpLI zn i0 of 12 patzents wzth essential hypertension was decreased 2hrs after admznzstration of clonldine. Five of the 12 patments showed the lowest value of plasma 6EpLI lhr after admlnzstratzon of clonzdzne. Clonzdzne szgnifzcantly decreased the plasma level of ACTH from 22.4 + 10.5 to ll.0 + 3.3 pg/ml (Fig. 2). The ACTH level zn the other 7 patments was ~ e l o w t h e sensltivlty of the ACTH assay (5 pg/ml).
Vol. 37, No. 16, 1985
Clonldine and Plasma 6-endorphin
(Pg/ml)
1465
(pg/ml)
p
E
1
30-
\
3O
1
L
a. v
PRE Fig. 2
i
2 HR
A
v
PRE
I
2 HR
Changes in the plasma level of ACTH before and 2hours after administration of clonidine (0.225 mg) in one dose.
1466
Clonldine and Plasma B-endorphln
Vol. 37, No. 16, 1985
DISCUSSION Clonldlne is a relatively selective alpha-2 receptor agonist and produces hypotenslon and bradycardia by actlvating the inhibitory pathways In the braln, particularly the brainstem(12). In thls report, we investlgated the effect of acute adminlstratlon of clonidlne on blood pressure, pulse rate and plasma ~EpLI and ACTH in an attempt to determlne the role of B-endorphln in its hypotenslve actlon. Our results indicate that the central ~-actlvatlon by clonidine admlnistration (0.225 mg) in one dose lowered mean blood pressure, decreased heart rate, and reduced the plasma level of BEpLI slgnlflcantly, while the placebo had no effect on blood pressure, heart rate or the plasma level of BEpLI. Recently, Farsang et al. reported that naloxone could inhlblt and reverse the fall in blood pressure and heart rate produced by clonidine(1). Naloxone was also reported to antagonlze the hypotenslve effect of clonldlne in humans(18). Clonidine was reported to increase the release of BEpLI from brainstem sllces in SHR(2). Therefore, it seems that central B-endorphin plays a contributory role in the antlhypertenslve actlon of clonidine. On the other hand, recent reports on the physiologlcal significance of clrculatlng ~EpLI are rather controverslal. Plasma ~EpLI level has been reported to increase after subacute clonidine administratlon (0.3 mg dally in three days) in patlents with essentlal hypertension(2), and this increase correlated with the antihypertensive and bradycardlac action of the drug(13). Also, acute clonldine admlnlstratlon has been shown to release BEpLI from the anterior pltultary(23) and to increase plasma levels of BEpLI in intact but not hypophysectomlzed rats(24). On the other hand, Conway et al. reported that clrculating B-endorphln does not paly a role in the antlhypertensive action of acute admlnlstration of clonidlne in normotensive and spontaneously hypertenslve rats(21), andnaloxone, whlch reverses the hypotensive effect of clon~dine, increased the plasma level of ~EpLI in dogs(20). In hypertensive patlents, increase in plasma BEpLI was observed in subacute clonldlne admlnistration(2), however, the same authors reported that there was no significant correlation between the effect of acute clonldlne administration on blood pressure and plsama ~EpLI level(13), whlch is contrary to results of their subacute administration tests. Therefore the effect of acute clonldlne admlnlstration on the plasma BEpLI level may dlffer from that of subacute clonidine admlnistratlon. The mechanlsms by whlch plasma level of ACTH and ~EpLI are lowered after ~dmlnlstratlon of clonidine remains to be elucldated. Eplnephrine has been reported to have an additive effect on cortlcotropln-releasing factor (CRF) -induced ACTH release(14). Since clonidlne inhlblts the centrally mediated stimulatory adrenerglc influences(15), and lowers not only the plasma level but also cerebrosplnal fluld (CSF) the level of catecholamines in patients with essentlal hypertenslon(16,17), clonidlne may decrease the CRF-induced ACTH and ~EpLI release from the pitultary. In conclusion, thls study does not support the hypothesis that clrculating B-endorphin is uniformly involved in the antlhyperten-
vol. 37, No. 16, 1985
Clonidine and
PlasmaB-endorphin
1467
sive action of clonidine. Futher investigation is required to after acute elucidate the mechanism of plasma BEpLI supression clonidine administration. REFERENCES 1. 2. 3.
4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
M.D. RAMIREZ-GONZALEZ, L. TCHAKAROV, R.M. GARCIA and G. KUNOS Circ. Res. 53 150-157 (1983). G. KUNOS, CTFARSANG, M.D. RAMIREZ-GONZALEZ Science 211 82-84 (1981). J. GENEST, J. GUTKOWSKA, J. JULESZ, E. SHIFFERIN, P. HAMES, M. CHRETIEN, N.G.SEIDAH and M. LIS In"Topics inhypertension" Villarreal and M.P. Sambhi, eds. p.508-509, Martinus Nijhoff (1984). W.F. GANONG, N. KRAMER, J. SALMON, I.A. REID, R. LOVINGER, U. SCAPAGNINI, A.T. BORYCZKA and R. SHACKLFORD Neuroscience 1 167-174 (1976). C.D. RUDOLPH, S.L. KAPLAN, and W.F. GANONG Neuroendofrinology 31 121-128 (1980). R. GUILLEMIN, T. VARGO, J. TOSSIER, S. MINICK, N. LING, C. RIVIER, W. VALE and F. BLOOM Science 197 1367-1368 (1977). N.S. HALMI, M.E. PETERSON, G.J. COLURSO, A.S. LIOTTA and D.T. KRIEGER Science 211 72-74 (1981). G. MEDILSOHN R. D'AGOSTINO, S.C. EGGLESTON and S.B. BAYLIN J. Clin. Invest. 63 1297-1301 (1979). G. PELIETIER, F. ECLERC, J.C. LABONE, M. CHRETEIN and N. LIS Endocrinology 100 770-776 (1977). J. ROSSIER, E.rFRENCH, C. RIVIER, N. LING, R. GUILLEMIN and F. BLOOM Nature 270 618-620 (1977). W. VALE, C. RIVIECL. YANG, S. MINICK and R. GUILLEMIN Endocrinology 103 1910-1915 (1978). W. KOBINGER Rev. Physiol. Biochem. Pharmacol. 81 39-100 (1978). C. FARSANG, K. VARGA, L. VAJDA, J. KAPOCSI, A. BLAS-ELTES and G. KUNOS Neuropeptides 4 293-302 (1984). V. GIGERE and F. LABRIE Biochem. Biophys. Res. Commu. Ie 456-462 (1983). G. HAEUSLER Naunyn Schmiedeverg's Arch. Pharmacol. 278 231-246 (1973). E.L. BRAVO, R.C. TARAZI, F.M. FOUAD, D.G. VIDT and R.W. GIFFORD, JR. N. Engl. J. Med. 305 623-626 (1981). L.X. CUBEDDU, I.S. HOFFMANN, J. DAVILA, Y.R. BARBELLA, and P. ORDAZ Life Sci. 35 1365-1371 (1984). C. FARSANG, J. KAPOCn, I. JUHASZ and G. KUNOS Circulation 66 1268-1272 (19821. D.A. BENNETT, J.J. DEREO, E.E. ELK0 and H. LAL Drug Dev. Res. 2 175-179 (1982). E.R. LEVIN, B. SHARP and H.E. CARLSON Life Sci. 35 1535-1545 (1984). E.L. CONWAY, M.J. BROWN and C.T. DOLLERY J. Pharmacol. Exp. Ther. 299 803-808 (1984). 47 S. WALmSTEIN, C.L. ZUCKER and J.L. FLEISS Circ. Res. l-9 (1980). D.J. PETTIBONE and G.P. MUELLER Brain Res. 221409-414 (1981) D.J. PETTINONE and G.P. MUELLER Endocrinology109 798-802 (1981).
Pergamon Press
CENTRAL ALPHA-ACTIVATION BY CLONIDINE REDUCES PLASMA LEVEL OF BETA-ENDORPHIN IN PATIENTS WITH ESSENTIAL HYPERTENSION K. Yasunari*, Y. Kanayama*, M. Kohno*, K. Murakawa*, T. Kawarabayashi*, T. Takeda*, N. Kotsuga1**, K. Sato** *First Department of Internal Mediclne, Osaka City University Medical School, 1-5-7, Asahi-machi Abeno-ku Osaka 545 Japan **RI Research Unit, Special Reference Laboratory Co. 5 1 K o m i y a - c h o Hachioji-shi Tokyo 192 Japan (Received in final form August 12, 1985) SUMMARY Whether peripheral B-endorphin contributes to the antlhypertensive action of clonidine was examined by measurlng plasma levels of B-endorphin-like immunoreactivity (BEpLI) after acute administration of clonldine in patlents wlth essentlal hypertension. Administratlon of clonldine (0.225 mg) in one dose significantly lowered blood pressure, decreased heart rate and reduced the plasma level of BEpLI and ACTH, while the placebo had no effect on blood pressure, heart rate or plasma level of ~EpLI suggesting that peripheral B-endorphin does not play a major role in the antihypertensive action of acute clonidlne admlnlstratlon. Clonidine is an antihypertensive drug which acts on the central ~-receptor. Recently, the posslble involvement of B-endorphin in the antlhypertensive action of clonldine has been proposed(1). Subacute admlnlstration of clonldine significantly increased plasma level of BEpLI in hypertensive patlents(2), and acute administration of clonidine resulted in a signiflcant decrease of plasma ACTH level in patients wlth essential hypertension(3) and in dogs(4,5). Since current evidence suggests that ACTH and ~-endorphin exist withln the same hypophyseal cells and are secreted together from the pltultary gland in response to secretagogues(6,7,8,9~10,11), these reports seem to be conflictlng. We examined the plasma level of BEpLI and ACTH slmultaneously after administratlon of clonidlne and Investlgated the relationshlp between blood pressure and plsma ~-endorphln level.
Adress reprint requests to: Kenichi Yasunari M.D., First Department of Internal Mediclne, Osaka Clth University Medlcal School, I-5-7 Asahi-machi Abeno-ku Osaka 545 Japan.
0024-3205/85 $3.00 + .00 Copyright (c) 1985 Pergamon Press Ltd.
1462
Clonldine and Plasma ~-endorphln
Vol. 37, No. 16, 1985
METHODS Patients
and Protocol
Seventeen patlents, I0 men and 7 women, with mild to moderate essentlal hypertension particlpated in the study. Age range was between 29 and 69 years, with a mean of 47.7 years. All patlents had dlscontinued antihypertenslve medicatlon at least one week before the study. An intravenous line was inserted into an antecubital veln for blood sampling. After 30 min recumbent rest blood samples were collected for determination of plasma levels of ~EpLI and ACTH. Then, 12 patients were given clonidine in one oral dose of 0.225 mg and 5 patients were glven placebo at about 1 p.m. to avoid interference by circadian v a r l a t l o n o f plasma BEpLI levels. Blood pressure and pulse rate were determlned as the average of three readings and measured before and 30 min, 60 min, 90 mln, 120 min, and 180 min after adminlstration of clonidine or placebo. Blood samples were withdrawn into chilled plastic syrlnges before and 60 min, 120 min, and 180 min after admlnistration of clonldine or placebo. All blood samples were immediately transferred to chilled, siliconize~ disposable glass tubes that contained Aprotinin (Trasylol~300 Kallikrein inactivation units/ml) and EDTA (img/ml). Plasma was separated by centrlfugation at 4°C and plasma samples were kept in -80~C untll assay. Plasma Extractlon BEpLI (Wako Pure eluted by containing
and Radioimmunoassay
was extracted from human plasma using a sillca gel Chemical Industries., Osaka, Japan). Then, it was 0.i N HCL-acetone. Extraction efficiency for plasma human B-endorphin was 81.3 ! 3.0%.
~EpLI was measured by radiolmmunoassay, uslng human ~-endorphln standards (Proteln Research Foundatlon, Osaka, Japan). Antibody was made in rabblts by weekly immunlzation of synthetlc human B-endorphin, whlch was not conjugated to any carrier proteln, in complete Freund's adjunant. The assay showed 3.3 % corssreactivity wlth human B-llpotropin but no tracer displacement by ~ a n d ~-endorphin, ACTH (1~39)(1410)(18~39), or methionlne and leucine enkephalin. The minimal detectable dose of human BEpLI was 3 pg/ml of plasma. The intra- and inter-assay coefficients of variation were 7.8 % and 6.5 %, respectively. Plasma ACTH was measured by ACTH Radioimmunoassay Kit (Commissariat A L'Energie Atomique, Paris, France). Statistlcal
Analysis
Statistical analyses were performed by multiple measures ANOVA(22). A ~ value less than 0.05 was considered a signiflcant level. RESULTS As shown in Table I, a signlficant r e d u c t i o n l n b l o o d p r e s s u r e , and heart rate was observed 30 mln, 60 min, 90 min, 120 min,150 min and 180 min after adminlstration of clonidine. The plasma
Vol. 37, No. 16, 1985
Clonidine and Plasma B-endorphin
1463
level of BEpLI was d e c r e a s e d s l g n l f l c a n t l y 120 m i n after administration, w h i l e p l a c e b o had no effect on b l o o d pressure, h e a r t rate, or the p l a s m a level of BEpLI in p a t i e n t s w i t h e s s e n t i a l h y p e r t e n sion. Table
I
C h a n g e s in m e a n b l o o d pressure, h e a r t rate B - e n d o r p h i n - l i k e i m m u n o r e a c t i v i t y (BEpLI) after c l o n i d i n e (0.225 mg) or p l a c e b o in one dose.
M e a n Blood P r e s s u r e (mmHg)
Control
group
(Placebo
H e a r t Rate (beats/min)
BEpLI (pg/ml)
37.2 + 5.6
admlnstratlon)
PRE
112.8 + 7.6
67.6 +7.6
30 M I N
ii0.0 + 9.9
67.2 + 7.0
60 M I N
109.2
+ 10.5
67.2
+ 6.6
90 M I N
110.2
+ 7.2
68.8
+ 7.4
120 M I N
109.4 + 9.1
67.2
+ 7.3
150 M I N
106.6
69.6
+ 7.7
180 M I N
109.4 + 8.5
Clonidine
+ 8.4
administration
39.0 + I0.9 NS
37.2 + 13.5 NS
71.2 + 7.6
35.6 + 11.7
group
113.8
30 M I N
107.3 + 14.4"
60 M I N
99.4 + 14.7 °
62.7
90 M I N
94.4 + 14.8 °
60.9 + 7.7 °
120 MIN
93.4 + 12.6 °
60.3 + 6.2
150 M I N
92.0 + 11.5 °
57.6 + 6.5 °
180 MIN
96.4 + 13.3 °
61.5 + 8.6 °
g~ven
32.4 + 8.8 NS
68.8 + 8.3
PRE
Values
and p l a s m a level of a d m i n i s t r a t i o n of
+ 12.6
are the m e a n ! S.D.
66.3 + 7.2 ° + 7.3 °
28.5 + 14.6 NS
26.6
+ 7.9*
28.5 + 15.5
o p(0.01 * pi0.05 NS not s i g n i f i c a n t
NS
1464
Clonldine and Plasma 6-endorphln
Vol. 37, No. 16, 1985
plasma /3EpL I I pg/m~)
60 50
40 _
-.,,.
30 20
10
Fzg.
1
I
I
I
I
PRE
1 HR
2HR
3HR
Changes placebo
in plasma ~EpLI level after admznistration of (above) and clonzdlne (below) for each patzent.
Figure 1 shows the changes zn plasma BEpLI level after admznistration of clonzdine or placebo for each patient. The plasma level of 6EpLI zn i0 of 12 patzents wzth essential hypertension was decreased 2hrs after admznzstration of clonldine. Five of the 12 patments showed the lowest value of plasma 6EpLI lhr after admlnzstratzon of clonzdzne. Clonzdzne szgnifzcantly decreased the plasma level of ACTH from 22.4 + 10.5 to ll.0 + 3.3 pg/ml (Fig. 2). The ACTH level zn the other 7 patments was ~ e l o w t h e sensltivlty of the ACTH assay (5 pg/ml).
Vol. 37, No. 16, 1985
Clonldine and Plasma 6-endorphin
(Pg/ml)
1465
(pg/ml)
p
E
1
30-
\
3O
1
L
a. v
PRE Fig. 2
i
2 HR
A
v
PRE
I
2 HR
Changes in the plasma level of ACTH before and 2hours after administration of clonidine (0.225 mg) in one dose.
1466
Clonldine and Plasma B-endorphln
Vol. 37, No. 16, 1985
DISCUSSION Clonldlne is a relatively selective alpha-2 receptor agonist and produces hypotenslon and bradycardia by actlvating the inhibitory pathways In the braln, particularly the brainstem(12). In thls report, we investlgated the effect of acute adminlstratlon of clonidlne on blood pressure, pulse rate and plasma ~EpLI and ACTH in an attempt to determlne the role of B-endorphln in its hypotenslve actlon. Our results indicate that the central ~-actlvatlon by clonidine admlnistration (0.225 mg) in one dose lowered mean blood pressure, decreased heart rate, and reduced the plasma level of BEpLI slgnlflcantly, while the placebo had no effect on blood pressure, heart rate or the plasma level of BEpLI. Recently, Farsang et al. reported that naloxone could inhlblt and reverse the fall in blood pressure and heart rate produced by clonidine(1). Naloxone was also reported to antagonlze the hypotenslve effect of clonldlne in humans(18). Clonidine was reported to increase the release of BEpLI from brainstem sllces in SHR(2). Therefore, it seems that central B-endorphin plays a contributory role in the antlhypertenslve actlon of clonidine. On the other hand, recent reports on the physiologlcal significance of clrculatlng ~EpLI are rather controverslal. Plasma ~EpLI level has been reported to increase after subacute clonidine administratlon (0.3 mg dally in three days) in patlents with essentlal hypertension(2), and this increase correlated with the antihypertensive and bradycardlac action of the drug(13). Also, acute clonldine admlnlstratlon has been shown to release BEpLI from the anterior pltultary(23) and to increase plasma levels of BEpLI in intact but not hypophysectomlzed rats(24). On the other hand, Conway et al. reported that clrculating B-endorphln does not paly a role in the antlhypertensive action of acute admlnlstration of clonidlne in normotensive and spontaneously hypertenslve rats(21), andnaloxone, whlch reverses the hypotensive effect of clon~dine, increased the plasma level of ~EpLI in dogs(20). In hypertensive patlents, increase in plasma BEpLI was observed in subacute clonldlne admlnistration(2), however, the same authors reported that there was no significant correlation between the effect of acute clonldlne administration on blood pressure and plsama ~EpLI level(13), whlch is contrary to results of their subacute administration tests. Therefore the effect of acute clonldlne admlnlstration on the plasma BEpLI level may dlffer from that of subacute clonidine admlnistratlon. The mechanlsms by whlch plasma level of ACTH and ~EpLI are lowered after ~dmlnlstratlon of clonidine remains to be elucldated. Eplnephrine has been reported to have an additive effect on cortlcotropln-releasing factor (CRF) -induced ACTH release(14). Since clonidlne inhlblts the centrally mediated stimulatory adrenerglc influences(15), and lowers not only the plasma level but also cerebrosplnal fluld (CSF) the level of catecholamines in patients with essentlal hypertenslon(16,17), clonidlne may decrease the CRF-induced ACTH and ~EpLI release from the pitultary. In conclusion, thls study does not support the hypothesis that clrculating B-endorphin is uniformly involved in the antlhyperten-
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Clonidine and
PlasmaB-endorphin
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sive action of clonidine. Futher investigation is required to after acute elucidate the mechanism of plasma BEpLI supression clonidine administration. REFERENCES 1. 2. 3.
4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
M.D. RAMIREZ-GONZALEZ, L. TCHAKAROV, R.M. GARCIA and G. KUNOS Circ. Res. 53 150-157 (1983). G. KUNOS, CTFARSANG, M.D. RAMIREZ-GONZALEZ Science 211 82-84 (1981). J. GENEST, J. GUTKOWSKA, J. JULESZ, E. SHIFFERIN, P. HAMES, M. CHRETIEN, N.G.SEIDAH and M. LIS In"Topics inhypertension" Villarreal and M.P. Sambhi, eds. p.508-509, Martinus Nijhoff (1984). W.F. GANONG, N. KRAMER, J. SALMON, I.A. REID, R. LOVINGER, U. SCAPAGNINI, A.T. BORYCZKA and R. SHACKLFORD Neuroscience 1 167-174 (1976). C.D. RUDOLPH, S.L. KAPLAN, and W.F. GANONG Neuroendofrinology 31 121-128 (1980). R. GUILLEMIN, T. VARGO, J. TOSSIER, S. MINICK, N. LING, C. RIVIER, W. VALE and F. BLOOM Science 197 1367-1368 (1977). N.S. HALMI, M.E. PETERSON, G.J. COLURSO, A.S. LIOTTA and D.T. KRIEGER Science 211 72-74 (1981). G. MEDILSOHN R. D'AGOSTINO, S.C. EGGLESTON and S.B. BAYLIN J. Clin. Invest. 63 1297-1301 (1979). G. PELIETIER, F. ECLERC, J.C. LABONE, M. CHRETEIN and N. LIS Endocrinology 100 770-776 (1977). J. ROSSIER, E.rFRENCH, C. RIVIER, N. LING, R. GUILLEMIN and F. BLOOM Nature 270 618-620 (1977). W. VALE, C. RIVIECL. YANG, S. MINICK and R. GUILLEMIN Endocrinology 103 1910-1915 (1978). W. KOBINGER Rev. Physiol. Biochem. Pharmacol. 81 39-100 (1978). C. FARSANG, K. VARGA, L. VAJDA, J. KAPOCSI, A. BLAS-ELTES and G. KUNOS Neuropeptides 4 293-302 (1984). V. GIGERE and F. LABRIE Biochem. Biophys. Res. Commu. Ie 456-462 (1983). G. HAEUSLER Naunyn Schmiedeverg's Arch. Pharmacol. 278 231-246 (1973). E.L. BRAVO, R.C. TARAZI, F.M. FOUAD, D.G. VIDT and R.W. GIFFORD, JR. N. Engl. J. Med. 305 623-626 (1981). L.X. CUBEDDU, I.S. HOFFMANN, J. DAVILA, Y.R. BARBELLA, and P. ORDAZ Life Sci. 35 1365-1371 (1984). C. FARSANG, J. KAPOCn, I. JUHASZ and G. KUNOS Circulation 66 1268-1272 (19821. D.A. BENNETT, J.J. DEREO, E.E. ELK0 and H. LAL Drug Dev. Res. 2 175-179 (1982). E.R. LEVIN, B. SHARP and H.E. CARLSON Life Sci. 35 1535-1545 (1984). E.L. CONWAY, M.J. BROWN and C.T. DOLLERY J. Pharmacol. Exp. Ther. 299 803-808 (1984). 47 S. WALmSTEIN, C.L. ZUCKER and J.L. FLEISS Circ. Res. l-9 (1980). D.J. PETTIBONE and G.P. MUELLER Brain Res. 221409-414 (1981) D.J. PETTINONE and G.P. MUELLER Endocrinology109 798-802 (1981).