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Potentiation of pressor response to angiotensin II at the preoptic area in spontaneously hypertensive rat
Life Sciences, Vol. 41, pp. 749-754 Printed in the U.S.A.
Pergamon Journals
POTENTIATION OF PRESSORRESPONSETO ANGIOTENSIN I I AT THE PREOPTIC AREA IN SPONTANEOUSLYHYPERTENSIVE RAT. Toshihiro Matsuda, Kazuhiko Shibata*, Masahiro Abe** Masamichi Tomonaga and Tatsuo Furukawa** Department of Neurosurgery, *Research Laboratory of Biodynamics and **Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka, 814-01, Japan (Received in final form June 2, 1987)
Summary Cardiovascular responses to angiotensin I I ( A I I ) at the preoptic area(POA) were compared between normotensive Wistar Kyoto rat (WKY) and spontaneously hypertensive rat(SHR) by measuring blood pressure and heart rate under unrestrained, conscious state via a catheter implanted c h r o n i c a l l y into the abdominal aorta and by i n j e c t i o n of drugs into POA through a chronic guide cannula. All injected into POA at doses of 0.3 ng and 1 ng produced a dose-dependent pressor response, accompanied with a s l i g h t decrease of heart rate, in both WKY and SHR. However, in SHR, the pressor response to All was more than 2 times greater than that in WKY and was quick inlonset~and lasted about 30 min. When A l l in combination with [Sar , lleU] angiotensin I I (0.5 pg), an All receptor antagonist, were simultaneously administered to POA, the pressor response to All was strongly i n h i b i t e d in both WKY and SHR. The results suggest that the pressor response to All due to i t s receptor stimulation at POA is markedly potentiated in SHR. I t has been generally accepted that renin-angiotensin system is existed in the brain since all the component of the system have now been demonstrated to be found in the brain tissue independently on the c i r c u l a t i n g reninangiotensin system(l-6). Most recently, Lind et al. have provided a detailed map of the neuron that contain A l l - l i k e immunoreactivity(7). Previous studies using cross c i r c u l a t i o n dogs showed that All appeared to produce an increase of blood pressure by two mechanisms; one is a d i r e c t peripheral action producing a marked increase in peripheral resistance and the other is central hypertensive e f f e c t due to stimulation of central sympathetic structures(8). In f a c t , administration of All into the cerebral v e n t r i c l e caused a r i s e of blood pressure (9, I0, I I ) and water intake (12, 13, 14) in anesthetized rat. Administration of All into the cerebrospinal f l u i d also produced a centrally-mediated hypertension not only anesthetized rats, but also in dogs and cats (15). S t i l l more, infusion of All into the vertebral a r t e r i e s of anesthetized dog e l i c i t e d a c e n t r a l l y mediated r i s e in blood pressure (16). On the basis of such findings the brain renin-angiotensin system is thought to play an important role in the regulation of blood pressure. Several areas in the brain, such as the area postrema(16), subnucleus medialis(17), organum vasculosum of the lamina terminalis(18), subfornical organ and anteroventral t h i r d v e n t r i c l e ( 1 9 , 20) are supposed to be important sites i~2~entral regulation of the blood pressure. According to examination using [ " l ] - a n g i o t e n s i n I I , S i r e t t et al. showed that All binding sites were 0024-3205/87 $3.00 + .00 Copyright (c) 1987 Pergamon Journals Ltd.
750
Angiotensin II and Preoptic Area
Vol. 41, No. 6, 1987
located at the midbrain, thalamus, septum, hypothalamus and medulla and very low level of binding were found in the cortex, hippocampus and striatum. And the l a t e r a l septum had the highest binding a c t i v i t y of a l l the tissues examined(21). Houten et a l . demonstrated that the greatest population of A l l binding sites was present in the central region of the subfornical organ(22). However, s i t e s of cardiovascular action of A l l in the brain s t i l l remains to be determined. As regards the preoptic area(POA), there was a recent report describing that the hypothalamic nuclei containing c e l l bodies include the suprachiasmatic nucleus, the medial POA and p e r i f o r n i c a l part of the l a t e r a l hypothalamic area, and f i b e r s were found at a l l level of the central nervous system, from the o l f a c t o r y bulbs to spinal cord(7). There was also a report mentioning that i n j e c t i o n of A l l into POA e l i c i t e s pressor response in anesthetized normotensive rat(23). These evidence indicates a p o s s i b i l i t y of presence of A l l receptor and neuron at POA. However, the p a r t i c i p a t i o n of A l l system at POA in central regulation of blood pressure is s t i l l unclear at present. The present experiment was therefore undertaken to investigate pressor response to A l l at POA and thereby study the difference in the pressor response between WKY and SHR under the unrestrained and conscious conditions. Methods Male SHR of Okamoto s t r a i n and control Male WKY r a t , aged 14 weeks to 16 weeks at the beginning of the study, were used. Animals were maintained food and drink f r e e l y . After anesthetized with sodium pentobarbital(4Omg/kg, i . p o ) , stainless guide cannulas were implanted u n i l a t e r a l l y to POA. The coordinates, a n t e r i o r (A) from the bregma, l a t e r a l (L) to the midline and horizontal (H) below dura were with the aid of KSnig and Klippel at A -0,5, L ~0.8, H -8.5 f o r SHR, A -0.5, L ±0.8, H -9.0 for WKY. Seven days a f t e r implantation of the guide cannula, the bevelled PE I0 end of cannula was inserted into the aorta through the femoral a r t e r y a f t e r anesthetized with ethylether. Seven days following implantation of the cannula, the experiment was performed under unrestrained, conscious state. The catheter was connected to a stathem P50 pressure transducer for continuous recording of blood pressure and heart rate via a San-ei polygraph. Drugslwere ~ n i l a t e r a l l y injected into the POA at the rate of I~I per 1.5 min. [Sar , l l e ]-angiotensin I I in combination with A l l were simultaneously injected into POA via the same guide cannula. A f t e r each experiment, rats were s a c r i f i c e d and brains perfused with 10% formalin. Brains were sectioned at 70~m and stained with cresyl v i o l e t to permit l o c a l i z a t i o n of the cannula t i p s . The rats in which both cannula t i p s were located out of POA were excluded from the experimental data. All values are expressed as mean ±S.E.M. S t a t i s t i c a l analysis was performed using Student's t t e s t . Differences were considered to be s i g n i f i c a n t when p
Vol. 41, No. 6, 1987
Angiotensin II and Preoptic Area
751
maximum w i t h i n one minute and lasted f o r over 30 min, blood pressure increasing from 165 mmHg to 215 mmHg. In WKY (lower panel of Fig I ) , the pressor response i n i t i a t e d r a t h e r slowly a f t e r i n j e c t i o n , reached a maximum in about one minute and l a s t e d l f o r about 20 min, blood pressure increasing from 150 mmHg to 165 mmHg. [Sar , l l e ] - a n g i o t e n s i n I I (0.5 ~ g ) , an A l l receptor antagonist, per se, d i d n ' t produce s i g n i f i c a n t changes of blood pressure and heart r a t e when i n j e c t e d i n t o POA. The e f f e c t of A l l (I ng) i n j e c t e d in combination with [Sar 1 l l e ] - a n g i o t e n s i n 11(0.5 ~g) i n t o POA are shown in Table I . The pressor response to A l l was s t r o n g l y i n h i b i t e d and was almost e l i m i n a t e d by simultaneous a d m i n i s t r a t i o n of an A l l receptor antagonist in both SHR and WKY, implying t h a t response is due to s t i m u l a t i o n of A l l receptor located at POA area. As demonstrated in Fig. 2, pressor response to A l l in SHR was more than 2 times g r e a t e r than t h a t in WKY, but there was no s i g n i f i c a n t d i f f e r e n c e s in weak negative chronotropic responses between SHR and WKY.
3mln HR
400~ 0L
(beats/mini BP 200 f 150 (mmHg)
I' 30mln
15mln
Angiotensln ]~ lng
3mln HR
400~ OL
(beats/mini
200[
"" .o I (mmHg)
I'
Anglotensln 11" lng
20rain
Fig
1
Representative t r a c i n g of A l l (I ng) administered i n t o POA on blood pressure and h e a r t r a t e in u n r e s t r a i n e d , conscious r a t s . The upper panel shows the e f f e c t in SHR and the l o w e r one t h a t in WKY. HR; h e a r t r a t e , BP; blood pressure.
752
Angiotensin
II and Preoptic Area
Volo 41, No. 6, 1987
(B)
(A) (8)
[ ] WKY
30 E
ms..
.= 0 A-i
0
(6)~
20
(8)
n-
~-10 <~ 3:
'~ 10
l
(8)
-2(I)
(5) 0,3ng
0.3ng 1.0ng Angiotensln X [ ] WKY
1,0ng
Angioten~n~nr
[] SHR
Fig
2
C a r d i o v a s c u l a r response to A l l (I ng, 0.3 ng) i n j e c t e d i n t o POA in unrestrained, conscious rats. The l e f t panel (A) indicate pressor response and the right one (B)negative chronotropic response. Vertical bars represent the S. E. M. Numbers of experimental animals are shown in parentheses. *; P
TABLE 1 Strong i n h i b i t i o n of p r e s s o r re~ponseoto A l l when A l l was into POA in combination w i t h [ S a ~ , l l e ° ] - a n g i o t e n s i n II. drug
n
BP(mmHg)
All(Ing)
9
+32.3±15.2
All(Ing)+[Sar I, l l e 8 ] - A l l
9
All(Ing)
8
All(Ing)+[Sar I, l l e 8 ] - A l l (0.5~g)
9
injected
HR(beats/min) -3.2±22.9
SHR
(0.5~g)
+6.5±8.7 **~ +10.6±8.2
-6.0±13.7 -10.7±10.7
WKY
*; P
+2.6±4.6* (I
ng) alone and A l l
-1.5±25.4 (I
ng) plus
Vol. 41, No. 6, 1987
Angiotensin II and Preoptic Area
753
Discussion There have been a few reports mentioning differences between WKY and SHR in central response to A l l antagonist or angiotensin converting enzyme i n h i b i t o r on blood pressure. Administration of Pll3(saralasin acetate), an A l l receptor antagonist, into the cerebroventricle caused depressor response only in the young SHR, but not in WKY(24). Infusion of [Sar , l l e 8 ] angiotensin I I , an All receptor antagonist, into the l a t e r a l v e n t r i c l e of mature SHR and WKY, maintained at rates of 1200 ng/hr for 6 days, induced a f a l l of blood pressure only in the SHR(25). I n j e c t i o n of captopril(2 mg/kg), an angiotensin converting enzyme i n h i b i t o r , into the v e n t r i c l e s in conscious SHR and WKY resulted in causing a rapid hypotensive response that lasted several hours in SHR, but had no s i g n i f i c a n t e f f e c t in WKY(26), Recently, we observed that A l l or renin injected into the l a t e r a l v e n t r i c l e of unrestrained, conscious rats produced pressor response and t h i s response was markedly greater in SHR than in WKY(unpublished observation). Differences between SHR and WKY of binding a f f i n i t y and capacity of A l l have been also reported. There were no s i g n i f i c a n t difference in All receptor population between SHR and WKY at the hypothalamus, thalamus, septum and midbrain(27). However, i t was reported that, at the organum vasculosum of the lamina t e r m i n a l i s , the binding of All was 0.24 fg/g protein in normotensive control r a t but was increased to 0.55 fg/g protein in SHR (28). As f o r POA, i n j e c t i o n of NaCI solution at higher concentration of 0.2 M into the l a t e r a l POA was reported to cause a s i g n i f i c a n t increase of a r t e r i a l pressure in unrestrained rat(29). In control study of this experiment on unrestrained, conscious rats, O.9%-physiological saline i n j e c t i o n to POA d i d n ' t cause a pressor response in both WKY as well as SHR. However, A l l injected at doses of 0.3 ng and 1 ng into POA e l i c i t e d a dose-dependent increase of blood pressure in both SHR and WKY POA i n j e c t i o n of All in combination with [Sar I , l l e 8 ] - a n g i o t e n s i n I I (0.5 ~$) exhibited a prominently reduced pressor response to A l l . Accordingly. i t is evident that the pressor response to A l l at POA is due to stimulation of All receptor. This pressor response to A l l at POA was markedly potentiated in SHR, becoming more than 2 times greater response as compared with that in WKY. Thus, the present study suggest that A l l system at POA may play an important role in central regulation of blood pressure and s e n s i t i v i t y to All at POA is markedly potentiated in SHR. Reference 1 2 3 4 5 6
I . A . REID, Circ. Res. 41147-153 (1977). S. HIROSE, H. YOKOSAWAand T. INAGAMI, Nature 274392-393 (1978). B . J . MORRIS and I. A. REID, Endocrinol. I0.__33492-500 (1978). H.-Y.T. YANG and N. H. NEFF, J. Neurochem. I_992443-2450 (1972). M. BENUCK and N. MARKS, J. Neurochem. 3(] 729-734 (1978). K. FUXE, D. GANTEN, T. HOKFEKT and P. BOLME, Central Action of Angiotensin and Related Hormones P515-518 (eds. J. P. BUCKLEY, C. M. FERRARIO and M. F. LOKHANDWALA) Pergamon Press, New York (1977). 7. R. W. LIND, L. W. SWANSONand D. GANTEN, Neuroendocrinol. 402-24 (1985). 8. R. K. BICKERTON and J. P. BUCKLEY, Proc. Soc. exp. Biol. Med. 106834-836 (I 961 ). 9. W. E. HOFFMANand M. I. PHILLIPS, L i f e Sci. 191323-1330 (1976). I0. W. E. HOFFMAN, P. G. SCHMID and M. I. PHILLIPS, Brain Res. 126376-381 (1977). I I . J. S. HUTCHINSON, P. SCHELLING, J. MOHRING and D. GANTEN, Clin. Sci. molec. Med. 5__!I391-394 (1976). 12. J. T. FITZSIMONS, A. N. EPSTEIN and A. K. JOHNSON, Central Action of Angiotensin and Related Hormones P407-415 (eds. J. P. BUCKLEY, C. M. FERRARIO and M.F. LOKHANDWALA) Pergamon Press, New York (1977).
754
13. 14. 15. 16. 17. 18 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
Angiotensin
II and Preoptic Area
Vol. 41, No. 6, 1987
A. K. JOHNSON and A. N. EPSTEIN, Brain Res. 86399-418 (1975). R. L. MALVIN, D. MOUWand A. J. VANDER, Science 19.__77171-173 (1977). W. B. SEVERS and A. E. DANIELS-SEVERS, Pharmacol. Rev. 25415-449 (1973). P. L. GILDENBERG, C. M. FERP~ARIOand J.W. MCCUBBIN, Clin. Sci. 44417-420 (1973). R. R. DEUBENand J. P. BUCKLEY, J. Pharmacol. Exp. Ther. 175139-146 (1970). M. I. PHILLIPS, Neuroendocrin. 25354-377 (1978). D. GANTEN and G. STOCK, Klin, Wochenshr. 56 (suppl. I) 31-41 (1978). M. ODAIR, L. C. CHERYL, L. B. KAREN, D. I. DIZ, R. M. SLUGG and C. M. FERRARIO, Hypertension 7!_(suppl. I) 1-80 - 1-87 (1985). N. E. SIRETT, A. S. MCLEAN, J. J. BRAY and J. I. HUBBARD, Brain Res. 122 299-312 (1977). M. VAN HOUTEN, E. L. SCHIFFRIN, J. F. E. MANN, B. I. POSNERand R. BOUCHER, Brain Res. 18___66480-485 (1980). E. E. BENARROCH, C. J. PIROLA, A. L. ALVAREZ and V. E. NAHMOD Neuropharmacol. 209-13 (1981). J. S HUTCHINSON, P. SCHELLING and D. GANTEN, Pflugers Arch. Eur. J. Physiol. 355 (suppl.) R28 (1975). W. MCDONALD, C. WICKRE, S. AUMANN, D. BAN and B. MOFFITT, Endocrinol. 107 1305-1308 (1980). J. S. HUTCHINSON, F. A. O. MENDELSOHNand A. E. DOYLE, Hypertension 2 5 4 6 550 (1980). F. E. COLE, E. D. FROHLICH and A. A. MACPHEE, Brain Res. 154178-181 (1978). M. I. PHILLIPS, J. WEYHENMEYER,D. FELIX, D. GANTEN and W. E. HOFFMAN Fed. Proc. 3__882260-2266 (1979). L. A. A. CAMARGO, J. V. MENANI, WILLIAM. A. SAAD and WILSON. A. SAAD, J. Physiol. 350 I-8 (1984).
Pergamon Journals
POTENTIATION OF PRESSORRESPONSETO ANGIOTENSIN I I AT THE PREOPTIC AREA IN SPONTANEOUSLYHYPERTENSIVE RAT. Toshihiro Matsuda, Kazuhiko Shibata*, Masahiro Abe** Masamichi Tomonaga and Tatsuo Furukawa** Department of Neurosurgery, *Research Laboratory of Biodynamics and **Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka, 814-01, Japan (Received in final form June 2, 1987)
Summary Cardiovascular responses to angiotensin I I ( A I I ) at the preoptic area(POA) were compared between normotensive Wistar Kyoto rat (WKY) and spontaneously hypertensive rat(SHR) by measuring blood pressure and heart rate under unrestrained, conscious state via a catheter implanted c h r o n i c a l l y into the abdominal aorta and by i n j e c t i o n of drugs into POA through a chronic guide cannula. All injected into POA at doses of 0.3 ng and 1 ng produced a dose-dependent pressor response, accompanied with a s l i g h t decrease of heart rate, in both WKY and SHR. However, in SHR, the pressor response to All was more than 2 times greater than that in WKY and was quick inlonset~and lasted about 30 min. When A l l in combination with [Sar , lleU] angiotensin I I (0.5 pg), an All receptor antagonist, were simultaneously administered to POA, the pressor response to All was strongly i n h i b i t e d in both WKY and SHR. The results suggest that the pressor response to All due to i t s receptor stimulation at POA is markedly potentiated in SHR. I t has been generally accepted that renin-angiotensin system is existed in the brain since all the component of the system have now been demonstrated to be found in the brain tissue independently on the c i r c u l a t i n g reninangiotensin system(l-6). Most recently, Lind et al. have provided a detailed map of the neuron that contain A l l - l i k e immunoreactivity(7). Previous studies using cross c i r c u l a t i o n dogs showed that All appeared to produce an increase of blood pressure by two mechanisms; one is a d i r e c t peripheral action producing a marked increase in peripheral resistance and the other is central hypertensive e f f e c t due to stimulation of central sympathetic structures(8). In f a c t , administration of All into the cerebral v e n t r i c l e caused a r i s e of blood pressure (9, I0, I I ) and water intake (12, 13, 14) in anesthetized rat. Administration of All into the cerebrospinal f l u i d also produced a centrally-mediated hypertension not only anesthetized rats, but also in dogs and cats (15). S t i l l more, infusion of All into the vertebral a r t e r i e s of anesthetized dog e l i c i t e d a c e n t r a l l y mediated r i s e in blood pressure (16). On the basis of such findings the brain renin-angiotensin system is thought to play an important role in the regulation of blood pressure. Several areas in the brain, such as the area postrema(16), subnucleus medialis(17), organum vasculosum of the lamina terminalis(18), subfornical organ and anteroventral t h i r d v e n t r i c l e ( 1 9 , 20) are supposed to be important sites i~2~entral regulation of the blood pressure. According to examination using [ " l ] - a n g i o t e n s i n I I , S i r e t t et al. showed that All binding sites were 0024-3205/87 $3.00 + .00 Copyright (c) 1987 Pergamon Journals Ltd.
750
Angiotensin II and Preoptic Area
Vol. 41, No. 6, 1987
located at the midbrain, thalamus, septum, hypothalamus and medulla and very low level of binding were found in the cortex, hippocampus and striatum. And the l a t e r a l septum had the highest binding a c t i v i t y of a l l the tissues examined(21). Houten et a l . demonstrated that the greatest population of A l l binding sites was present in the central region of the subfornical organ(22). However, s i t e s of cardiovascular action of A l l in the brain s t i l l remains to be determined. As regards the preoptic area(POA), there was a recent report describing that the hypothalamic nuclei containing c e l l bodies include the suprachiasmatic nucleus, the medial POA and p e r i f o r n i c a l part of the l a t e r a l hypothalamic area, and f i b e r s were found at a l l level of the central nervous system, from the o l f a c t o r y bulbs to spinal cord(7). There was also a report mentioning that i n j e c t i o n of A l l into POA e l i c i t e s pressor response in anesthetized normotensive rat(23). These evidence indicates a p o s s i b i l i t y of presence of A l l receptor and neuron at POA. However, the p a r t i c i p a t i o n of A l l system at POA in central regulation of blood pressure is s t i l l unclear at present. The present experiment was therefore undertaken to investigate pressor response to A l l at POA and thereby study the difference in the pressor response between WKY and SHR under the unrestrained and conscious conditions. Methods Male SHR of Okamoto s t r a i n and control Male WKY r a t , aged 14 weeks to 16 weeks at the beginning of the study, were used. Animals were maintained food and drink f r e e l y . After anesthetized with sodium pentobarbital(4Omg/kg, i . p o ) , stainless guide cannulas were implanted u n i l a t e r a l l y to POA. The coordinates, a n t e r i o r (A) from the bregma, l a t e r a l (L) to the midline and horizontal (H) below dura were with the aid of KSnig and Klippel at A -0,5, L ~0.8, H -8.5 f o r SHR, A -0.5, L ±0.8, H -9.0 for WKY. Seven days a f t e r implantation of the guide cannula, the bevelled PE I0 end of cannula was inserted into the aorta through the femoral a r t e r y a f t e r anesthetized with ethylether. Seven days following implantation of the cannula, the experiment was performed under unrestrained, conscious state. The catheter was connected to a stathem P50 pressure transducer for continuous recording of blood pressure and heart rate via a San-ei polygraph. Drugslwere ~ n i l a t e r a l l y injected into the POA at the rate of I~I per 1.5 min. [Sar , l l e ]-angiotensin I I in combination with A l l were simultaneously injected into POA via the same guide cannula. A f t e r each experiment, rats were s a c r i f i c e d and brains perfused with 10% formalin. Brains were sectioned at 70~m and stained with cresyl v i o l e t to permit l o c a l i z a t i o n of the cannula t i p s . The rats in which both cannula t i p s were located out of POA were excluded from the experimental data. All values are expressed as mean ±S.E.M. S t a t i s t i c a l analysis was performed using Student's t t e s t . Differences were considered to be s i g n i f i c a n t when p
Vol. 41, No. 6, 1987
Angiotensin II and Preoptic Area
751
maximum w i t h i n one minute and lasted f o r over 30 min, blood pressure increasing from 165 mmHg to 215 mmHg. In WKY (lower panel of Fig I ) , the pressor response i n i t i a t e d r a t h e r slowly a f t e r i n j e c t i o n , reached a maximum in about one minute and l a s t e d l f o r about 20 min, blood pressure increasing from 150 mmHg to 165 mmHg. [Sar , l l e ] - a n g i o t e n s i n I I (0.5 ~ g ) , an A l l receptor antagonist, per se, d i d n ' t produce s i g n i f i c a n t changes of blood pressure and heart r a t e when i n j e c t e d i n t o POA. The e f f e c t of A l l (I ng) i n j e c t e d in combination with [Sar 1 l l e ] - a n g i o t e n s i n 11(0.5 ~g) i n t o POA are shown in Table I . The pressor response to A l l was s t r o n g l y i n h i b i t e d and was almost e l i m i n a t e d by simultaneous a d m i n i s t r a t i o n of an A l l receptor antagonist in both SHR and WKY, implying t h a t response is due to s t i m u l a t i o n of A l l receptor located at POA area. As demonstrated in Fig. 2, pressor response to A l l in SHR was more than 2 times g r e a t e r than t h a t in WKY, but there was no s i g n i f i c a n t d i f f e r e n c e s in weak negative chronotropic responses between SHR and WKY.
3mln HR
400~ 0L
(beats/mini BP 200 f 150 (mmHg)
I' 30mln
15mln
Angiotensln ]~ lng
3mln HR
400~ OL
(beats/mini
200[
"" .o I (mmHg)
I'
Anglotensln 11" lng
20rain
Fig
1
Representative t r a c i n g of A l l (I ng) administered i n t o POA on blood pressure and h e a r t r a t e in u n r e s t r a i n e d , conscious r a t s . The upper panel shows the e f f e c t in SHR and the l o w e r one t h a t in WKY. HR; h e a r t r a t e , BP; blood pressure.
752
Angiotensin
II and Preoptic Area
Volo 41, No. 6, 1987
(B)
(A) (8)
[ ] WKY
30 E
ms..
.= 0 A-i
0
(6)~
20
(8)
n-
~-10 <~ 3:
'~ 10
l
(8)
-2(I)
(5) 0,3ng
0.3ng 1.0ng Angiotensln X [ ] WKY
1,0ng
Angioten~n~nr
[] SHR
Fig
2
C a r d i o v a s c u l a r response to A l l (I ng, 0.3 ng) i n j e c t e d i n t o POA in unrestrained, conscious rats. The l e f t panel (A) indicate pressor response and the right one (B)negative chronotropic response. Vertical bars represent the S. E. M. Numbers of experimental animals are shown in parentheses. *; P
TABLE 1 Strong i n h i b i t i o n of p r e s s o r re~ponseoto A l l when A l l was into POA in combination w i t h [ S a ~ , l l e ° ] - a n g i o t e n s i n II. drug
n
BP(mmHg)
All(Ing)
9
+32.3±15.2
All(Ing)+[Sar I, l l e 8 ] - A l l
9
All(Ing)
8
All(Ing)+[Sar I, l l e 8 ] - A l l (0.5~g)
9
injected
HR(beats/min) -3.2±22.9
SHR
(0.5~g)
+6.5±8.7 **~ +10.6±8.2
-6.0±13.7 -10.7±10.7
WKY
*; P
+2.6±4.6* (I
ng) alone and A l l
-1.5±25.4 (I
ng) plus
Vol. 41, No. 6, 1987
Angiotensin II and Preoptic Area
753
Discussion There have been a few reports mentioning differences between WKY and SHR in central response to A l l antagonist or angiotensin converting enzyme i n h i b i t o r on blood pressure. Administration of Pll3(saralasin acetate), an A l l receptor antagonist, into the cerebroventricle caused depressor response only in the young SHR, but not in WKY(24). Infusion of [Sar , l l e 8 ] angiotensin I I , an All receptor antagonist, into the l a t e r a l v e n t r i c l e of mature SHR and WKY, maintained at rates of 1200 ng/hr for 6 days, induced a f a l l of blood pressure only in the SHR(25). I n j e c t i o n of captopril(2 mg/kg), an angiotensin converting enzyme i n h i b i t o r , into the v e n t r i c l e s in conscious SHR and WKY resulted in causing a rapid hypotensive response that lasted several hours in SHR, but had no s i g n i f i c a n t e f f e c t in WKY(26), Recently, we observed that A l l or renin injected into the l a t e r a l v e n t r i c l e of unrestrained, conscious rats produced pressor response and t h i s response was markedly greater in SHR than in WKY(unpublished observation). Differences between SHR and WKY of binding a f f i n i t y and capacity of A l l have been also reported. There were no s i g n i f i c a n t difference in All receptor population between SHR and WKY at the hypothalamus, thalamus, septum and midbrain(27). However, i t was reported that, at the organum vasculosum of the lamina t e r m i n a l i s , the binding of All was 0.24 fg/g protein in normotensive control r a t but was increased to 0.55 fg/g protein in SHR (28). As f o r POA, i n j e c t i o n of NaCI solution at higher concentration of 0.2 M into the l a t e r a l POA was reported to cause a s i g n i f i c a n t increase of a r t e r i a l pressure in unrestrained rat(29). In control study of this experiment on unrestrained, conscious rats, O.9%-physiological saline i n j e c t i o n to POA d i d n ' t cause a pressor response in both WKY as well as SHR. However, A l l injected at doses of 0.3 ng and 1 ng into POA e l i c i t e d a dose-dependent increase of blood pressure in both SHR and WKY POA i n j e c t i o n of All in combination with [Sar I , l l e 8 ] - a n g i o t e n s i n I I (0.5 ~$) exhibited a prominently reduced pressor response to A l l . Accordingly. i t is evident that the pressor response to A l l at POA is due to stimulation of All receptor. This pressor response to A l l at POA was markedly potentiated in SHR, becoming more than 2 times greater response as compared with that in WKY. Thus, the present study suggest that A l l system at POA may play an important role in central regulation of blood pressure and s e n s i t i v i t y to All at POA is markedly potentiated in SHR. Reference 1 2 3 4 5 6
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