A. Ermisch, R . Landgraf and H.-J. Riihle (Eds.) Progress in Brain Research, Vol. 91 0 1992 Elsevier Science Publishers B.V. All rights reserved.
19
CHAPTER 4
Effect of central administration of angiotensin I1 on cerebrospinal fluid formation in rabbits A. Chodobski*, J. Szmydynger-Chodobska", M.B. Segal' and I.A. McPherson Department of Clinical and Applied Physiology, Institute of Physiological Sciences, School of Medicine, Warsaw, Poland; and I Sherrington School of Physiology, United Medical and Dental Schools of Guy's and St. Thomas's Hospitals, St. Thomas's Campus, London, U.K.
The effect of central administration of A11 on CSF formation was studied in alpha-chloralose and urethane anesthetized rabbits using the ventriculocisternal perfusion method. A11 infused i.c.v. at rates of 5.5 and 55 pg/min significantly decreased CSF production by 2 5 % and 3 5 % , respectively. In contrast, A11 when given at 5 . 5 ng/min did not change CSF formation. It seems that drop in CSF production observed during central administration of A11 at low doses is mediated by both increased vasopressin
release and activation of the sympathetic nervous system. The lack of changes in CSF formation with the highest A11 dose used is not clear at present and awaits further investigation. Specific A11 antagonist, saralasin, was found to significantly increase CSF production in four of five animals studied. It is suggested that in normal conditions A11 may exert a tonic inhibitory effect on CSF formation.
Introduction
release of vasopressin and activate the sympathetic nervous system (Phillips, 1987). Both of these factors, in turn, were reported to affect CSF production (Lindvall and Owman, 1981; Faraci et al., 1990). It was the aim of this study to investigate the effect of centrally administered A11 on CSF formation. For this purpose the ventriculocisternal perfusion method of Pappenheimer et al. (1962) was employed in anesthetized rabbits.
Considerable body of evidence has accumulated indicating the presence in brain of the independent renin-angiotensin system (Ganong, 1984; Moffett et al., 1987). Centrally released angiotensin I1 (AII) was postulated to play an important role in the regulation of systemic arterial blood pressure and the maintenance of whole body fluid and electrolyte balance (Phillips, 1987). A11 was also found to affect brain vascular permeability when administered into the cerebral ventricular system (Grubb and Raichle, 1981). The presence of A11 receptor sites in the choroid plexus (Gehlert et al., 1986; Mendelsohn et al., 1987), which is a major source of the cerebrospinal fluid (CSF), suggests that A11 may influence its formation. Central A11 is known to both enhance the
* Recipients of the Wellcome Trust
Research Grant.
Methods
The experiments were performed on New Zealand whiterabbits ofeither sex weighing 2.5 - 3.2 kg. The animals were initially anesthetized with intravenous alpha-chloralose and urethane (50 mg/kg and 0.5 g/kg, respectively). To maintain anesthesia, the above anesthetics were administered at a dose of 10 mg/kg per hour and 0.1 g/kg per hour, respectively.
20
A tracheostomy was performed and catheters inserted into the femoral artery and vein for measurement of systemic arterial blood pressure, collection of arterial blood samples, and intravenous administration of drugs and solutions. Fluid loss was replaced (Ringer and 5% glucose solutions) at a rate of 2 ml/kg per hour. Arterial oxygen tension was maintained at 100 - 120 mm Hg by adjusting the inspiratory oxygen content, and arterial carbon dioxide tension was within the range of 32 - 36 mm Hg. Rectal temperature was kept at 37 - 38°C. Cerebrospinal fluid formation rate was measured using a modification of the ventriculocisternal perfusion method of Pappenheimer et al. (1962). For this purpose, the rabbits were mounted in a stereotaxic frame and two cannulas introduced into both lateral ventricles (10 mm caudally to the bregma and 8 mm laterally to the sagittal suture). Through these cannulas, an artificial CSF was infused at a rate of 25 pl/min for each ventricle, and intraventricular pressure continuously monitored by means of T connectors inserted into the infusion lines. A needle was inserted into the cisterna magna to enable CSF outflow, and outflow pressure was maintained at - 10 cm H20. Artificial CSF composition was as follows (mM): NaCl 125, KC12.5, CaC12 1.2, MgCl, 0.9, NaHC03 25, Na2HP0, 0.5, KH2P0, 0.5, glucose 4.3, urea 6.5. This fluid contained also blue dextran 2000 at a concentration of 2 mg/ml, used as an indicator substance. CSF samples were collected at 15-min intervals, and their indicator substancecontents determined colorimetrically by measuring absorbance at 620 nm. Before performing these measurements, samples were chilled and centrifuged to eliminate contaminants (Haywood and Vogh, 1978). CSF formation rate was calculated according to Heisey et al. (1962). Since there is a gradual decrease in CSF formation rate during the course of the ventriculocisternal perfusion (Zlokovic et al., 1987), the value of CSF production obtained at 2 h of perfusion was arbitrarily chosen for further consideration, assuming that at that time the nascent CSF and the perfusate are already well mixed. Becauseof this, separate control
and experimental series were performed. There were five series of experiments; one control series, three series where A11 (Sigma, St. Louis, MO) was administered intracerebroventricularly (i.c.v.) at doses of 0.0055, 0.055 and 5.5 ng/min, and one series where a specific A11 antagonist, [Sar',Ala8]-AII (saralasin; Sigma), was administered i.c.v. at a dose of 5.5 ng/min. During A11 administration, systemic arterial blood pressure was kept constant by withdrawing blood. Results are presented as means f S.E. For statistical data assessment, one-way analysis of variance, followed by the Dunnett test, was employed.
Results and conclusions Control CSF formation rate was 11.5 f 0.6 pl/min (n = 5 ) . Central administration of A11 at doses of 5.5 and 55 pg/min significantly lowered CSF production by 25% ( P < 0.05) and 35% ( P < 0.01), respectively (Fig. 1). In contrast, the highest A11 dose used (5.5 nglmin) did not change the CSF production (Fig. 1). The base-line A11 levels in CSF are low (about 20 - 30 pg/ml) and do not change much in different physiological or pathophysiological situations (Schelling et al., 1980; Simon-Oppermann et al., 1986). Since the activity of angiotensinase in CSF is negligible (Schelling et al., 1980; Ganong, 1984), we assumed that i.c.v. administration of A11 resulted in
(5)
(5)
(5)
(4)
(5)
Fig. I , Changes in cerebrospinal fluid production during central administration of All and its specific antagonist, saralasin. Number of animals is given in parentheses. * P < 0.05; **P < 0.01 compared with control.
21
CSF peptide concentrations of about 0.1, 1 and 100 ng/ml at its infusion rates of 0.0055,0.055, and 5.5 ng/min, respectively. All these A11 doses were associated with a pressor response of 10- 15 mm Hg. Central administration of A11 is followed by both increased vasopressin release (Share, 1979; Phillips, 1987) and activation of the sympathetic nervous system (Buckley, 1972; Phillips, 1987). Both of these factors are responsible for the increase in arterial blood pressure after i.c.v. administration of AII. Vasopressin was found to decrease the CSF formation rate when given into the systemic circulation (Faraci et al., 1990). Similarly, the sympathetic nervous system was observed to exert a significant influence on CSF flow (Lindvall and Owman, 1981). It seems, therefore, that both vasopressin and the sympathetic nervous system may act in concert to mediate a drop in CSF production which follows the central administration of A11 at low doses. The lack of changes in CSF formation during i.c.v. A11 infusion at the highest dose used suggests that in this situation there are probably additional A11 actions counterbalancing the fall in CSF production which would otherwise appear. It could be hypothesized that A11 at this high dose has also a direct stimulatory effect on CSF formation by augmenting sodium transport in the choroid plexus. A11 was found to increase sodium reabsorption in the renal proximal tubules; however, this effect was observed at low A11 concentrations, whereas A11 at high concentrations inhibited sodium transport in these epithelia (for review, see Navar et al., 1987; Cogan, 1990). The presence of A11 receptor sites in the choroid plexus was confirmed (Gehlert et al., 1986; Mendelsohn et al., 1987), but their cellular localization has not yet been determined. One cannot exclude, therefore, that these sites are localized to the basolateral part of the choroid plexus epithelial cells. With such localization of A11 receptor sites, the peptide contained in CSF would not be able to reach them easily because of the presence of tight junctions between the apical parts (facing CSF) of the choroid plexus epithelial cells (Davson et al., 1987). Thus, only a small frac-
tion of A11 administered i.c.v. would have an access to these sites, and, therefore, the peptide infused at the high rate could stimulate sodium transport in the choroid plexus (similarly as A11 at low concentrations does in the renal epithelia), whereas the lower rates of A11 infusion would be ineffective. If A11 receptors sites were localized to the apical part of the choroid plexus epithelial cells, then A11 infused at the lower rates would tend to increase CSF production, while higher A11 doses would have an inhibitory action. In fact, the opposite effects were observed. Further studies are necessary to clarify the mechanisms mediating the effect of high A11 doses on CSF formation. Central administration of a specific A11 antagonist, saralasin, increased the CSF formation rate by 20070,but this change was found not to be statistically significant (Fig. 1). The rise in CSF production was observed in four of five animals studied for which it attained a statistical significance (14.6 k 0.4 pl/min, P c 0.01). These results suggest, therefore, that in normal conditions A11 may exert a tonic inhibitory effect on CSF formation. References Buckley, J.P. (1972) Actions of angiotensin on the central nervous system. Fed. Proc., 31: 1332- 1337. Cogan, M.G. (1990) Angiotensin 11: a powerful controller of sodium transport in the early proximal tubule. Hypertension, 15: 451 -458. Davson, H., Welch, K. and Segal, M.B. (1987) Physiology and Pathophysiology of the Cerebrospinal Fluid, Churchill Livingstone, Edinburgh. Faraci, F.M., Mayhan, W.G. and Heistad, D.D. (1990) Effect of vasopressin on production of cerebrospinal fluid: possible role of vasopressin (V,)-receptors. Am. J . Physiol., 258: R94 - R98. Ganong, W.F. (1984)The brain renin-angiotensinsystem. Annu. Rev. Physiol., 46: 17-31. Gehlert, D.R., Speth, R.C. and Wamsley, J.K. (1986) Distribution of ['251]angiotensin 11 binding sites in the rat brain: a quantitative autoradiographic study. Neuroscience, 18: 837 - 856. Grubb, R.L., Jr. and Raichle, M.E. (1981) Intraventricular angiotensin I1 increases brain vascular permeability. Brain Rex, 210: 426 - 430. Haywood, J.R. and Vogh, B.P. (1978) Entry of protein into cerebral ventricles during ventriculo-cisternal perfusion and
22
the administration of anti-inflammatory agents. J. Neurochem., 30: 1621 - 1623. Heisey, S.R., Held, D. and Pappenheimer, J.R. (1962)Bulk flow and diffusion in the cerebrospinal fluid system of the goat. Am. J. Physiol., 203: 775 - 781. Lindvall, M. and Owman, C. (1981) Autonomic nerves in the mammalian choroid plexus and their influence on the formation of cerebrospinal fluid. J. Cereb. Blood Flow Metab., l : 245 - 266. Mendelsohn, F.A.O., Allen, A.M., Chai, S.Y., Sexton, P.M. and Figdor, R. (1987) Overlapping distribution of receptors for atrial natriuretic peptide and angiotensin I1 visualized by in vitro autoradiography: morphological basis of physiological antagonism. Can. J. Physiol. Pharmacol., 65: 1517 - 1521. Moffett, R.B., Bumpus, F.M. and Husain, A. (1987) Cellular organization of the brain renin-angiotensin system. Life Sci., 41: 1867-1879. Navar, L.G., Carmines, P.K., Huang, W .-C. and Mitchell, K.D. (1987) The tubular effects of angiotensin 11. Kidney In(. (SUPPI.20), 31: S81 - S 8 8 .
Pappenheimer, J.R., Heisey, S.R., Jordan, E.F. and Downer, J . deC. (1962) Perfusion of the cerebral ventricular system in unanesthetized goats. Am. J . Physiol., 203: 763 - 774. Phillips, M.I. (1987) Functions of angiotensin in the central nervous system. Annu. Rev. Physiol., 49: 413-435. Schelling, P., Ganten, U., Sponer, G . , Unger, T. and Ganten, D. (1980) Components of the renin-angiotensin system in the cerebrospinal fluid of rats and dogs with special consideration of the origin and fate of angiotensin 11. Neuroendocrinology, 31: 297-308. Share, L. (1979) Interrelations between vasopressin and the renin-angiotensin system. Fed. Proc., 38: 2267 - 2271. Simon-Oppermann, C., Gray, D.A. and Simon, E. (1986) Independent osmoregulatory control of central and systemic angiotensin I1 concentrations in dogs. Am. J. Physiol., 250: R918 - R925. Zlokovic, B.V., Davson, H., Preston, J.E. and Segal, M.B. (1987) The effects of aluminum chloride on the rate of secretion of the cerebrospinal fluid. Exp. Neurol., 98: 436 - 452.
19
CHAPTER 4
Effect of central administration of angiotensin I1 on cerebrospinal fluid formation in rabbits A. Chodobski*, J. Szmydynger-Chodobska", M.B. Segal' and I.A. McPherson Department of Clinical and Applied Physiology, Institute of Physiological Sciences, School of Medicine, Warsaw, Poland; and I Sherrington School of Physiology, United Medical and Dental Schools of Guy's and St. Thomas's Hospitals, St. Thomas's Campus, London, U.K.
The effect of central administration of A11 on CSF formation was studied in alpha-chloralose and urethane anesthetized rabbits using the ventriculocisternal perfusion method. A11 infused i.c.v. at rates of 5.5 and 55 pg/min significantly decreased CSF production by 2 5 % and 3 5 % , respectively. In contrast, A11 when given at 5 . 5 ng/min did not change CSF formation. It seems that drop in CSF production observed during central administration of A11 at low doses is mediated by both increased vasopressin
release and activation of the sympathetic nervous system. The lack of changes in CSF formation with the highest A11 dose used is not clear at present and awaits further investigation. Specific A11 antagonist, saralasin, was found to significantly increase CSF production in four of five animals studied. It is suggested that in normal conditions A11 may exert a tonic inhibitory effect on CSF formation.
Introduction
release of vasopressin and activate the sympathetic nervous system (Phillips, 1987). Both of these factors, in turn, were reported to affect CSF production (Lindvall and Owman, 1981; Faraci et al., 1990). It was the aim of this study to investigate the effect of centrally administered A11 on CSF formation. For this purpose the ventriculocisternal perfusion method of Pappenheimer et al. (1962) was employed in anesthetized rabbits.
Considerable body of evidence has accumulated indicating the presence in brain of the independent renin-angiotensin system (Ganong, 1984; Moffett et al., 1987). Centrally released angiotensin I1 (AII) was postulated to play an important role in the regulation of systemic arterial blood pressure and the maintenance of whole body fluid and electrolyte balance (Phillips, 1987). A11 was also found to affect brain vascular permeability when administered into the cerebral ventricular system (Grubb and Raichle, 1981). The presence of A11 receptor sites in the choroid plexus (Gehlert et al., 1986; Mendelsohn et al., 1987), which is a major source of the cerebrospinal fluid (CSF), suggests that A11 may influence its formation. Central A11 is known to both enhance the
* Recipients of the Wellcome Trust
Research Grant.
Methods
The experiments were performed on New Zealand whiterabbits ofeither sex weighing 2.5 - 3.2 kg. The animals were initially anesthetized with intravenous alpha-chloralose and urethane (50 mg/kg and 0.5 g/kg, respectively). To maintain anesthesia, the above anesthetics were administered at a dose of 10 mg/kg per hour and 0.1 g/kg per hour, respectively.
20
A tracheostomy was performed and catheters inserted into the femoral artery and vein for measurement of systemic arterial blood pressure, collection of arterial blood samples, and intravenous administration of drugs and solutions. Fluid loss was replaced (Ringer and 5% glucose solutions) at a rate of 2 ml/kg per hour. Arterial oxygen tension was maintained at 100 - 120 mm Hg by adjusting the inspiratory oxygen content, and arterial carbon dioxide tension was within the range of 32 - 36 mm Hg. Rectal temperature was kept at 37 - 38°C. Cerebrospinal fluid formation rate was measured using a modification of the ventriculocisternal perfusion method of Pappenheimer et al. (1962). For this purpose, the rabbits were mounted in a stereotaxic frame and two cannulas introduced into both lateral ventricles (10 mm caudally to the bregma and 8 mm laterally to the sagittal suture). Through these cannulas, an artificial CSF was infused at a rate of 25 pl/min for each ventricle, and intraventricular pressure continuously monitored by means of T connectors inserted into the infusion lines. A needle was inserted into the cisterna magna to enable CSF outflow, and outflow pressure was maintained at - 10 cm H20. Artificial CSF composition was as follows (mM): NaCl 125, KC12.5, CaC12 1.2, MgCl, 0.9, NaHC03 25, Na2HP0, 0.5, KH2P0, 0.5, glucose 4.3, urea 6.5. This fluid contained also blue dextran 2000 at a concentration of 2 mg/ml, used as an indicator substance. CSF samples were collected at 15-min intervals, and their indicator substancecontents determined colorimetrically by measuring absorbance at 620 nm. Before performing these measurements, samples were chilled and centrifuged to eliminate contaminants (Haywood and Vogh, 1978). CSF formation rate was calculated according to Heisey et al. (1962). Since there is a gradual decrease in CSF formation rate during the course of the ventriculocisternal perfusion (Zlokovic et al., 1987), the value of CSF production obtained at 2 h of perfusion was arbitrarily chosen for further consideration, assuming that at that time the nascent CSF and the perfusate are already well mixed. Becauseof this, separate control
and experimental series were performed. There were five series of experiments; one control series, three series where A11 (Sigma, St. Louis, MO) was administered intracerebroventricularly (i.c.v.) at doses of 0.0055, 0.055 and 5.5 ng/min, and one series where a specific A11 antagonist, [Sar',Ala8]-AII (saralasin; Sigma), was administered i.c.v. at a dose of 5.5 ng/min. During A11 administration, systemic arterial blood pressure was kept constant by withdrawing blood. Results are presented as means f S.E. For statistical data assessment, one-way analysis of variance, followed by the Dunnett test, was employed.
Results and conclusions Control CSF formation rate was 11.5 f 0.6 pl/min (n = 5 ) . Central administration of A11 at doses of 5.5 and 55 pg/min significantly lowered CSF production by 25% ( P < 0.05) and 35% ( P < 0.01), respectively (Fig. 1). In contrast, the highest A11 dose used (5.5 nglmin) did not change the CSF production (Fig. 1). The base-line A11 levels in CSF are low (about 20 - 30 pg/ml) and do not change much in different physiological or pathophysiological situations (Schelling et al., 1980; Simon-Oppermann et al., 1986). Since the activity of angiotensinase in CSF is negligible (Schelling et al., 1980; Ganong, 1984), we assumed that i.c.v. administration of A11 resulted in
(5)
(5)
(5)
(4)
(5)
Fig. I , Changes in cerebrospinal fluid production during central administration of All and its specific antagonist, saralasin. Number of animals is given in parentheses. * P < 0.05; **P < 0.01 compared with control.
21
CSF peptide concentrations of about 0.1, 1 and 100 ng/ml at its infusion rates of 0.0055,0.055, and 5.5 ng/min, respectively. All these A11 doses were associated with a pressor response of 10- 15 mm Hg. Central administration of A11 is followed by both increased vasopressin release (Share, 1979; Phillips, 1987) and activation of the sympathetic nervous system (Buckley, 1972; Phillips, 1987). Both of these factors are responsible for the increase in arterial blood pressure after i.c.v. administration of AII. Vasopressin was found to decrease the CSF formation rate when given into the systemic circulation (Faraci et al., 1990). Similarly, the sympathetic nervous system was observed to exert a significant influence on CSF flow (Lindvall and Owman, 1981). It seems, therefore, that both vasopressin and the sympathetic nervous system may act in concert to mediate a drop in CSF production which follows the central administration of A11 at low doses. The lack of changes in CSF formation during i.c.v. A11 infusion at the highest dose used suggests that in this situation there are probably additional A11 actions counterbalancing the fall in CSF production which would otherwise appear. It could be hypothesized that A11 at this high dose has also a direct stimulatory effect on CSF formation by augmenting sodium transport in the choroid plexus. A11 was found to increase sodium reabsorption in the renal proximal tubules; however, this effect was observed at low A11 concentrations, whereas A11 at high concentrations inhibited sodium transport in these epithelia (for review, see Navar et al., 1987; Cogan, 1990). The presence of A11 receptor sites in the choroid plexus was confirmed (Gehlert et al., 1986; Mendelsohn et al., 1987), but their cellular localization has not yet been determined. One cannot exclude, therefore, that these sites are localized to the basolateral part of the choroid plexus epithelial cells. With such localization of A11 receptor sites, the peptide contained in CSF would not be able to reach them easily because of the presence of tight junctions between the apical parts (facing CSF) of the choroid plexus epithelial cells (Davson et al., 1987). Thus, only a small frac-
tion of A11 administered i.c.v. would have an access to these sites, and, therefore, the peptide infused at the high rate could stimulate sodium transport in the choroid plexus (similarly as A11 at low concentrations does in the renal epithelia), whereas the lower rates of A11 infusion would be ineffective. If A11 receptors sites were localized to the apical part of the choroid plexus epithelial cells, then A11 infused at the lower rates would tend to increase CSF production, while higher A11 doses would have an inhibitory action. In fact, the opposite effects were observed. Further studies are necessary to clarify the mechanisms mediating the effect of high A11 doses on CSF formation. Central administration of a specific A11 antagonist, saralasin, increased the CSF formation rate by 20070,but this change was found not to be statistically significant (Fig. 1). The rise in CSF production was observed in four of five animals studied for which it attained a statistical significance (14.6 k 0.4 pl/min, P c 0.01). These results suggest, therefore, that in normal conditions A11 may exert a tonic inhibitory effect on CSF formation. References Buckley, J.P. (1972) Actions of angiotensin on the central nervous system. Fed. Proc., 31: 1332- 1337. Cogan, M.G. (1990) Angiotensin 11: a powerful controller of sodium transport in the early proximal tubule. Hypertension, 15: 451 -458. Davson, H., Welch, K. and Segal, M.B. (1987) Physiology and Pathophysiology of the Cerebrospinal Fluid, Churchill Livingstone, Edinburgh. Faraci, F.M., Mayhan, W.G. and Heistad, D.D. (1990) Effect of vasopressin on production of cerebrospinal fluid: possible role of vasopressin (V,)-receptors. Am. J . Physiol., 258: R94 - R98. Ganong, W.F. (1984)The brain renin-angiotensinsystem. Annu. Rev. Physiol., 46: 17-31. Gehlert, D.R., Speth, R.C. and Wamsley, J.K. (1986) Distribution of ['251]angiotensin 11 binding sites in the rat brain: a quantitative autoradiographic study. Neuroscience, 18: 837 - 856. Grubb, R.L., Jr. and Raichle, M.E. (1981) Intraventricular angiotensin I1 increases brain vascular permeability. Brain Rex, 210: 426 - 430. Haywood, J.R. and Vogh, B.P. (1978) Entry of protein into cerebral ventricles during ventriculo-cisternal perfusion and
22
the administration of anti-inflammatory agents. J. Neurochem., 30: 1621 - 1623. Heisey, S.R., Held, D. and Pappenheimer, J.R. (1962)Bulk flow and diffusion in the cerebrospinal fluid system of the goat. Am. J. Physiol., 203: 775 - 781. Lindvall, M. and Owman, C. (1981) Autonomic nerves in the mammalian choroid plexus and their influence on the formation of cerebrospinal fluid. J. Cereb. Blood Flow Metab., l : 245 - 266. Mendelsohn, F.A.O., Allen, A.M., Chai, S.Y., Sexton, P.M. and Figdor, R. (1987) Overlapping distribution of receptors for atrial natriuretic peptide and angiotensin I1 visualized by in vitro autoradiography: morphological basis of physiological antagonism. Can. J. Physiol. Pharmacol., 65: 1517 - 1521. Moffett, R.B., Bumpus, F.M. and Husain, A. (1987) Cellular organization of the brain renin-angiotensin system. Life Sci., 41: 1867-1879. Navar, L.G., Carmines, P.K., Huang, W .-C. and Mitchell, K.D. (1987) The tubular effects of angiotensin 11. Kidney In(. (SUPPI.20), 31: S81 - S 8 8 .
Pappenheimer, J.R., Heisey, S.R., Jordan, E.F. and Downer, J . deC. (1962) Perfusion of the cerebral ventricular system in unanesthetized goats. Am. J . Physiol., 203: 763 - 774. Phillips, M.I. (1987) Functions of angiotensin in the central nervous system. Annu. Rev. Physiol., 49: 413-435. Schelling, P., Ganten, U., Sponer, G . , Unger, T. and Ganten, D. (1980) Components of the renin-angiotensin system in the cerebrospinal fluid of rats and dogs with special consideration of the origin and fate of angiotensin 11. Neuroendocrinology, 31: 297-308. Share, L. (1979) Interrelations between vasopressin and the renin-angiotensin system. Fed. Proc., 38: 2267 - 2271. Simon-Oppermann, C., Gray, D.A. and Simon, E. (1986) Independent osmoregulatory control of central and systemic angiotensin I1 concentrations in dogs. Am. J. Physiol., 250: R918 - R925. Zlokovic, B.V., Davson, H., Preston, J.E. and Segal, M.B. (1987) The effects of aluminum chloride on the rate of secretion of the cerebrospinal fluid. Exp. Neurol., 98: 436 - 452.
