- Email: [email protected]
Adenosine and gastric function
345
TIPS - October 1988 [Vol. 9]
role for the ischaemia-induced fall of intracellular pH in the deterioration of contractile performance during ischaemia. Solaro (Chicago) showed that in skinned preparations there is a substantial reduction in the Ca 2+ sensitivity of the actomyosin ATPase at a lower pH such as that found in ischaemic hearts, and suggested that the change in pH affected the thin filaments. Interestingly this was not evident in neonatal hearts. The Ca 2+ binding protein troponin C appears to be the same, and present in similar amounts, in both adult and neonatal hearts. However, the inhibitory component of troponin, troponin I, is different in the two age groups. It was therefore suggested that the decrease in Ca 2+ binding to troponin C during acidosis may be secondary to an effect of acidosis on troponin I. Allen (London) presented an interesting experimental model of ischaemia involving a N2-gas perfusion system. An increase in cytosolic Ca 2+ was clearly seen under such conditions, and it was stressed that all of the observations could be mimicked by perfusion with lactic acid, and, for instance, that no increase in Ca 2+ was observed in glycogendepleted hearts. Others (e.g. Vaughan-Jones, Oxford) presented data to suggest the involvement of both the sarcolemmal Na+-H + and Na+-Ca 2+ exchanges (Fig. 1) in bringing about the rise in intracellular Ca 2+, though again it was evident that more progress could be achieved in this important area if better and more specific drugs could be developed to interact with these proteins. []
[]
[]
Current awareness Adenosine and gastric function Adenosine is an important endogenous regulator of many physiological processes including blood flow, seizure activity, airway resistance and neuronal activity. Its actions are apparently mediated by functional adenosine receptors 1. Rank orders of agonist potencies have been used to characterize adenosine receptor subtypes 2. R-N6-phenylisopropyl adenosine (R-PIA) and Nt'-cyclo hexyladenosine are potent ligands for adenosine A1 receptors which are generally associated with a decrease in adenylate cyclase activity, whereas 5'-N-ethylcarboxyamidoadenosine (NECA) is more potent at A2 receptors, stimulation of which is generally associaLed with an increase in adenylate cyclase activity. There is now increasing direct and indirect evidence that adenosine and its receptors are involved in the control of gastric acidity and modulation of gastric responses to the secretagogues histamine and acetylcholine (Fig. 1). Moreover, adenosine analogs have been shown unde:" certain circumstances to exert an ameliorating effect on experimentally induced gastric pathology 3-5. The notion that adenosine serves as a gastric protective agent is further suggested by findings that the methylxanthines caffeine and theophylline, which ar~: known to be competitive antagonists at adenosine receptors at appropriate concentrations, stimulate gastric acid
Abstracts from this meeting have been published in J. Mol. Cell. Cardi.ol. (1988) 20, Suppl. IV. JAMES G. McCORMACK, MARK R. BOYETT*, BRIAN R. JEWELL* AND CLIVE H. ORCHARD*
Departments of Biochemistry and *Physiology, The University of Leeds, Leeds Lq2 9JT, UK.
References 1 Carafoli, E. (1987) Annu. Rev. Biochem. 56, 395--433 2 Katz, K. A., Koretsky, A= P. and Balaban, R. S. (1987) FEBS Left. 221, 270-276 3 Vaghy, P. L., Johnson, J. D., Matlib, M. A., Wang, T. and Schwartz, A. (1982) J. Biol. Chem. 257, 6000-6002 4 Zernig, G. and GIossmann, H. (1988) Biochem. 1. 253, 49-58
secretion and predispose mammals to gastric pathology 6'7.
Gastric acid secretion Evidence from in-vitro experiments strongly suggests that exogenous and endogenous adenosine regulates basal ~z',.d histaminestimulated acid secretion. In 1982, two brief reports noted that adenosine s and the adenosine deaminaseresistant analog 2-chloroadenosine 9 decreased histaminestimulated aminopyrine accumulation by isolated canine parietal cells - an indirect measure of acid production. Extending these findings, Gerber and colleagues 1° showed that 2-chloroadenosine and another adenosine analog, R-PIA, inhibited histaminestimulated acid secretion from isolated parietal cells. Using a cytochemical stain for hydroxyl ion productiot~. Heldsinger and co-workers 11 found that R-PIA inhibited histamine-stimulated acid production in guinea-pig cells and that it was more potent than NECA. Adenosine also decreased basal gastric acid secretion in an isolated rat stomach preparation j2. Adenosine did not affect carbacholor dibutyryl-cAMP-stimulated acid secretion 1°'11. Thus adenosine appears not to affect cAMP levels directly, but rather through specific receptors coupled to adenylate cyclase tl. These receptors may be negatively coupled to adenylate cyclase, since low concentrations of R-PIA
histamine acetylcholine ADENOSINE= AGONISTS
(-)
~[<
1+)
ADENOSINE ANTAGONISTS
(-) ~._gastric acidity .,~ (+) ( - ) ~ gastric ulceration ~ (+) Fig. I. The opposing modulatory influences of adenosine a~7onistsand antagonists on basal and secretagogue-induced levels of gastric acid output, and gastric ulceration. (~)1988,ElsevierPubltcat:ons,Cambridge 0165- 6147/88/502.00
346 inhibited histamine-stinmlated cAMP accumulation in isolated parietal cells ~°. On the basis of the above results and the findings that the potent adenosine receptor antagonists (which are both weak inhibitors of cAMP phosphodiesterase activity) 1,3-diethylphenylxanthine 11 and 8-phenyltheophylline m blocked the responses to adenosine compounds, it was suggested that adenosine receptors, possibly of the A1 subtype, were being stimulated, in contrast, however, Puurunen and co-workers 13 reported that R-PIA and NECA at concentrations of up to 10 ~M affected neither basal, nor carbachol- or histamine-stimulated acid secretion by isolated parietal cells from rat. As suggested by these authors, species differences may account for the disparate findings. Recently, the involvement of endogenous adenosine in the regulation of gastric acid secretion was indicated by findings that 8phenyltheophyUine increased and dipyridamole (an inhibitor of adenosine inf,ux into and effiux from cells) decreased histaminebut not carbachol- or dibutyrylcAMP-induced acid secretion 14. The decrease by dipyridamole was attributed to blockade of the extrusion of endogenous adenosine from gastric cells. Evidence from studies in vivo has also demonstrated that adenosine regulates gastric acid secretion. Gerber et al. ~5 showed that adenosine administered into the splenogastric artery inhibited both histamine- and methacholinestimulated gastric acid secretion in anesthetized dogs. This response was blocked by theophy!line. In conscious rats, but not in anesthetized rats, R-PIA given i.c.v, inhibited gastric acid output. However, adenosine analogs given i.v. to anesthetized rats increased gastric acid secretion 16 These effects were blocked by prior administration of the adenosine recepto:- antagonists theophylline ar,.d 8-phenyltheophyt!ine. Pretreatment with atropine or vagotomization of the animal also prevented these effects, suggesting that an intact and nor,no;reactive vagal system is necessary for the expression of the effects cf adenosine on stimulated gastric secretion. We recently found that adeno-
TIPS - October 1988 [Vol. 9]
sine compounds elevated the intraluminal pH and decreased basal gastric acid secretions in conscious rats (Ref. 17 and unpublished). Furthermore, 8-phenyltheophylline at low concentrations blocked the acid reducing effects of R-PIA and at higher concentrations actually stimulated acid secretion 17. The finding ~lat R-PIA was far more potent tha ° s-PIA in inhibiting basal gastri; acid secretion suggested that A~ receptors were involved. However, because A1, A3 (Ref. 18), and possibly A2 sites 19 may all exhibit some degree of stereoselectivity for .~-PIA, we have conducted further studies to characterize the adenosine receptors responsible for the observed decreases in the volume and acid content, and increases in the pH of basal gastric secretions; preliminary results suggest that sites other than A1 sites may be involved in the regulation of the volume and acid content of basal gastric secretions (unpublished). Using a different type of animal preparation, Scarpignato and colleagues 2° found that adenosine when given s.c., but not intraduodenally, significantly decreased the volume but not the acid concentration of gastric secretions from the pylorus-ligated rat. In addition, R-PIA, following its administration by either route, decreased the volume of gastric acid secretions at concentrations four times lower than that necessary to reduce acid concentration. These effects were blocked by a d~,se of theophylline that did not affect gastric secretion alone. The results of the in-vitro ar.~,dinvivo studies summarized ~/bove clearly indicate that adenosinq~ and adenosine receptors are inw:ived in regulating various param.~ters re!ated to gastric acid secre:lion. However, further work is necessary: (1) to understand why under different circumstances adencl~sine compounds can either ir~crease or decrease gastric acid secretion; (2) to distinguish between the adenosine receptol" subtypes mediating these effects; (3) to determine the locations of these receptors; and (4) to determine the possible physiological significance of these findings.
Gastric pathology Gastric hyperacidity is generally regarded as one of the primary
causative factors in the development of gastric ulceration 21. Therefore it is significant that methylxanthines, possibly acting by blocking the actions of adenosine tha~ are being mediated through its receptors, stimulate the volume and acid content of gastric secretions 22 and promote gastric ulceration in animals 23'24 and possibly humans 25'26. Experimentally, adenosine and related compounds have been found to decrease gastric ulceration induced by exposing an animal to a cold, stressful environment 5-7 and to high concentrations of aspirin placed directly into the stomach 27. The greater potency of R-PIA versus s-PIA (Ref. 5), the protection afforded by R-PIA when given peripherally or i.c.v. 5-'7, and the blockaae of the effects of R-P!A by 8-phenyltheophylline given peripherally or 8-sulphophenyltheophylline given centrally suggest that adenosine receptors resembling A1 sites located peripherally and/or centrally were mediating these effects. Others have found adenosine analogs to exacerbate gastric ulceration in response to prolonged exposure to a stressful environment28; however they used a model with no basal level of ulceration, which might have been insufficiently sensitive (see Ref. 6). Dipyridamole, possibly by increasing extracellular adenosine levels, significantly reduced the extent of gastric bleeding and ulcer formation in rats restrained in a cold environment 29. Thus most studies suggest that adenosine and/or adenosine compounds may s e r e as protective agents against the paihological responses to stress.
Possible underlying mechanisms The possible mechanisms by which adenosine compounds exert these protective effects may include: • Increased production of prostaglandins which are known inhibitors of gastric acid secretion. Evidence both for 11 and against s'!° this proposal has been presented. • Adenosine-induced increases in blood flow. The ability of adenosine to decrease gastric acid secretion was dissociable from and opposite to effect~ that might be anticipated if they were secondary to vasodilatation ~6.
347
TIPS - O c t o b e r 1988 [Vol. 9]
• Decreased p r o d u c t i o n of gastrin, a k n o w n s t i m u l a n t of gastric acid secretions. A d e n o s i n e has b e e n s h o w n to s t i m u l a t e the basal secretion of gastrin from parietal cells 3° a n d i n h i b i t adrenergica n d c h o l i n e r g i c - s t i m u l a t e d gastrin secretion 3:. • Decreased release of h i s t a m i n e a n d acetylcholine, t w o k n o w n gastric acid secretagogues. A d e n o s i n e c o m p o u n d s decrease the release of these a n d o t h e r p h y s i o l o g i c a l l y active substances. • The effects of a d e n o s i n e comp o u n d s m a y be exerted b y different receptor s u b t y p e s a n d at different location~. T h u s m u c h m o r e i n l o r m a t i o n is n e e d e d to d e t e r m i n e the m e c h a n isms a n d p h y s i o l o g i c a l significance of some of the o b s e r v e d gastric r e s p o n s e s to a d e n o s i n e . Acknowledgements We w i s h to t h a n k Dr G. Glavin, K. K i e r n a n a n d G. M a y for their assistance w i t h some of the experim e n t s d e s c r i b e d here. S u p p o r t e d b y grants from the M a n i t o b a H e a l t h Research C o u n c i l a n d the Medical Research Council of Canada. VSW w~s s u p p o r t e d by a Postdoctoral F e l l o w s h i p from the St Boniface General Hospital Research F o u n d a t i o n Inc. JDG is a Scholar of the Medical Research C o u n c i l of Canada. V. S. WESTERBERG AND J. D. GEIGER*
Department of Psychology, University of New Mexico Main Campus, Albuquerque, NM 87131, USA, and *Department of Pharmacology and Therapeutics, University of Manitoba Faculty of Medicine, 770 Bannatyne Avenue, Winnipeg, Manitoba R3E OW3, Canada.
References 1 Geiger, J. D. and Nagy, J. I. in Adenosine Receptors (Williams, M., ed.), Humana Press (in press) 2 Williams, M. (1987) Annu. Rev. Pharmacol. Toxicol. 27, 315-345 3 Geiger, J. D. and Glavin, G. B. (1985)Eur. J. Pharmacol. 115, 185-190 4 Wes~.erberg,V. S. and Geiger~|. D. (1987) Life Sci. 41, 2201-2205 5 Westerberg, V. S., Glavin, G. I3. and Geiger, J. D. (1986) Proc. West. Pharmacol. Soc. 29, 425--427 6 Fredholm, B. B. (1984) Prag. Clin. Biol. Res. 158, 331-354 7 Daly, J. W. (1982) ]. Med. Chem. 25, 197-207 8 Skoglund, M. L., Vinik, A. I. and Feller, M. R. (1982) Physiologist 25, 219 9 Gerber, ]. G., Payne, N. A. and Nies, A. S. (1982) CIin. Re~. 30, 282
10 Gerber, J. G., Nies, A.S. and Payne, N. A. (1985)J. Pharmacol. Exp. Ther. 233, 623-627 11 Heldsinger, A. A., Vinik, A. I. and Fox, I. H. (1986) J. Pharmacol. Exp. Ther. 237, 351-356 1,~ r',--,J ..... J. ~. . . . . L. F., Rodrigo, C. E., Goifiena, j. j., Gomez, R. and Martinez, I. (1985) Rev Esp. Fisiol. 41, 83-87 13 Puurunen, J., Ruoff, H-J. and Schwabe, U. (1987) Pharmacol. Toxico160, 315--317 14 Gerber, J. G. and Payne, N. A. (1988) J. Pharmacol. Exp. Ther. 244, 190-194 15 Gerber, J. G., Fadul, S., Payne, N. A. and Nies, A. S. (1984)J. Pharmacol. Exp. Ther. 231, 109-113 16 Puurunen, J., Aittakumpu, R. and Tanskanen, T. (1986) Acta Pharmacol. Toxicol. 58, 265-271 17 Glavin, G. B., Westerberg, V.S. and Geiger, J.D. (1987) Can. J. Physiol. Pharmacol. 65, 1182-1185 18 Ribeiro, J. A. and Sebast:ao, A. M. (1986) Prog. Neurobiol. 26, 179-209 19 Fredholm, B. B., Jonzon, B., Lindgren, E. and Lindstrom, K. (1982) J. Neurochem. 39, 165-175 20 Scarpignato, C., Tramacere, R., Zappia,
L. and Del Soldato, P. (1987) Pharmacology 34, 264--268 21 Goldman, H. and Rosoff, C. B. (I968) Am. J. Pathol. 52, 227-244 22 Johannesson, N., Andersson, K-E., Joelsson, B. and Persson, C. G. A. (1985) Am. Rev. Respir. Dis. 131, 26-31 23 Henry, J. and Stephens, P. (1980) Pharmacol. Biochem. Behav. 13, 719-727 24 Roth, J. A. and Ivy, A. C. (1944) Gastroenterol. 2, 274-285 25 Ernster, V. L. (1984) Prog. Clin. Biol. Res. 158, 377-400 26 Guss, C., Schneider, A. T. and Chiaramonte, L.T. (1986) Ann. Allergy 56, 237-240 27 Feller, M. R. and Moorhead, D. P. (1982) Physiologist 25, 250 28 Ushijima, I., Mizuki, Y. and Yamada, M. (1985) Brain Res. 339, 351-355 29 Paret, R. S., Kumashiro, R., Kodama, Y. and Matsumoto, T. (1982) Am. Surg. 48, 594-598 30 Soil, A. H., Rodrigo, R. and Ferrari, J. C. (1981) Fed. Proc. 40, 2519-2523 31 DeSchryver-Keckemeti, K., Greider, M. H., Rieders, E. R., Komyati, S. E. and McGuigan, J. E. (1981) Lab. Invest. 44, 158-163
Neuromelanin-containing neurons are selectively vulnerable in parkinsonism W h i l e it has b e e n k n o w n for over 60 years that nerve cells in the s u b s t a n t i a nigra die in P a r k i n s o n ' s disease, the reason for their deg e n e r a t i o n r e m a i n s a mystery. N e u r o m e l a n i n , a p i g m e n t e d substance w h i c h is f o u n d in m a n y n e u r o n s in the s u b s t a n t i a nigra a n d is r e s p o n s i b l e for its d a r k e r color (and h e n c e its name), has long b e e n on the list of suspects. It accumulates in n e u r o n s t h r o u g h out m o s t of life, p r o b a b l y as the result of the c o n t i n u o u s catabolism of catecholamines. M a n n a n d Yates 1 s h o w e d that the more h e a v i l y p i g m e n t e d n e u r o n s app e a r e d to be preferentially lost (1) d u r i n g the gradual attrition of n e u r o n s w h i c h occurs w i t h n o r m a l aging, a n d (2) in Parkinso•'s disease. N e u r o m e l a n i n was further t h r o w n into the spotlight w i t h the recent d e m o n s t r a t i o n that MPP +, the p u t a t i v e toxic m e t a b o l i t e of MPTP, a selective nigral toxin w h i c h causes p a r k i n s o n i s m , b i n d s to n e u r o m e l a n i n 2. In a recent issue of N a t u r e , Hirsch a n d colleagues 3 p r o v i d e n e w i n f o r m a t i o n on n e u r o m e i a n i n w h i c h m a y be of great interest for those p u r s u i n g the cause of P a r k i n s o n ' s disease. In a cal'efui
study c o m p a r i n g the substantia nigra in control a n d p a r k i n s o n i a n brains, they f o u n d that the population of n e u r o n s c o n t a i n i n g neurom e l a n i n a p p e a r e d to be particularly v u l n e r a b l e to the neurodegenerative process of Parkinson's disease. In fact, there appeared to be an almost direct relationship b e t w e e n the. d i s t r i b u t i o n of pigm e n t e d n e u r o n s normally pre ~.ent, a n d the d i s t r i b u t i o n of cell lo:,s in the substantia nigra of i n d i v i d u a l s d y i n g w i t h the disease. This same relationship was found, t h o u g h to a lesser degree, in a n o t h e r form of p a r k i n s o n i s m k n o w n as progressive s u p r a n u c l e a r palsy. W h a t is all of this telling us? Does n e u r o m e t a n i n damage neurons or p r o m o t e tp,eir selective v u l n e r a b i l i t y to some causative agent? Will n e u r o m e l a n i n provide the thread of c o m m o n a l i t y between the factors at work in P a r k i n s o n ' s disease a n d those that are responsible for MPTP neurotoxicity? Will MPTP be a useful tool to further investigate the predilection of certain neuronal groups a n d not others in the idiopathic disease? MPTP has already p r o v i d e d a w i d e l y used animal model for the disease 4 and may
(~ 1988.E l s e v i e r Publtcatton-~.Cambridge 0165- 6147187/$02.00
TIPS - October 1988 [Vol. 9]
role for the ischaemia-induced fall of intracellular pH in the deterioration of contractile performance during ischaemia. Solaro (Chicago) showed that in skinned preparations there is a substantial reduction in the Ca 2+ sensitivity of the actomyosin ATPase at a lower pH such as that found in ischaemic hearts, and suggested that the change in pH affected the thin filaments. Interestingly this was not evident in neonatal hearts. The Ca 2+ binding protein troponin C appears to be the same, and present in similar amounts, in both adult and neonatal hearts. However, the inhibitory component of troponin, troponin I, is different in the two age groups. It was therefore suggested that the decrease in Ca 2+ binding to troponin C during acidosis may be secondary to an effect of acidosis on troponin I. Allen (London) presented an interesting experimental model of ischaemia involving a N2-gas perfusion system. An increase in cytosolic Ca 2+ was clearly seen under such conditions, and it was stressed that all of the observations could be mimicked by perfusion with lactic acid, and, for instance, that no increase in Ca 2+ was observed in glycogendepleted hearts. Others (e.g. Vaughan-Jones, Oxford) presented data to suggest the involvement of both the sarcolemmal Na+-H + and Na+-Ca 2+ exchanges (Fig. 1) in bringing about the rise in intracellular Ca 2+, though again it was evident that more progress could be achieved in this important area if better and more specific drugs could be developed to interact with these proteins. []
[]
[]
Current awareness Adenosine and gastric function Adenosine is an important endogenous regulator of many physiological processes including blood flow, seizure activity, airway resistance and neuronal activity. Its actions are apparently mediated by functional adenosine receptors 1. Rank orders of agonist potencies have been used to characterize adenosine receptor subtypes 2. R-N6-phenylisopropyl adenosine (R-PIA) and Nt'-cyclo hexyladenosine are potent ligands for adenosine A1 receptors which are generally associated with a decrease in adenylate cyclase activity, whereas 5'-N-ethylcarboxyamidoadenosine (NECA) is more potent at A2 receptors, stimulation of which is generally associaLed with an increase in adenylate cyclase activity. There is now increasing direct and indirect evidence that adenosine and its receptors are involved in the control of gastric acidity and modulation of gastric responses to the secretagogues histamine and acetylcholine (Fig. 1). Moreover, adenosine analogs have been shown unde:" certain circumstances to exert an ameliorating effect on experimentally induced gastric pathology 3-5. The notion that adenosine serves as a gastric protective agent is further suggested by findings that the methylxanthines caffeine and theophylline, which ar~: known to be competitive antagonists at adenosine receptors at appropriate concentrations, stimulate gastric acid
Abstracts from this meeting have been published in J. Mol. Cell. Cardi.ol. (1988) 20, Suppl. IV. JAMES G. McCORMACK, MARK R. BOYETT*, BRIAN R. JEWELL* AND CLIVE H. ORCHARD*
Departments of Biochemistry and *Physiology, The University of Leeds, Leeds Lq2 9JT, UK.
References 1 Carafoli, E. (1987) Annu. Rev. Biochem. 56, 395--433 2 Katz, K. A., Koretsky, A= P. and Balaban, R. S. (1987) FEBS Left. 221, 270-276 3 Vaghy, P. L., Johnson, J. D., Matlib, M. A., Wang, T. and Schwartz, A. (1982) J. Biol. Chem. 257, 6000-6002 4 Zernig, G. and GIossmann, H. (1988) Biochem. 1. 253, 49-58
secretion and predispose mammals to gastric pathology 6'7.
Gastric acid secretion Evidence from in-vitro experiments strongly suggests that exogenous and endogenous adenosine regulates basal ~z',.d histaminestimulated acid secretion. In 1982, two brief reports noted that adenosine s and the adenosine deaminaseresistant analog 2-chloroadenosine 9 decreased histaminestimulated aminopyrine accumulation by isolated canine parietal cells - an indirect measure of acid production. Extending these findings, Gerber and colleagues 1° showed that 2-chloroadenosine and another adenosine analog, R-PIA, inhibited histaminestimulated acid secretion from isolated parietal cells. Using a cytochemical stain for hydroxyl ion productiot~. Heldsinger and co-workers 11 found that R-PIA inhibited histamine-stimulated acid production in guinea-pig cells and that it was more potent than NECA. Adenosine also decreased basal gastric acid secretion in an isolated rat stomach preparation j2. Adenosine did not affect carbacholor dibutyryl-cAMP-stimulated acid secretion 1°'11. Thus adenosine appears not to affect cAMP levels directly, but rather through specific receptors coupled to adenylate cyclase tl. These receptors may be negatively coupled to adenylate cyclase, since low concentrations of R-PIA
histamine acetylcholine ADENOSINE= AGONISTS
(-)
~[<
1+)
ADENOSINE ANTAGONISTS
(-) ~._gastric acidity .,~ (+) ( - ) ~ gastric ulceration ~ (+) Fig. I. The opposing modulatory influences of adenosine a~7onistsand antagonists on basal and secretagogue-induced levels of gastric acid output, and gastric ulceration. (~)1988,ElsevierPubltcat:ons,Cambridge 0165- 6147/88/502.00
346 inhibited histamine-stinmlated cAMP accumulation in isolated parietal cells ~°. On the basis of the above results and the findings that the potent adenosine receptor antagonists (which are both weak inhibitors of cAMP phosphodiesterase activity) 1,3-diethylphenylxanthine 11 and 8-phenyltheophylline m blocked the responses to adenosine compounds, it was suggested that adenosine receptors, possibly of the A1 subtype, were being stimulated, in contrast, however, Puurunen and co-workers 13 reported that R-PIA and NECA at concentrations of up to 10 ~M affected neither basal, nor carbachol- or histamine-stimulated acid secretion by isolated parietal cells from rat. As suggested by these authors, species differences may account for the disparate findings. Recently, the involvement of endogenous adenosine in the regulation of gastric acid secretion was indicated by findings that 8phenyltheophyUine increased and dipyridamole (an inhibitor of adenosine inf,ux into and effiux from cells) decreased histaminebut not carbachol- or dibutyrylcAMP-induced acid secretion 14. The decrease by dipyridamole was attributed to blockade of the extrusion of endogenous adenosine from gastric cells. Evidence from studies in vivo has also demonstrated that adenosine regulates gastric acid secretion. Gerber et al. ~5 showed that adenosine administered into the splenogastric artery inhibited both histamine- and methacholinestimulated gastric acid secretion in anesthetized dogs. This response was blocked by theophy!line. In conscious rats, but not in anesthetized rats, R-PIA given i.c.v, inhibited gastric acid output. However, adenosine analogs given i.v. to anesthetized rats increased gastric acid secretion 16 These effects were blocked by prior administration of the adenosine recepto:- antagonists theophylline ar,.d 8-phenyltheophyt!ine. Pretreatment with atropine or vagotomization of the animal also prevented these effects, suggesting that an intact and nor,no;reactive vagal system is necessary for the expression of the effects cf adenosine on stimulated gastric secretion. We recently found that adeno-
TIPS - October 1988 [Vol. 9]
sine compounds elevated the intraluminal pH and decreased basal gastric acid secretions in conscious rats (Ref. 17 and unpublished). Furthermore, 8-phenyltheophylline at low concentrations blocked the acid reducing effects of R-PIA and at higher concentrations actually stimulated acid secretion 17. The finding ~lat R-PIA was far more potent tha ° s-PIA in inhibiting basal gastri; acid secretion suggested that A~ receptors were involved. However, because A1, A3 (Ref. 18), and possibly A2 sites 19 may all exhibit some degree of stereoselectivity for .~-PIA, we have conducted further studies to characterize the adenosine receptors responsible for the observed decreases in the volume and acid content, and increases in the pH of basal gastric secretions; preliminary results suggest that sites other than A1 sites may be involved in the regulation of the volume and acid content of basal gastric secretions (unpublished). Using a different type of animal preparation, Scarpignato and colleagues 2° found that adenosine when given s.c., but not intraduodenally, significantly decreased the volume but not the acid concentration of gastric secretions from the pylorus-ligated rat. In addition, R-PIA, following its administration by either route, decreased the volume of gastric acid secretions at concentrations four times lower than that necessary to reduce acid concentration. These effects were blocked by a d~,se of theophylline that did not affect gastric secretion alone. The results of the in-vitro ar.~,dinvivo studies summarized ~/bove clearly indicate that adenosinq~ and adenosine receptors are inw:ived in regulating various param.~ters re!ated to gastric acid secre:lion. However, further work is necessary: (1) to understand why under different circumstances adencl~sine compounds can either ir~crease or decrease gastric acid secretion; (2) to distinguish between the adenosine receptol" subtypes mediating these effects; (3) to determine the locations of these receptors; and (4) to determine the possible physiological significance of these findings.
Gastric pathology Gastric hyperacidity is generally regarded as one of the primary
causative factors in the development of gastric ulceration 21. Therefore it is significant that methylxanthines, possibly acting by blocking the actions of adenosine tha~ are being mediated through its receptors, stimulate the volume and acid content of gastric secretions 22 and promote gastric ulceration in animals 23'24 and possibly humans 25'26. Experimentally, adenosine and related compounds have been found to decrease gastric ulceration induced by exposing an animal to a cold, stressful environment 5-7 and to high concentrations of aspirin placed directly into the stomach 27. The greater potency of R-PIA versus s-PIA (Ref. 5), the protection afforded by R-PIA when given peripherally or i.c.v. 5-'7, and the blockaae of the effects of R-P!A by 8-phenyltheophylline given peripherally or 8-sulphophenyltheophylline given centrally suggest that adenosine receptors resembling A1 sites located peripherally and/or centrally were mediating these effects. Others have found adenosine analogs to exacerbate gastric ulceration in response to prolonged exposure to a stressful environment28; however they used a model with no basal level of ulceration, which might have been insufficiently sensitive (see Ref. 6). Dipyridamole, possibly by increasing extracellular adenosine levels, significantly reduced the extent of gastric bleeding and ulcer formation in rats restrained in a cold environment 29. Thus most studies suggest that adenosine and/or adenosine compounds may s e r e as protective agents against the paihological responses to stress.
Possible underlying mechanisms The possible mechanisms by which adenosine compounds exert these protective effects may include: • Increased production of prostaglandins which are known inhibitors of gastric acid secretion. Evidence both for 11 and against s'!° this proposal has been presented. • Adenosine-induced increases in blood flow. The ability of adenosine to decrease gastric acid secretion was dissociable from and opposite to effect~ that might be anticipated if they were secondary to vasodilatation ~6.
347
TIPS - O c t o b e r 1988 [Vol. 9]
• Decreased p r o d u c t i o n of gastrin, a k n o w n s t i m u l a n t of gastric acid secretions. A d e n o s i n e has b e e n s h o w n to s t i m u l a t e the basal secretion of gastrin from parietal cells 3° a n d i n h i b i t adrenergica n d c h o l i n e r g i c - s t i m u l a t e d gastrin secretion 3:. • Decreased release of h i s t a m i n e a n d acetylcholine, t w o k n o w n gastric acid secretagogues. A d e n o s i n e c o m p o u n d s decrease the release of these a n d o t h e r p h y s i o l o g i c a l l y active substances. • The effects of a d e n o s i n e comp o u n d s m a y be exerted b y different receptor s u b t y p e s a n d at different location~. T h u s m u c h m o r e i n l o r m a t i o n is n e e d e d to d e t e r m i n e the m e c h a n isms a n d p h y s i o l o g i c a l significance of some of the o b s e r v e d gastric r e s p o n s e s to a d e n o s i n e . Acknowledgements We w i s h to t h a n k Dr G. Glavin, K. K i e r n a n a n d G. M a y for their assistance w i t h some of the experim e n t s d e s c r i b e d here. S u p p o r t e d b y grants from the M a n i t o b a H e a l t h Research C o u n c i l a n d the Medical Research Council of Canada. VSW w~s s u p p o r t e d by a Postdoctoral F e l l o w s h i p from the St Boniface General Hospital Research F o u n d a t i o n Inc. JDG is a Scholar of the Medical Research C o u n c i l of Canada. V. S. WESTERBERG AND J. D. GEIGER*
Department of Psychology, University of New Mexico Main Campus, Albuquerque, NM 87131, USA, and *Department of Pharmacology and Therapeutics, University of Manitoba Faculty of Medicine, 770 Bannatyne Avenue, Winnipeg, Manitoba R3E OW3, Canada.
References 1 Geiger, J. D. and Nagy, J. I. in Adenosine Receptors (Williams, M., ed.), Humana Press (in press) 2 Williams, M. (1987) Annu. Rev. Pharmacol. Toxicol. 27, 315-345 3 Geiger, J. D. and Glavin, G. B. (1985)Eur. J. Pharmacol. 115, 185-190 4 Wes~.erberg,V. S. and Geiger~|. D. (1987) Life Sci. 41, 2201-2205 5 Westerberg, V. S., Glavin, G. I3. and Geiger, J. D. (1986) Proc. West. Pharmacol. Soc. 29, 425--427 6 Fredholm, B. B. (1984) Prag. Clin. Biol. Res. 158, 331-354 7 Daly, J. W. (1982) ]. Med. Chem. 25, 197-207 8 Skoglund, M. L., Vinik, A. I. and Feller, M. R. (1982) Physiologist 25, 219 9 Gerber, ]. G., Payne, N. A. and Nies, A. S. (1982) CIin. Re~. 30, 282
10 Gerber, J. G., Nies, A.S. and Payne, N. A. (1985)J. Pharmacol. Exp. Ther. 233, 623-627 11 Heldsinger, A. A., Vinik, A. I. and Fox, I. H. (1986) J. Pharmacol. Exp. Ther. 237, 351-356 1,~ r',--,J ..... J. ~. . . . . L. F., Rodrigo, C. E., Goifiena, j. j., Gomez, R. and Martinez, I. (1985) Rev Esp. Fisiol. 41, 83-87 13 Puurunen, J., Ruoff, H-J. and Schwabe, U. (1987) Pharmacol. Toxico160, 315--317 14 Gerber, J. G. and Payne, N. A. (1988) J. Pharmacol. Exp. Ther. 244, 190-194 15 Gerber, J. G., Fadul, S., Payne, N. A. and Nies, A. S. (1984)J. Pharmacol. Exp. Ther. 231, 109-113 16 Puurunen, J., Aittakumpu, R. and Tanskanen, T. (1986) Acta Pharmacol. Toxicol. 58, 265-271 17 Glavin, G. B., Westerberg, V.S. and Geiger, J.D. (1987) Can. J. Physiol. Pharmacol. 65, 1182-1185 18 Ribeiro, J. A. and Sebast:ao, A. M. (1986) Prog. Neurobiol. 26, 179-209 19 Fredholm, B. B., Jonzon, B., Lindgren, E. and Lindstrom, K. (1982) J. Neurochem. 39, 165-175 20 Scarpignato, C., Tramacere, R., Zappia,
L. and Del Soldato, P. (1987) Pharmacology 34, 264--268 21 Goldman, H. and Rosoff, C. B. (I968) Am. J. Pathol. 52, 227-244 22 Johannesson, N., Andersson, K-E., Joelsson, B. and Persson, C. G. A. (1985) Am. Rev. Respir. Dis. 131, 26-31 23 Henry, J. and Stephens, P. (1980) Pharmacol. Biochem. Behav. 13, 719-727 24 Roth, J. A. and Ivy, A. C. (1944) Gastroenterol. 2, 274-285 25 Ernster, V. L. (1984) Prog. Clin. Biol. Res. 158, 377-400 26 Guss, C., Schneider, A. T. and Chiaramonte, L.T. (1986) Ann. Allergy 56, 237-240 27 Feller, M. R. and Moorhead, D. P. (1982) Physiologist 25, 250 28 Ushijima, I., Mizuki, Y. and Yamada, M. (1985) Brain Res. 339, 351-355 29 Paret, R. S., Kumashiro, R., Kodama, Y. and Matsumoto, T. (1982) Am. Surg. 48, 594-598 30 Soil, A. H., Rodrigo, R. and Ferrari, J. C. (1981) Fed. Proc. 40, 2519-2523 31 DeSchryver-Keckemeti, K., Greider, M. H., Rieders, E. R., Komyati, S. E. and McGuigan, J. E. (1981) Lab. Invest. 44, 158-163
Neuromelanin-containing neurons are selectively vulnerable in parkinsonism W h i l e it has b e e n k n o w n for over 60 years that nerve cells in the s u b s t a n t i a nigra die in P a r k i n s o n ' s disease, the reason for their deg e n e r a t i o n r e m a i n s a mystery. N e u r o m e l a n i n , a p i g m e n t e d substance w h i c h is f o u n d in m a n y n e u r o n s in the s u b s t a n t i a nigra a n d is r e s p o n s i b l e for its d a r k e r color (and h e n c e its name), has long b e e n on the list of suspects. It accumulates in n e u r o n s t h r o u g h out m o s t of life, p r o b a b l y as the result of the c o n t i n u o u s catabolism of catecholamines. M a n n a n d Yates 1 s h o w e d that the more h e a v i l y p i g m e n t e d n e u r o n s app e a r e d to be preferentially lost (1) d u r i n g the gradual attrition of n e u r o n s w h i c h occurs w i t h n o r m a l aging, a n d (2) in Parkinso•'s disease. N e u r o m e l a n i n was further t h r o w n into the spotlight w i t h the recent d e m o n s t r a t i o n that MPP +, the p u t a t i v e toxic m e t a b o l i t e of MPTP, a selective nigral toxin w h i c h causes p a r k i n s o n i s m , b i n d s to n e u r o m e l a n i n 2. In a recent issue of N a t u r e , Hirsch a n d colleagues 3 p r o v i d e n e w i n f o r m a t i o n on n e u r o m e i a n i n w h i c h m a y be of great interest for those p u r s u i n g the cause of P a r k i n s o n ' s disease. In a cal'efui
study c o m p a r i n g the substantia nigra in control a n d p a r k i n s o n i a n brains, they f o u n d that the population of n e u r o n s c o n t a i n i n g neurom e l a n i n a p p e a r e d to be particularly v u l n e r a b l e to the neurodegenerative process of Parkinson's disease. In fact, there appeared to be an almost direct relationship b e t w e e n the. d i s t r i b u t i o n of pigm e n t e d n e u r o n s normally pre ~.ent, a n d the d i s t r i b u t i o n of cell lo:,s in the substantia nigra of i n d i v i d u a l s d y i n g w i t h the disease. This same relationship was found, t h o u g h to a lesser degree, in a n o t h e r form of p a r k i n s o n i s m k n o w n as progressive s u p r a n u c l e a r palsy. W h a t is all of this telling us? Does n e u r o m e t a n i n damage neurons or p r o m o t e tp,eir selective v u l n e r a b i l i t y to some causative agent? Will n e u r o m e l a n i n provide the thread of c o m m o n a l i t y between the factors at work in P a r k i n s o n ' s disease a n d those that are responsible for MPTP neurotoxicity? Will MPTP be a useful tool to further investigate the predilection of certain neuronal groups a n d not others in the idiopathic disease? MPTP has already p r o v i d e d a w i d e l y used animal model for the disease 4 and may
(~ 1988.E l s e v i e r Publtcatton-~.Cambridge 0165- 6147187/$02.00