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Hexamethonium and secretory diarrhea
332
CORRESPONDENCE
FERNANDO AZPIROZ FRANCISCO GUARNER
Digestive System Research Unit Hospital General Vall d'Hebron 08035 Barcelona, Spain BENOYT COFFIN
lnstitut National de la RechercheMedicine, Unitd 290 H@ital Saint-Lazare Paris, France JUAN-R. MALAGELADA
Digestive System Research Unit Hospital General Vall d'Hebron 08035 Barcelona, Spain 1. Coffin B, Azpiroz F, Guarner F, Malagelada J-R. Selective gastric hypersensitivity and reflex hyporeactivity in functional dyspepsia. Gastroenterology 1994; 1 0 7 : 1 3 4 5 - 1 3 5 1 . 2. Peterson C, Youmane WB. The intestino-intestinal inhibitory reflex: threshold variations, sensitization and summation. Am J Physiol 1945; 1 4 3 : 4 0 7 - 4 1 2 . 3. Serra J, Azpiroz F, Malagelada J-R. Temporo-spatial modulation of perception and reflex responses to intestinal stimuli in humans (abstr). Gastroenterology 1994;106:A565. 4. Holtmann G, HOber J, Fischer H, Fleiter B, Goebell H, Talley NJ. Functional dyspepsia: a sensory duodenal defect with impaired intestino-intestinal reflexes (abstr). Gastroenterology 1994;106: A511. 5. Whitehead WE, Delvaux M, and Members of the Working Team. Standardization of barostat test procedures: report of an international working team. Gastroenterology (in press).
Hexamethonium and Secretory Diarrhea Dear Sir: In the early 1980s, Cassuto et al. 1'2 proposed an enteric, neurogenic link in the secretory action of cholera toxin. This hypothesis was based mainly on results from experiments on anaesthetized rats and cats, in which the cholera t o x i n - i n d u c e d intestinal secretion could be antagonized by some nerve-blocking drugs. Among such, the ganglionic, nicotinic receptor blocker, hexamethonium, became in subsequent studies a tool for the demonstration of a neuronal involvement in the intestinal response to various other secretagogues, including Escherichia coli heat-stable enterotoxin and Salmonella typhimurium. 3 Another enterotoxin, Chlostridium difficile toxin A, has a mechanism of action which seemingly is completely different to that of cholera toxin. Thus, Beubler et al. 4 reported that the secretion elicited by toxin A was unchanged by hexamethonium and could, therefore, be nonneural in origin. Two of the coauthors of that paper 4 appear also as coauthors of a recently published article on the similar subject in GASTROENTEROLOGY.5 In the latter paper, the opposite conclusion was reached as to the involvement of enteric nerves in toxin A - i n d u c e d secretion. This, indeed, was found to be antagonized by hexamethonium. Although the authors refer to the report by Beubler et al., 4 it is only with regard to a possible role for 5-hydroxytryptamine in the secretory response to different enterotoxins. Therefore, it should be very helpful to obtain a comment from the authors of the Gastroenterology article 5 on the discrepancy between their data and those of Beubler et al. 4 on the effect of hexamethonium on toxin A - i n d u c e d intestinal secretion.
GASTROENTEROLOGY Vol. 109, No. 1
DICK S. DELBRO, M.D., PH.D.
Department of Surgery University of G#teborg Sahlgren Hospital S-413 45 G#teborg, Sweden 1. Cassuto J, Jodal M, Tuttle R, Lundgren O. On the role of intramural nerves in the pathogenesis of cholera toxin-induced intestinal secretion. Scand J Gastroenterol 1 9 8 1 ; 1 6 : 3 7 7 - 3 8 4 . 2. Cassuto J, Jodal M, Lundgren O. The effect of nicotinic and muscarinic receptor blockade on cholera toxin induced intestinal secretion in rats and cats. Acta Physiol Scand 1 9 8 2 ; 1 1 4 : 5 7 3 - 5 7 7 . 3. Lundgren O, Svanvik J, Jiveg~rd J. Enteric nervous system. I. Physiology and pathophysiology of the intestinal tract. Dig Dis Sci 1989; 3 4 : 2 6 4 - 2 8 3 . 4. Beubler E, Schirgi-Degen A, Pabst MA, Pothoulakis C, LaMont JT. Effects of purified Clostridium difficfle toxin A in the small intestine of the rat in vivo. Natural Toxins 1993; 1 : 3 6 9 - 3 7 5 . 5. Castagliuolo I, LaMont JT, Letourneau R, Kelly C, O'Keane JC, Jaffer A, Theoharides TC, Pothouiakis C. Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum. Gastroenterology 1994;107: 657-665. Reply. Dr. Delbro's letter points out a minor discrepancy between two articles from our laboratory regarding the effect of hexamethonium on the intestinal actions of C. difficile toxin A. In our article in GASTROENTEROLOGY1 we reported that hexamethonium produced a significant decrease in fluid secretion, mannitol permeability, and myeloperoxidase activity when given 15 minutes before administration of toxin A to rat ileal loops. In our previous paper, 2 Beubler et al. reported no effect of hexamethonium in similar experiments using rat jejunum. However, it should be noted that a significant difference in experimental technique between these two studies may explain the discrepancy. In the GASTROENTEROLOGY paper, 1 hexamethonium was administered by intravenous bolus injection 15 minutes before exposure to toxin, whereas in the earlier study, 2 the ganglionic blocker was administered subcutaneously. It is conceivable that this difference in administration resulted in the different effects. The conclusions from both papers are essentially the same. As noted previously in their classic studies, Cassuto et al. 3'4 observed that the action of cholera toxin is inhibited by nicotinic and muscarinic receptor blockade as well by lidocaine. Our recent work, including a study involving specific exploration of the role of substance p,5 indicates that the signal transduction mechanism of C. difficile toxin A in rat ileum involves the mediation of substance P in primary sensory afferent nerves. Thus, our work provides an interesting counterpoint to the classic studies from Cassuto et al. <4 performed over a decade earlier using a similar model. Clearly, the effects of bacterial exotoxins are not generic but are mediated by a toxin-specific set of complex neuronal and cellular interactions. CHARALABOS POTHOULAKIS, M.D. J. THOMAS LAMONT, M.D.
Gastroenterology Section University Hospital 88 East Newton Street Boston, Massachusetts 02118 1. Castagliuolo I, LaMent JT, Letourneau R, Kelly CP, O'Keane JC, Jaffer A, Theoharides TC, Pothoulakis C. Neuronal involvement in the intestinal effects of Clostridium difficfle toxin A and Vibrio cholerae enterotoxin in rat ileum. Gastroenterology 1994;107: 657-665. 2. Beubler E, Schirgi-Degen A, Pabst MA, Pothoulakis C, LaMont JT.
CORRESPONDENCE
FERNANDO AZPIROZ FRANCISCO GUARNER
Digestive System Research Unit Hospital General Vall d'Hebron 08035 Barcelona, Spain BENOYT COFFIN
lnstitut National de la RechercheMedicine, Unitd 290 H@ital Saint-Lazare Paris, France JUAN-R. MALAGELADA
Digestive System Research Unit Hospital General Vall d'Hebron 08035 Barcelona, Spain 1. Coffin B, Azpiroz F, Guarner F, Malagelada J-R. Selective gastric hypersensitivity and reflex hyporeactivity in functional dyspepsia. Gastroenterology 1994; 1 0 7 : 1 3 4 5 - 1 3 5 1 . 2. Peterson C, Youmane WB. The intestino-intestinal inhibitory reflex: threshold variations, sensitization and summation. Am J Physiol 1945; 1 4 3 : 4 0 7 - 4 1 2 . 3. Serra J, Azpiroz F, Malagelada J-R. Temporo-spatial modulation of perception and reflex responses to intestinal stimuli in humans (abstr). Gastroenterology 1994;106:A565. 4. Holtmann G, HOber J, Fischer H, Fleiter B, Goebell H, Talley NJ. Functional dyspepsia: a sensory duodenal defect with impaired intestino-intestinal reflexes (abstr). Gastroenterology 1994;106: A511. 5. Whitehead WE, Delvaux M, and Members of the Working Team. Standardization of barostat test procedures: report of an international working team. Gastroenterology (in press).
Hexamethonium and Secretory Diarrhea Dear Sir: In the early 1980s, Cassuto et al. 1'2 proposed an enteric, neurogenic link in the secretory action of cholera toxin. This hypothesis was based mainly on results from experiments on anaesthetized rats and cats, in which the cholera t o x i n - i n d u c e d intestinal secretion could be antagonized by some nerve-blocking drugs. Among such, the ganglionic, nicotinic receptor blocker, hexamethonium, became in subsequent studies a tool for the demonstration of a neuronal involvement in the intestinal response to various other secretagogues, including Escherichia coli heat-stable enterotoxin and Salmonella typhimurium. 3 Another enterotoxin, Chlostridium difficile toxin A, has a mechanism of action which seemingly is completely different to that of cholera toxin. Thus, Beubler et al. 4 reported that the secretion elicited by toxin A was unchanged by hexamethonium and could, therefore, be nonneural in origin. Two of the coauthors of that paper 4 appear also as coauthors of a recently published article on the similar subject in GASTROENTEROLOGY.5 In the latter paper, the opposite conclusion was reached as to the involvement of enteric nerves in toxin A - i n d u c e d secretion. This, indeed, was found to be antagonized by hexamethonium. Although the authors refer to the report by Beubler et al., 4 it is only with regard to a possible role for 5-hydroxytryptamine in the secretory response to different enterotoxins. Therefore, it should be very helpful to obtain a comment from the authors of the Gastroenterology article 5 on the discrepancy between their data and those of Beubler et al. 4 on the effect of hexamethonium on toxin A - i n d u c e d intestinal secretion.
GASTROENTEROLOGY Vol. 109, No. 1
DICK S. DELBRO, M.D., PH.D.
Department of Surgery University of G#teborg Sahlgren Hospital S-413 45 G#teborg, Sweden 1. Cassuto J, Jodal M, Tuttle R, Lundgren O. On the role of intramural nerves in the pathogenesis of cholera toxin-induced intestinal secretion. Scand J Gastroenterol 1 9 8 1 ; 1 6 : 3 7 7 - 3 8 4 . 2. Cassuto J, Jodal M, Lundgren O. The effect of nicotinic and muscarinic receptor blockade on cholera toxin induced intestinal secretion in rats and cats. Acta Physiol Scand 1 9 8 2 ; 1 1 4 : 5 7 3 - 5 7 7 . 3. Lundgren O, Svanvik J, Jiveg~rd J. Enteric nervous system. I. Physiology and pathophysiology of the intestinal tract. Dig Dis Sci 1989; 3 4 : 2 6 4 - 2 8 3 . 4. Beubler E, Schirgi-Degen A, Pabst MA, Pothoulakis C, LaMont JT. Effects of purified Clostridium difficfle toxin A in the small intestine of the rat in vivo. Natural Toxins 1993; 1 : 3 6 9 - 3 7 5 . 5. Castagliuolo I, LaMont JT, Letourneau R, Kelly C, O'Keane JC, Jaffer A, Theoharides TC, Pothouiakis C. Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum. Gastroenterology 1994;107: 657-665. Reply. Dr. Delbro's letter points out a minor discrepancy between two articles from our laboratory regarding the effect of hexamethonium on the intestinal actions of C. difficile toxin A. In our article in GASTROENTEROLOGY1 we reported that hexamethonium produced a significant decrease in fluid secretion, mannitol permeability, and myeloperoxidase activity when given 15 minutes before administration of toxin A to rat ileal loops. In our previous paper, 2 Beubler et al. reported no effect of hexamethonium in similar experiments using rat jejunum. However, it should be noted that a significant difference in experimental technique between these two studies may explain the discrepancy. In the GASTROENTEROLOGY paper, 1 hexamethonium was administered by intravenous bolus injection 15 minutes before exposure to toxin, whereas in the earlier study, 2 the ganglionic blocker was administered subcutaneously. It is conceivable that this difference in administration resulted in the different effects. The conclusions from both papers are essentially the same. As noted previously in their classic studies, Cassuto et al. 3'4 observed that the action of cholera toxin is inhibited by nicotinic and muscarinic receptor blockade as well by lidocaine. Our recent work, including a study involving specific exploration of the role of substance p,5 indicates that the signal transduction mechanism of C. difficile toxin A in rat ileum involves the mediation of substance P in primary sensory afferent nerves. Thus, our work provides an interesting counterpoint to the classic studies from Cassuto et al. <4 performed over a decade earlier using a similar model. Clearly, the effects of bacterial exotoxins are not generic but are mediated by a toxin-specific set of complex neuronal and cellular interactions. CHARALABOS POTHOULAKIS, M.D. J. THOMAS LAMONT, M.D.
Gastroenterology Section University Hospital 88 East Newton Street Boston, Massachusetts 02118 1. Castagliuolo I, LaMent JT, Letourneau R, Kelly CP, O'Keane JC, Jaffer A, Theoharides TC, Pothoulakis C. Neuronal involvement in the intestinal effects of Clostridium difficfle toxin A and Vibrio cholerae enterotoxin in rat ileum. Gastroenterology 1994;107: 657-665. 2. Beubler E, Schirgi-Degen A, Pabst MA, Pothoulakis C, LaMont JT.