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Gastrointestinal reflexes
GASTROENTEROLOGY
1988;95:524-33
EDITORIALS
Gastrointestinal Reflexes Sherrington, in 1906, originally developed the classification of exteroceptors and interoceptors, referring to sensory receptors located either in the skin or internally in somatic and visceral regions (1). Activation of interoceptors including those in the abdominal visceral region has long been known to elicit reflex cardiovascular changes. Sherrington also was the first to suggest that mechanical stimulation of abdominal organs could elicit cardiovascular changes in association with pain (2). Subsequent studies showed that certain chemicals also are capable of stimulating chemosensitive visceral receptors to produce reflex responses. In this issue, Rozsa and coworkers (3) demonstrate that changes in local temperature likewise may mediate reflex cardiovascular responses. The cardiovascular reflexes elicited by mechanoreceptor and chemoreceptor stimulation in abdominal visceral organs are largely excitatory, i.e., they cause increases in heart rate, myocardial contractility, and peripheral vasoconstriction leading to an increase in arterial blood pressure (4-7). Interestingly, Rozsa and colleagues report that application of fluids at 45°C to the mucosal or serosal surface of the rat’s stomach, jejunum, or ileum provokes tachycardia and peripheral vasodilation leading to arterial hypotension and a reduction in intestinal blood flow as well as a locally mediated vasodilation. Their work confirms that of others who have shown that alterations in local temperature of visceral organs evoke reflex cardiovascular responses (1). The reason for the difference in the cardiovascular responses, i.e., previously described hypertension and peripheral vasoconstriction and the hypotension and peripheral vasodilation described in this study, is not clear. Furthermore, local axoaxonal reflexes that mediate mesenteric vasodilation have not been described previously. Earlier studies of chemosensitive sympathetic afferents indicated that most abdominal visceral afferent endings are located closer to the serosal surface and are stimulated most easily by chemicals that have access to the serosa rather than the mucosa of viscus organs (6,8). Rozsa et al. confirm this general
observation, as mildly warm fluid (40°C) caused consistent reflex responses only when applied to the serosal surface. Warmer fluids (4.6”~50°C) induced responses when they were applied to either the mucosal or serosal surfaces, but it is likely that transmural temperature changes occurred. Rozsa and colleagues report that P-adrenoceptor blockade did not alter the chronotropic response. This is different from previous studies, which have suggested that the cardiac chronotropic and inotropit responses to abdominal visceral mechanoreceptor stimulation are mediated mainly by adrenergic efferent nerves (9). Rozsa et al. speculate that another neurotransmitter such as calcitonin gene-related peptide may play a role. However, other possibilities also should be considered. For instance, nonadrenergic, noncholinergic mechanisms of vasodilation mediated by the purinergic nervous system have been identified (10). Adenine nucleotides and nucleosides, which stimulate purinergic receptors, also can inhibit norepinephrine release from adrenergic other neurotransnerve endings (11).Potentially, mitters such as vasoactive intestinal polypeptide and neuropeptide Y, both of which have been found in the heart (12,13),likewise could mediate certain aspects of the reflex cardiovascular response to abdominal visceral organ stimulation. Many sensory receptors normally activated by mechanical stimuli also can be activated by certain chemicals. A large number of chemicals have been reported to stimulate visceral afferent endings, which may produce reflex cardiovascular responses. These include capsaicin (4,14), bradykinin (14-171, acetylcholine (8),serotonin (18,19), histamine (19), acidic (including lactic acid) and alkaline solutions (I), hypertonic and hypotonic solutions (l),potassium (ZO), hypercapnia (l), hypoxia (20), peptone solutions (22), tryptophan (19), substance P (18), and nicotine (1). It is not clear that all of these substances stimulate strictly chemosensitive afferents because many of the afferents activated are polymodal (i.e., they also respond to mechanical stimuli) and because many of
August1988
the substances (including bradykinin, acetylcholine, serotonin, and substance P) may cause activation of sensory receptors secondary to contraction of the visceral smooth muscle. There is disagreement about whether these reflex responses are merely the response to a nociceptive stimulus or whether these responses would occur in the absence of pain (23). There is some evidence that cardiovascular reflex responses can occur after administration of subalgesic concentrations of chemicals such as bradykinin or capsaicin (19). Furthermore, some chemicals that do not cause pain, such as methacholine, pilocarpine, and histamine, elicit reflex responses. Therefore, it appears that pain is not a prerequisite for reflex cardiorespiratory responses to occur. Rozsa and colleagues used capsaicin to deplete substance P, substance P antigen to neutralize substance P, and somatostatin to inhibit substance P. Using this approach they provided evidence supporting the role of substance P as the neurotransmitter for the primary afferent neurons mediating the thermal reflex. Substance P is considered to be an important central neurotransmitter for afferents concerned with nociception (24). This suggests the possibility that reflex thermal visceral cardiovascular responses are mediated by pathways concerned with nociception. There are many physiologic and pathological circumstances during which reflex cardiovascular responses caused by stimulation of abdominal organs may be important. Rozsa and coworkers suggest that activation of a thermal cardiovascular reflex could occur during ingestion of warm or cold liquids. Changes in mesenteric blood flow could redistribute flow within the gastrointestinal region to provide for alterations in local smooth muscle activity and to aid in digestion and absorption. Reflex redistribution of intestinal blood flow away from the intestines and toward the stomach also has been observed during gastric mechanoreceptor stimulation (25). Nociceptive responses to intestinal ischemia, similar to those elicited by capsaicin and high concentrations of bradykinin, cause generalized stimulation of the cardiorespiratory system. Presumably, these reflexes are an attempt to increase mesenteric flow or, in the case of other noxious stimuli, to call upon cardiovascular reserve to allow the organism to escape. However, in some circumstances, such as the inflammation associated with acute pancreatitis, the reflex effects can be deleterious because intense renal vasoconstriction can lead to acute renal failure (26). Other pathological situations during which cardiorespiratory reflexes from the abdominal visceral region may occur include the carcinoid and dumping syndromes (27.28). Bradykinin is released during both
EDITORIALS
525
of these conditions and may stimulate visceral sensory nerve endings to activate autonomic reflexes. Much work still remains to be done to fully understand the importance of reflex control by abdominal visceral sensory nerves. To the list of the many possible chemical and mechanical stimuli that can elicit reflex responses we now should add temperature. However, several important questions remain. It is unclear if cold solutions are as important a stimulus as warm solutions. Is the rat similar to or different than other species with regard to thermal and other types of reflexes? Certainly the reduction in blood pressure during thermal stimulation is different than the pressor response associated with activation of spinal reflexes during chemoreceptor and mechanoreceptor stimulation. What types of afferents are stimulated? Although the work of Rozsa et al. suggests that C fiber afferents are important, it is clear that finely myelinated A6 fibers also are important in many reflex responses from interoceptors. Does temperature work through afferent endings that are strictly thermosensitive or is it altering activity indirectly by changing visceral smooth muscle activity? Are thermosensitive aff erent endings unimodal or polymodal? Where is the substance P located that functions as a neurotransmitter in the thermoreflex? Previous studies have suggested that substance P is widespread throughout the gastrointestinal sensory and central nervous systems (29). Are other neurotransmitters such as somatostatin important in the thermoreceptor and other chemoreceptor and mechanoreceptor reflexes ? Are pathways in the central nervous system spinal or supraspinal? Studies of spinal animals and quadraplegic patients suggest that spinal pathways may be sufficient to transmit much of the reflex cardiovascular response during visceral (i.e., urinary bladder) receptor stimulation (30). What are the efferent effector limbs of the abdominal visceral cardiovascular reflex? Clearly the sympathetic division of the autonomic nervous system is important. However, most studies have been conducted in acutely anesthetized animals, which have little remaining parasympathetic tone. Studies in decerebrate animals or conscious humans may yield an entirely different answer and may indicate that the parasympathetic nervous system is much more important than previously realized. Rozsa et al. speculate that calcitonin gene-related peptide may be an important neuroeffector underlying the chronotropic response in the thermal reflex. The purinergic nervous system or other modulators such as vasoactive intestinal polypeptide or neuropeptide Y likewise may play an important role. Finally, the overall significance of gastrointestinal reflexes in humans needs to be defined. Although it has been
526
EDITORIALS
suggested that bradykinin released in the carcinoid and dumping syndromes and the pain associated with mesenteric ischemia may engender reflex responses, the evidence is, at best, circumstantial. We need to determine if these reflexes are important for the digestion and absorption of food and nutrients and other normal physiologic functions of the gastrointestinal system. Furthermore, we need to clarify the role of these reflex responses in the various syndromes mentioned above as well as others, such as postprandial angina pectoris and acute pancreatitis, in which such reflexes may play a role. Thus, it seems clear that much necessary but exciting work still lies ahead in the decades to come.
J.C. LONGHURST, M.D., Ph.D. Professor of Medicine and Cardiology University of California Davis, California
References 1. Chernigovskiy VN. In: Lindsley DB, ed. Interoceptors. Washington, D.C.: American Psychological Association, 1960. 2. Sherrington CS. The integrative action of the nervous system. New York: Scribners, 1906. 3. Rozsa Z, Mattila J, Jacobson ED. Substance P mediates a gastrointestinal thermoreflex in rats. Gastroenterology 198%; 95:265-76. 4. Ordway GA, Boheler KR, Longhurst JC. Stimulating intestinal afferents reflexly activates the cardiovascular system in cats. Am J Physiol 19%%;254:H354-60. 5. Longhurst JC, Spilker HL, Ordway GA. Cardiovascular reflexes elicited by passive gastric distension in anesthetized cats. Am J Physiol 19%1;240:H539+5. GA, Longhurst JC. Cardiovascular reflexes arising 6. Ordway from the gallbladder of the cat: effects of capsaicin, bradykinin and distension. Circ Res 19%3;52:26-35. 7. Ordway GA, Longhurst JC. Mitchell JH. Stimulation of pancreatic afferents reflexly activates the cardiovascular system in cats. Am J Physiol 19%4;245:R%20-6. JC, Stebbins CL, Ordway GA. Chemically-induced 8. Longhurst cardiovascular reflexes arising from the stomach of the cat. Am J Physiol 1984;247:H459-66. JC, Ibarra J. Sympatho-adrenal mechanisms in 9. Longhurst hemodynamic responses to gastric distension in cats. Am J Physiol 19%2:243:H74%-53. G. Cholinergic and purinergic regulation of blood 10. Burnstock vessels. In: Bohr DF, Somlyo AP, Sparks HV Jr, eds.. The cardiovascular system. Volume II. Vascular smooth muscle. Bethesda, Md.: American Physiological Society, 1980:567612. AS, Johns A, Paton DM. Presynaptic inhibitory 11. Clanachan actions of adenosine nucleotides and adenosine on neurotransmission in the rat vas deferens. Neuroscience 1977;2: 597-602.
GASTROENTEROLOGY Vol. 95, No. 2
12. Said SI. Vasoactive intestinal polypeptide (VIP]: current status Peptides 19%4;5:143-50. 13. Gu J, Adrian TE. Tatemoto K, et al. Neuropeptide tyrosine (NPY): a major cardiac neuropeptide. Lancet 19%3;i:1008-10. 14. Longhurst JC, Kaufman MP, Ordway GA, et al. Effects of bradykinin and capsaicin on endings of afferent fibers from abdominal visceral organs in cats. Am J Physiol 19%4;247: R552-9. 15. Morrison JFB. The afferent innervation of the gastrointestinal tract. In: Evers PW, ed. Nerves and the gut. Thorofare, N.J.: Charles B Slack, 1977:297-326. 16. Floyd K, Hick VE. Koley J, et al. Effects of bradykinin mediated by autonomic efferent nerves. Q J Exp Physiol 1977:62: 11-7. 17. Floyd K, Hick VE, Koley J, et al. The effects of bradykinin on afferent units in intra-abdominal sympathetic nerve trunks. Q J Exp Physiol 1977;62:19-25. 18. Lew WYW, Longhurst JC. Substance P, 5-hydroxytryptamine. and bradykinin stimulate abdominal visceral afferent fiber endings in cats. Am J Physiol 1986;250:R465-73, 19. Khayutin VM, Baraz LA, Lukoshkova EV, et al. Chemosensitive spinal afferents: threshold of specific and nociceptive reflexes as compared with thresholds of excitation for receptors and axons. Prog Brain Res 1976;43:293-306. 20. Khayutin VM. Mitsany A, Sonina RS, et al. Reflex responses of the vascular system and renal sympathetic efferents induced by potassium ions injected into the superior mesenteric artery and the effect of tonic baroreceptor inflow thereon. Arch Int Physiol Biochem 1969;77:829-54. 21. Longhurst JC. Dittman LE. Ischemically sensitive abdominal visceral afferents of cats: responses to hypoxia, bradykinin and prostaglandins. Am J Physiol 1987:253:H556-67. 22. Bykov KM. Chernigovskiy VN. Interoceptors of the stomach. J Physiol [USSR] 1947;33:3-15. 23. Longhurst JC. Cardiovascular reflexes of gastrointestinal origin. In: Shephard AP, Granger DN, eds., The physiology of the intestinal circulation. New York: Raven, 19%4:165-78. JO, Nilsson G, et al. Experimental im24. Hokfelt T, Kellerth munohistochemical studies in the localization and distribution of substance P in cat primary sensory neurons. Brain Res 1975:100:235-52, JC. Ibarra J. Reflex regional vascular responses 25. Longhurst during passive gastric distension in cats. Am J Physiol 1984; 247:R257-65. 26. Werner MH. Hayes DF, Lucas CE, et al. Renal vasoconstriction in association with acute pancreatitis. Am J Surg 1974; 127:185-90. 27. Oates JA. Pettinger WA, Doctor RB. Evidence for the release of bradykinin in carcinoid syndrome. J Clin Invest 1966;45:173-8. IJ, Smith AN. 5-Hydroxyindoles and kinin in 2%. Zeitlin the carcinoid and dumping syndromes. Lancet 1966;ii: 986-91. F. Distribution of capsaicin29. Holzer P, Bucsics A, Lembeck sensitive nerve fibers containing immunoreactive substance P in cutaneous and visceral tissues of the rat. Neurosci Lett 1982;31:253-7. CBB, McSwiney BA. Reflexes elicited by visceral 30. Downman stimulation in the acute spinal animal. J Physiol (Land) 1946: 105:80-94.
Address request for reprints to: John C. Longhurst, M.D., Ph.D., Cardiovascular Medicine, TB172. University of California, Davis, California 95616. 0 198% by the American Gastroenterological Association
1988;95:524-33
EDITORIALS
Gastrointestinal Reflexes Sherrington, in 1906, originally developed the classification of exteroceptors and interoceptors, referring to sensory receptors located either in the skin or internally in somatic and visceral regions (1). Activation of interoceptors including those in the abdominal visceral region has long been known to elicit reflex cardiovascular changes. Sherrington also was the first to suggest that mechanical stimulation of abdominal organs could elicit cardiovascular changes in association with pain (2). Subsequent studies showed that certain chemicals also are capable of stimulating chemosensitive visceral receptors to produce reflex responses. In this issue, Rozsa and coworkers (3) demonstrate that changes in local temperature likewise may mediate reflex cardiovascular responses. The cardiovascular reflexes elicited by mechanoreceptor and chemoreceptor stimulation in abdominal visceral organs are largely excitatory, i.e., they cause increases in heart rate, myocardial contractility, and peripheral vasoconstriction leading to an increase in arterial blood pressure (4-7). Interestingly, Rozsa and colleagues report that application of fluids at 45°C to the mucosal or serosal surface of the rat’s stomach, jejunum, or ileum provokes tachycardia and peripheral vasodilation leading to arterial hypotension and a reduction in intestinal blood flow as well as a locally mediated vasodilation. Their work confirms that of others who have shown that alterations in local temperature of visceral organs evoke reflex cardiovascular responses (1). The reason for the difference in the cardiovascular responses, i.e., previously described hypertension and peripheral vasoconstriction and the hypotension and peripheral vasodilation described in this study, is not clear. Furthermore, local axoaxonal reflexes that mediate mesenteric vasodilation have not been described previously. Earlier studies of chemosensitive sympathetic afferents indicated that most abdominal visceral afferent endings are located closer to the serosal surface and are stimulated most easily by chemicals that have access to the serosa rather than the mucosa of viscus organs (6,8). Rozsa et al. confirm this general
observation, as mildly warm fluid (40°C) caused consistent reflex responses only when applied to the serosal surface. Warmer fluids (4.6”~50°C) induced responses when they were applied to either the mucosal or serosal surfaces, but it is likely that transmural temperature changes occurred. Rozsa and colleagues report that P-adrenoceptor blockade did not alter the chronotropic response. This is different from previous studies, which have suggested that the cardiac chronotropic and inotropit responses to abdominal visceral mechanoreceptor stimulation are mediated mainly by adrenergic efferent nerves (9). Rozsa et al. speculate that another neurotransmitter such as calcitonin gene-related peptide may play a role. However, other possibilities also should be considered. For instance, nonadrenergic, noncholinergic mechanisms of vasodilation mediated by the purinergic nervous system have been identified (10). Adenine nucleotides and nucleosides, which stimulate purinergic receptors, also can inhibit norepinephrine release from adrenergic other neurotransnerve endings (11).Potentially, mitters such as vasoactive intestinal polypeptide and neuropeptide Y, both of which have been found in the heart (12,13),likewise could mediate certain aspects of the reflex cardiovascular response to abdominal visceral organ stimulation. Many sensory receptors normally activated by mechanical stimuli also can be activated by certain chemicals. A large number of chemicals have been reported to stimulate visceral afferent endings, which may produce reflex cardiovascular responses. These include capsaicin (4,14), bradykinin (14-171, acetylcholine (8),serotonin (18,19), histamine (19), acidic (including lactic acid) and alkaline solutions (I), hypertonic and hypotonic solutions (l),potassium (ZO), hypercapnia (l), hypoxia (20), peptone solutions (22), tryptophan (19), substance P (18), and nicotine (1). It is not clear that all of these substances stimulate strictly chemosensitive afferents because many of the afferents activated are polymodal (i.e., they also respond to mechanical stimuli) and because many of
August1988
the substances (including bradykinin, acetylcholine, serotonin, and substance P) may cause activation of sensory receptors secondary to contraction of the visceral smooth muscle. There is disagreement about whether these reflex responses are merely the response to a nociceptive stimulus or whether these responses would occur in the absence of pain (23). There is some evidence that cardiovascular reflex responses can occur after administration of subalgesic concentrations of chemicals such as bradykinin or capsaicin (19). Furthermore, some chemicals that do not cause pain, such as methacholine, pilocarpine, and histamine, elicit reflex responses. Therefore, it appears that pain is not a prerequisite for reflex cardiorespiratory responses to occur. Rozsa and colleagues used capsaicin to deplete substance P, substance P antigen to neutralize substance P, and somatostatin to inhibit substance P. Using this approach they provided evidence supporting the role of substance P as the neurotransmitter for the primary afferent neurons mediating the thermal reflex. Substance P is considered to be an important central neurotransmitter for afferents concerned with nociception (24). This suggests the possibility that reflex thermal visceral cardiovascular responses are mediated by pathways concerned with nociception. There are many physiologic and pathological circumstances during which reflex cardiovascular responses caused by stimulation of abdominal organs may be important. Rozsa and coworkers suggest that activation of a thermal cardiovascular reflex could occur during ingestion of warm or cold liquids. Changes in mesenteric blood flow could redistribute flow within the gastrointestinal region to provide for alterations in local smooth muscle activity and to aid in digestion and absorption. Reflex redistribution of intestinal blood flow away from the intestines and toward the stomach also has been observed during gastric mechanoreceptor stimulation (25). Nociceptive responses to intestinal ischemia, similar to those elicited by capsaicin and high concentrations of bradykinin, cause generalized stimulation of the cardiorespiratory system. Presumably, these reflexes are an attempt to increase mesenteric flow or, in the case of other noxious stimuli, to call upon cardiovascular reserve to allow the organism to escape. However, in some circumstances, such as the inflammation associated with acute pancreatitis, the reflex effects can be deleterious because intense renal vasoconstriction can lead to acute renal failure (26). Other pathological situations during which cardiorespiratory reflexes from the abdominal visceral region may occur include the carcinoid and dumping syndromes (27.28). Bradykinin is released during both
EDITORIALS
525
of these conditions and may stimulate visceral sensory nerve endings to activate autonomic reflexes. Much work still remains to be done to fully understand the importance of reflex control by abdominal visceral sensory nerves. To the list of the many possible chemical and mechanical stimuli that can elicit reflex responses we now should add temperature. However, several important questions remain. It is unclear if cold solutions are as important a stimulus as warm solutions. Is the rat similar to or different than other species with regard to thermal and other types of reflexes? Certainly the reduction in blood pressure during thermal stimulation is different than the pressor response associated with activation of spinal reflexes during chemoreceptor and mechanoreceptor stimulation. What types of afferents are stimulated? Although the work of Rozsa et al. suggests that C fiber afferents are important, it is clear that finely myelinated A6 fibers also are important in many reflex responses from interoceptors. Does temperature work through afferent endings that are strictly thermosensitive or is it altering activity indirectly by changing visceral smooth muscle activity? Are thermosensitive aff erent endings unimodal or polymodal? Where is the substance P located that functions as a neurotransmitter in the thermoreflex? Previous studies have suggested that substance P is widespread throughout the gastrointestinal sensory and central nervous systems (29). Are other neurotransmitters such as somatostatin important in the thermoreceptor and other chemoreceptor and mechanoreceptor reflexes ? Are pathways in the central nervous system spinal or supraspinal? Studies of spinal animals and quadraplegic patients suggest that spinal pathways may be sufficient to transmit much of the reflex cardiovascular response during visceral (i.e., urinary bladder) receptor stimulation (30). What are the efferent effector limbs of the abdominal visceral cardiovascular reflex? Clearly the sympathetic division of the autonomic nervous system is important. However, most studies have been conducted in acutely anesthetized animals, which have little remaining parasympathetic tone. Studies in decerebrate animals or conscious humans may yield an entirely different answer and may indicate that the parasympathetic nervous system is much more important than previously realized. Rozsa et al. speculate that calcitonin gene-related peptide may be an important neuroeffector underlying the chronotropic response in the thermal reflex. The purinergic nervous system or other modulators such as vasoactive intestinal polypeptide or neuropeptide Y likewise may play an important role. Finally, the overall significance of gastrointestinal reflexes in humans needs to be defined. Although it has been
526
EDITORIALS
suggested that bradykinin released in the carcinoid and dumping syndromes and the pain associated with mesenteric ischemia may engender reflex responses, the evidence is, at best, circumstantial. We need to determine if these reflexes are important for the digestion and absorption of food and nutrients and other normal physiologic functions of the gastrointestinal system. Furthermore, we need to clarify the role of these reflex responses in the various syndromes mentioned above as well as others, such as postprandial angina pectoris and acute pancreatitis, in which such reflexes may play a role. Thus, it seems clear that much necessary but exciting work still lies ahead in the decades to come.
J.C. LONGHURST, M.D., Ph.D. Professor of Medicine and Cardiology University of California Davis, California
References 1. Chernigovskiy VN. In: Lindsley DB, ed. Interoceptors. Washington, D.C.: American Psychological Association, 1960. 2. Sherrington CS. The integrative action of the nervous system. New York: Scribners, 1906. 3. Rozsa Z, Mattila J, Jacobson ED. Substance P mediates a gastrointestinal thermoreflex in rats. Gastroenterology 198%; 95:265-76. 4. Ordway GA, Boheler KR, Longhurst JC. Stimulating intestinal afferents reflexly activates the cardiovascular system in cats. Am J Physiol 19%%;254:H354-60. 5. Longhurst JC, Spilker HL, Ordway GA. Cardiovascular reflexes elicited by passive gastric distension in anesthetized cats. Am J Physiol 19%1;240:H539+5. GA, Longhurst JC. Cardiovascular reflexes arising 6. Ordway from the gallbladder of the cat: effects of capsaicin, bradykinin and distension. Circ Res 19%3;52:26-35. 7. Ordway GA, Longhurst JC. Mitchell JH. Stimulation of pancreatic afferents reflexly activates the cardiovascular system in cats. Am J Physiol 19%4;245:R%20-6. JC, Stebbins CL, Ordway GA. Chemically-induced 8. Longhurst cardiovascular reflexes arising from the stomach of the cat. Am J Physiol 1984;247:H459-66. JC, Ibarra J. Sympatho-adrenal mechanisms in 9. Longhurst hemodynamic responses to gastric distension in cats. Am J Physiol 19%2:243:H74%-53. G. Cholinergic and purinergic regulation of blood 10. Burnstock vessels. In: Bohr DF, Somlyo AP, Sparks HV Jr, eds.. The cardiovascular system. Volume II. Vascular smooth muscle. Bethesda, Md.: American Physiological Society, 1980:567612. AS, Johns A, Paton DM. Presynaptic inhibitory 11. Clanachan actions of adenosine nucleotides and adenosine on neurotransmission in the rat vas deferens. Neuroscience 1977;2: 597-602.
GASTROENTEROLOGY Vol. 95, No. 2
12. Said SI. Vasoactive intestinal polypeptide (VIP]: current status Peptides 19%4;5:143-50. 13. Gu J, Adrian TE. Tatemoto K, et al. Neuropeptide tyrosine (NPY): a major cardiac neuropeptide. Lancet 19%3;i:1008-10. 14. Longhurst JC, Kaufman MP, Ordway GA, et al. Effects of bradykinin and capsaicin on endings of afferent fibers from abdominal visceral organs in cats. Am J Physiol 19%4;247: R552-9. 15. Morrison JFB. The afferent innervation of the gastrointestinal tract. In: Evers PW, ed. Nerves and the gut. Thorofare, N.J.: Charles B Slack, 1977:297-326. 16. Floyd K, Hick VE. Koley J, et al. Effects of bradykinin mediated by autonomic efferent nerves. Q J Exp Physiol 1977:62: 11-7. 17. Floyd K, Hick VE, Koley J, et al. The effects of bradykinin on afferent units in intra-abdominal sympathetic nerve trunks. Q J Exp Physiol 1977;62:19-25. 18. Lew WYW, Longhurst JC. Substance P, 5-hydroxytryptamine. and bradykinin stimulate abdominal visceral afferent fiber endings in cats. Am J Physiol 1986;250:R465-73, 19. Khayutin VM, Baraz LA, Lukoshkova EV, et al. Chemosensitive spinal afferents: threshold of specific and nociceptive reflexes as compared with thresholds of excitation for receptors and axons. Prog Brain Res 1976;43:293-306. 20. Khayutin VM. Mitsany A, Sonina RS, et al. Reflex responses of the vascular system and renal sympathetic efferents induced by potassium ions injected into the superior mesenteric artery and the effect of tonic baroreceptor inflow thereon. Arch Int Physiol Biochem 1969;77:829-54. 21. Longhurst JC. Dittman LE. Ischemically sensitive abdominal visceral afferents of cats: responses to hypoxia, bradykinin and prostaglandins. Am J Physiol 1987:253:H556-67. 22. Bykov KM. Chernigovskiy VN. Interoceptors of the stomach. J Physiol [USSR] 1947;33:3-15. 23. Longhurst JC. Cardiovascular reflexes of gastrointestinal origin. In: Shephard AP, Granger DN, eds., The physiology of the intestinal circulation. New York: Raven, 19%4:165-78. JO, Nilsson G, et al. Experimental im24. Hokfelt T, Kellerth munohistochemical studies in the localization and distribution of substance P in cat primary sensory neurons. Brain Res 1975:100:235-52, JC. Ibarra J. Reflex regional vascular responses 25. Longhurst during passive gastric distension in cats. Am J Physiol 1984; 247:R257-65. 26. Werner MH. Hayes DF, Lucas CE, et al. Renal vasoconstriction in association with acute pancreatitis. Am J Surg 1974; 127:185-90. 27. Oates JA. Pettinger WA, Doctor RB. Evidence for the release of bradykinin in carcinoid syndrome. J Clin Invest 1966;45:173-8. IJ, Smith AN. 5-Hydroxyindoles and kinin in 2%. Zeitlin the carcinoid and dumping syndromes. Lancet 1966;ii: 986-91. F. Distribution of capsaicin29. Holzer P, Bucsics A, Lembeck sensitive nerve fibers containing immunoreactive substance P in cutaneous and visceral tissues of the rat. Neurosci Lett 1982;31:253-7. CBB, McSwiney BA. Reflexes elicited by visceral 30. Downman stimulation in the acute spinal animal. J Physiol (Land) 1946: 105:80-94.
Address request for reprints to: John C. Longhurst, M.D., Ph.D., Cardiovascular Medicine, TB172. University of California, Davis, California 95616. 0 198% by the American Gastroenterological Association