Control of Human Airway Smooth Muscle 1 - 3 JUDITH L. BLACK
Introduction The modulation of autonomic neural control has been proposed as a mechanism for airway hyperresponsiveness. This short review will focus on the evidence for this arising out of in vitro studies on airway smooth muscle. It is apparent that large differences in airway smooth muscle behavior exist between species, and because of this, there is a need to study human airway smooth muscle when possible. It is well established that the principal autonomic excitatory input to human airway smooth muscle is via parasympathetic cholinergic fibers arising from the vagus nerve (1). Little is known of the inhibitory neural pathway, but vasoactive intestinal peptide (VIP) is likely to be the principal neurotransmitter (2). Even less is known of the modulation of the inhibitory neural pathway, although endogenous enzymes such as chymase and tryptase may be important (3). Noncholinergic excitatory pathways have been demonstrated in guinea pig airways (4), but this is still under investigation in humans. Preganglionic cholinergic fibers synapse at ganglia in the airway wall, and short postganglionic fibers terminate on airway smooth muscle and mucous glands. It is convenient to consider the modulation of cholinergic neural function in terms of possible sites of this input, viz, at the parasympathetic ganglion, at the presynaptic nerve ending, and at the postsynaptic site on the airway smooth muscle cell. Ganglionic Modulation It is possible to localize modulation to the ganglionic level by studying neurally mediated contractile responses in an intact nerve muscle preparation. Such a preparation, which can differentiate the effects of preganglionic and postganglionic cholinergic neurotransmission, was pioneered by Skoogh and coworkers (5) in ferret airways, and several other laboratories have since developed innervated airway smooth muscle preparations in other species (6, 7). Results from these studies have shown that beta-adrenoceptor stimulation can modulate neurotransmission in some animal species (8). There is as yet only one report of an innervated human airway smooth muscle preparation. Ullman and coworkers (9) have studied parasympathetic ganglion transmission in one human bronchial preparation, and the results of further studies are eagerly awaited. Although neuropeptide-containing nerve fibers have been demonstrated in the vicinity of parasympathetic ganglia (10), functional evidence for a modulatory role at this level is so far lacking in humans. A number of different neuropeptides have been localized AM REV RESPIR DIS 1991; 143:S11-S12
to cell bodies in parasympathetic ganglia (10, 11), but whether these neuropeptides modulate cholinergic transmission at this site is not known. Van Koppen and cowor kers (12) have demonstrated in autoradiographic studies that muscarinic receptors are located on ganglia in human bronchi. Evidence for a functional role is as yet unavailable, and whether this function would be excitatory or inhibitory is not known. In characterizing the muscarinic receptor subtypes in human peripheral lung membranes, Bloom and coworkers (13) have shown that 600/0 of the receptors have a high affinity for pirenzipine. Such receptors are found in autonomic ganglia in other tissues, but no evidence exists so far that this is true for human airway ganglia.
Postganglionic Presynaptic Modulation It is likely that there are receptors on nerve terminals that playa critical role in modulating cholinergic transmission.
Modulation by Cyclooxygenase Products Various types of prostaglandin receptors exist on presynaptic nerve terminals, but the effect of their stimulation varies markedly between species. Several groups have reported that exogenous PGE2 inhibits neurotransmission in canine and cat airways (14-16), and we have confirmed this in the rabbit (17). We have also found that similar concentrations of PGE2 have no such effect in human airways (17). Aizawa and coworkers (18) however have reported that PGE2 does inhibit neurotransmission in human airways and the reason for these differences is not apparent. By contrast, there is increasing evidence to suggest that PGF2ll potentiates cholinergically mediated responses, and this has been demonstrated in rabbit (7), canine (19), and human airways (20). Tamaoki and coworkers (21)have reported presynaptic augmentation of the parasympathetic contractile response in canine airways by PGD2, but we have found that PGD 2 at similar concentrations had no effect in field-stimulated rabbit or human airway preparations (20). Recently, another cyclooxygenase product, a thromboxane A 2analogue, has demonstrated a similar potentiating effect (22), but studies in human tissue are lacking.
Modulation by Neuropeptides Recently, a role for neuropeptides and, in particular, the tachykinins in airway disease has been proposed. Substance P and neurokinin A have potent direct contractile effects on airway smooth muscle of several species including humans (23-25). It is possible that neuropeptides released during neurogenic inflammation may modulate cholinergic trans-
mission. In ferret airways, VIP both inhibits (at high doses) and potentiates (at low doses) responses to cholinergic nerve stimulation (26), and the inhibitory role has recently been confirmed in guinea pigs (27). Tanaka and Grunstein (28) demonstrated that substance P accelerates prejunctional release of acetylcholine in rabbit airways, and this has been reported in ferret (29) and guinea pig preparations (30). Despite this growing body of evidence supporting a neuropeptide-induced potentiation of cholinergic neural contraction in animal airways, no similar results in human tissue are as yet available.
Modulation by Muscarinic Receptors Recently, the existence of presynaptic postganglionic muscarinic receptors has been described in some but not in all airways. Stimulation of these receptors in human bronchus by muscarinic agonists such as pilocarpine leads to an inhibition of transmitter release, and, conversely, blockade with antagonists such as gallamine potentiates the effects of pilocarpine (31).
Miscellaneous Gamma amino butyric acid (GABA) has a well-recognized role as an inhibitory transmitter in the central nervous system, and some recent work has examined the role of GABA receptors in the airways (32). Shirakawa and coworkers (33) reported that there are two types of GABA receptor on postganglionic cholinergic neurones: GABA A , which promotes acetylcholine release, and GABAB, which may inhibit release. Presynaptic adrenoceptors also may play a modulatory role in cholinergic neural responses. Both Grundstrom and coworkers (34) and McCaig (35) have reported inhibition by stimulation of urreceptors and a similar effect but mediated by ~l-receptors in canine trachea (36), and ~2-receptorsin human bronchus (37) has been described.
Postganglionic Postsynaptic Modulation The ultimate response to neural stimulation, i.e., contraction of the airway smooth muscle cell, will depend on excitation-contraction coupling mechanisms. There is now good indirect evidence for the involvement of voltagedependent calcium channels in human air1 From the Department of Pharmacology, University of Sydney, New South Wales, Australia. 2 Supported by the National Health and Medical Research Council of Australia. 3 Correspondence and requests for reprints should be addressed to Judith L. Black, Department of Pharmacology, Universityof Sydney, New South Wales, Australia 2006.
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way smooth muscle contraction (38, 39) and, recently, some direct evidence from electrophysiologic studies on human isolated bronchial smooth muscle cells (40). Contraction of airway smooth muscle cells also can occur independently of voltage-dependent calcium channels, and this is probably the excitation coupling mechanism for cholinergic stimuli. In addition, the role of K+ channels in regulating tone has aroused interest. Compounds such as BRL34915(41)open K+ channels and hyperpolarize the muscle membrane. K+ channel inhibitors such as tetraethylammonium and 4-aminopyridine oppose these effects. Because airway smooth muscle displays rectifying behavior, these channels are likely to be important, and thus the contribution of K+ channels to the regulation of airway smooth muscle tone warrants further investigation.
References 1. Richardson JB. Nerve supply to the lungs. Am Rev Respir Dis 1979; 119:785-802. 2. Said SI. Vasoactive peptides in the lung, with special reference to vasoactive intestinal peptide. Exp Lung Res 1982; 3:343-8. 3. Caughey GH, LeidigF, Viro NF, Nadel JA. Substance P and vasoactive intestinal peptide degradation by mast cell tryptase and chymase. J Pharmacol Exp Ther 1988; 224:133-7. 4. Karlsson JA, Persson CGA. Evidence against vasoactive intestinal polypeptide (VIP) as a dilator and in favour of substance P as a constrictor in airway neurogenic responses. Br J Pharmacol 1983; 79:634-6. 5. Skoogh B-E, Holtzman MJ, Sheller JR, Nadel JA. Barbiturates depress vagal motor pathway to ferret trachea at ganglia. J Appl Physiol 1982; 53:253-7. 6. Blackman JG, McCaig DJ. Studies on an isolated innervated preparation of guinea-pig trachea. Br J Pharmacol 1983; 80:703-10. 7. Armour CL, Johnson PRA, Marthan R, Black JL. Prostaglandin F2« augments the response to parasympathetic fibre stimulation in an isolated innervated preparation of rabbit trachea. J Auton Pharmacol 1988; 8:248-55. 8. Skoogh B-E, Svedmyr N.132-adrenoceptorstimulation inhibits ganglionic transmission in ferret trachea (abstract). Am Rev Respir Dis 1984; 129:A232. 9. Ullman A, Lofdahl C-G, Petterson G, Svedmyr N, Skoogh B-E. Parasympathetic ganglionic transmission demonstrated in an isolated human bronchus: a case report (abstract). Am Rev Respir Dis 1988; 137:AI99. 10. Lundberg JM, Lundblad L, Martling C-R, Saria A, Stjarne P, Anggard A. Coexistence of multiple peptides and classic transmitters in airway neurons: functional and pathophysiological aspects. Am RevRespir Dis 1987; 136(Suppl:16-22).
11. Palmer JBD, Cuss FMC, Mulderry PK, et al. Calcitonin gene-related peptide is localised to human airway nerves and potently constricts human airway smooth muscle. Br J Pharmacol 1987; 91: 95-101. 12. van Koppen CJ, Blackesteijn WM, Klaassen ABM, de Miranda JFR, Beld AJ, van Ginneken CAM. Autoradiographic visualization of muscarinic receptors in pulmonary nerves and ganglia. Neurosci Lett 1987; 83:237-40. 13. Bloom JW, Halonen M, Yamamura HI. Characterization of muscarinic cholinergic receptor subtypes in human peripheral lung. J Pharmacol Exp Ther 1988; 244:625-32. 14. Walters EH, O'Byrne PM, Fabbri LM, Graf PD, Holtzman MJ, Nadel JA. Control of neurotransmission by prostaglandins in canine trachealis smooth muscle. J Appl Physiol1984; 57: 129-34. 15. Daniel E, Davis C, Sharma V. Effects of endogenous and exogenous prostaglandins in neurotransmission in canine trachea. Can J Physiol Pharmacol 1987; 65:1433-41. 16. Inoue Y, Ito Y, Takeda K. Prostaglandininduced inhibition of acetylcholine release from neuronal elements of cat tracheal tissue. J Physiol (Lond) 1984; 349:553-70. 17. Black JL, Armour CL, Johnson PRA. The direct and modulatory effects of PGE2 in rabbit and human isolated airways (abstract). Am Rev Respir Dis 1988; 137:A97. 18. Aizawa H, Miyazaki N, Sigematsu N, Suzuki H, Ito Y. Electrical and mechanical properties of human bronchial smooth muscle (abstract). Am Rev Respir Dis 1988; 137:A377. 19. Leff AR, Munoz NM, Tallet J, Cavigelli M, David AC. Augmentation of parasympathetic contraction in tracheal and bronchial airways by PGF 2« in situ. J Appl Physiol 1985; 58:1558-64. 20. Armour CL, Black JL, Johnson PRA. A role for inflammatory mediators in airway hyperresponsiveness. In: Armour CL, Black JL, eds. Mechanisms in asthma: pharmacology, physiology and management. New York:Alan R. Liss, 1988;99-108. 21. Tamaoki J, Sekizawa K, Graf PD, Nadel JA. Cholinergic neuromodulation by PGD 2 in canine smooth muscle. J Appl Physiol1987; 63:1396-1400. 22. Serio R, Daniel EE. Thromboxane effects on canine trachealis neuromuscular function. J Appl Physiol 1988; 64:1979-88. 23. Lundberg JM, Martling C-R, Saria A. Substance P and capsaicin-induced contraction of human bronchi. Acta Physiol Scand 1983; 119:49-53. 24. Advenier C, Naline E, Drapeau G, Regoli D. Relative potencies of neurokinins in guinea-pig trachea and human bronchus. Eur J Pharmacol1987; 139:133-7. 25. Black JL, Johnson PRA, Armour CL. Potentiation of the contractile effects of neuropeptides in human bronchus by an enkephalinase inhibitor. Pulmon Pharmacol 1988; 1:21-3. 26. Sekizawa K, Tamaoki J, GrafPD, Nadel JA. Modulation of cholinergic neurotransmission by vasoactive intestinal peptide in ferret trachea. J Appl Physiol 1988; 64:2433-7.
27. Martin JG, Wang A, Reid S, Zacour M. Vasoactive intestinal peptide and cholinergic neurotransmission in an isolated innervated guineapig tracheal preparation (abstract). Am Rev Respir Dis 1988; 137:AI97. 28. Tanaka DT, Grunstein MM. Effect of substance P on neurally mediated contraction of rabbit airway smooth muscle. J Appl Physiol 1986: 60:458-63. 29. Sekizawa K, Tamaoki J, Nadel JA, Borson DB. Enkephalinase inhibitor potentiates substance P-and electrically-induced contraction in ferret trachea. J Appl Physiol 1987; 63:1401-5. 30. Barnes PJ, MacLagan J, Meldrum LA. Effects of tachykinins on cholinergic neural responses in guinea-pig trachea. Br J Pharmacol 1987; 90: 138P. 31. Minette PA, Barnes PJ. Prejunctional inhibitory muscarinic receptors on cholinergic nerves in human and guinea-pig airways.J Appl Physiol1988; 64:2532-7. 32. Tamaoki J, Graf PD, Nadel JA. Effect of y-aminobutyric acid on neurally mediated contraction of guinea-pig trachea1issmooth muscle. J Pharmacol Exp Ther 1987; 243:86-90. 33. Shirakawa J, Tanujama K, Tanaka C. y-Aminobutyric acid-induced modulation of ACh release from the guinea-pig lung. J Pharmacol Exp Ther 1987; 243:364-9. 34. Grundstrom N, Andersson RGG, Wikberg JES. Prejunctional alphas-adrenoceptors inhibit contraction of tracheal smooth muscle by inhibiting cholinergic neurotransmission. Life Sci 1981; 28:2981-6. 35. McCaig OJ. Effects of sympathetic stimulation and applied catecholamines on mechanical and electrical responses to stimulation of the vagus nerve in guinea-pig isolated trachea. Br J Pharmacol1987; 91:385-94. 36. Danser AHJ, van den Ende R, Lorenz RR, Flavahan NA, Vanhoutte PM. Prejunctional 131 adrenoceptors inhibit cholinergic transmission in canine bronchi. J Appl Physiol 1987; 62:785-90. 37. Rhoden KJ, Meldrum LA, Barnes PJ. Inhibition of cholinergic neurotransmission in human airways by 132-receptors. J Appl Physiol 1988; 65:700-5. 38. Black J, Armour C, Johnson P, Vincenc K. The calcium dependence of histamine, carbachol, and KCI-induced contraction in human airways in vitro. Eur J Pharmacol 1986; 125:159-68. 39. Marthan R, Armour CL, Johnson PRA, Black JL. The calcium channel agonist BAY K8644 enhances the responsiveness of human airway muscle to KCl and histamine but not to carbachol. Am Rev Respir Dis 1987; 135:185-9. 40. Marthan R, Martin C, Amedee T, Mironneau J. Calcium channel currents in isolated smooth muscle cellsfrom human bronchus. J Appl Physiol1989; 66:1706-14. 41. Allen SL, Boyle JP, Contijo J, Foster RW,Morgan GP, Small RC. Electrical and mechanical effects of BRL 34915in guinea-pig isolated trachealis. Br J Pharmacol 1986; 89:395-405.
Introduction The modulation of autonomic neural control has been proposed as a mechanism for airway hyperresponsiveness. This short review will focus on the evidence for this arising out of in vitro studies on airway smooth muscle. It is apparent that large differences in airway smooth muscle behavior exist between species, and because of this, there is a need to study human airway smooth muscle when possible. It is well established that the principal autonomic excitatory input to human airway smooth muscle is via parasympathetic cholinergic fibers arising from the vagus nerve (1). Little is known of the inhibitory neural pathway, but vasoactive intestinal peptide (VIP) is likely to be the principal neurotransmitter (2). Even less is known of the modulation of the inhibitory neural pathway, although endogenous enzymes such as chymase and tryptase may be important (3). Noncholinergic excitatory pathways have been demonstrated in guinea pig airways (4), but this is still under investigation in humans. Preganglionic cholinergic fibers synapse at ganglia in the airway wall, and short postganglionic fibers terminate on airway smooth muscle and mucous glands. It is convenient to consider the modulation of cholinergic neural function in terms of possible sites of this input, viz, at the parasympathetic ganglion, at the presynaptic nerve ending, and at the postsynaptic site on the airway smooth muscle cell. Ganglionic Modulation It is possible to localize modulation to the ganglionic level by studying neurally mediated contractile responses in an intact nerve muscle preparation. Such a preparation, which can differentiate the effects of preganglionic and postganglionic cholinergic neurotransmission, was pioneered by Skoogh and coworkers (5) in ferret airways, and several other laboratories have since developed innervated airway smooth muscle preparations in other species (6, 7). Results from these studies have shown that beta-adrenoceptor stimulation can modulate neurotransmission in some animal species (8). There is as yet only one report of an innervated human airway smooth muscle preparation. Ullman and coworkers (9) have studied parasympathetic ganglion transmission in one human bronchial preparation, and the results of further studies are eagerly awaited. Although neuropeptide-containing nerve fibers have been demonstrated in the vicinity of parasympathetic ganglia (10), functional evidence for a modulatory role at this level is so far lacking in humans. A number of different neuropeptides have been localized AM REV RESPIR DIS 1991; 143:S11-S12
to cell bodies in parasympathetic ganglia (10, 11), but whether these neuropeptides modulate cholinergic transmission at this site is not known. Van Koppen and cowor kers (12) have demonstrated in autoradiographic studies that muscarinic receptors are located on ganglia in human bronchi. Evidence for a functional role is as yet unavailable, and whether this function would be excitatory or inhibitory is not known. In characterizing the muscarinic receptor subtypes in human peripheral lung membranes, Bloom and coworkers (13) have shown that 600/0 of the receptors have a high affinity for pirenzipine. Such receptors are found in autonomic ganglia in other tissues, but no evidence exists so far that this is true for human airway ganglia.
Postganglionic Presynaptic Modulation It is likely that there are receptors on nerve terminals that playa critical role in modulating cholinergic transmission.
Modulation by Cyclooxygenase Products Various types of prostaglandin receptors exist on presynaptic nerve terminals, but the effect of their stimulation varies markedly between species. Several groups have reported that exogenous PGE2 inhibits neurotransmission in canine and cat airways (14-16), and we have confirmed this in the rabbit (17). We have also found that similar concentrations of PGE2 have no such effect in human airways (17). Aizawa and coworkers (18) however have reported that PGE2 does inhibit neurotransmission in human airways and the reason for these differences is not apparent. By contrast, there is increasing evidence to suggest that PGF2ll potentiates cholinergically mediated responses, and this has been demonstrated in rabbit (7), canine (19), and human airways (20). Tamaoki and coworkers (21)have reported presynaptic augmentation of the parasympathetic contractile response in canine airways by PGD2, but we have found that PGD 2 at similar concentrations had no effect in field-stimulated rabbit or human airway preparations (20). Recently, another cyclooxygenase product, a thromboxane A 2analogue, has demonstrated a similar potentiating effect (22), but studies in human tissue are lacking.
Modulation by Neuropeptides Recently, a role for neuropeptides and, in particular, the tachykinins in airway disease has been proposed. Substance P and neurokinin A have potent direct contractile effects on airway smooth muscle of several species including humans (23-25). It is possible that neuropeptides released during neurogenic inflammation may modulate cholinergic trans-
mission. In ferret airways, VIP both inhibits (at high doses) and potentiates (at low doses) responses to cholinergic nerve stimulation (26), and the inhibitory role has recently been confirmed in guinea pigs (27). Tanaka and Grunstein (28) demonstrated that substance P accelerates prejunctional release of acetylcholine in rabbit airways, and this has been reported in ferret (29) and guinea pig preparations (30). Despite this growing body of evidence supporting a neuropeptide-induced potentiation of cholinergic neural contraction in animal airways, no similar results in human tissue are as yet available.
Modulation by Muscarinic Receptors Recently, the existence of presynaptic postganglionic muscarinic receptors has been described in some but not in all airways. Stimulation of these receptors in human bronchus by muscarinic agonists such as pilocarpine leads to an inhibition of transmitter release, and, conversely, blockade with antagonists such as gallamine potentiates the effects of pilocarpine (31).
Miscellaneous Gamma amino butyric acid (GABA) has a well-recognized role as an inhibitory transmitter in the central nervous system, and some recent work has examined the role of GABA receptors in the airways (32). Shirakawa and coworkers (33) reported that there are two types of GABA receptor on postganglionic cholinergic neurones: GABA A , which promotes acetylcholine release, and GABAB, which may inhibit release. Presynaptic adrenoceptors also may play a modulatory role in cholinergic neural responses. Both Grundstrom and coworkers (34) and McCaig (35) have reported inhibition by stimulation of urreceptors and a similar effect but mediated by ~l-receptors in canine trachea (36), and ~2-receptorsin human bronchus (37) has been described.
Postganglionic Postsynaptic Modulation The ultimate response to neural stimulation, i.e., contraction of the airway smooth muscle cell, will depend on excitation-contraction coupling mechanisms. There is now good indirect evidence for the involvement of voltagedependent calcium channels in human air1 From the Department of Pharmacology, University of Sydney, New South Wales, Australia. 2 Supported by the National Health and Medical Research Council of Australia. 3 Correspondence and requests for reprints should be addressed to Judith L. Black, Department of Pharmacology, Universityof Sydney, New South Wales, Australia 2006.
511
JUDITH L. BLACK
512
way smooth muscle contraction (38, 39) and, recently, some direct evidence from electrophysiologic studies on human isolated bronchial smooth muscle cells (40). Contraction of airway smooth muscle cells also can occur independently of voltage-dependent calcium channels, and this is probably the excitation coupling mechanism for cholinergic stimuli. In addition, the role of K+ channels in regulating tone has aroused interest. Compounds such as BRL34915(41)open K+ channels and hyperpolarize the muscle membrane. K+ channel inhibitors such as tetraethylammonium and 4-aminopyridine oppose these effects. Because airway smooth muscle displays rectifying behavior, these channels are likely to be important, and thus the contribution of K+ channels to the regulation of airway smooth muscle tone warrants further investigation.
References 1. Richardson JB. Nerve supply to the lungs. Am Rev Respir Dis 1979; 119:785-802. 2. Said SI. Vasoactive peptides in the lung, with special reference to vasoactive intestinal peptide. Exp Lung Res 1982; 3:343-8. 3. Caughey GH, LeidigF, Viro NF, Nadel JA. Substance P and vasoactive intestinal peptide degradation by mast cell tryptase and chymase. J Pharmacol Exp Ther 1988; 224:133-7. 4. Karlsson JA, Persson CGA. Evidence against vasoactive intestinal polypeptide (VIP) as a dilator and in favour of substance P as a constrictor in airway neurogenic responses. Br J Pharmacol 1983; 79:634-6. 5. Skoogh B-E, Holtzman MJ, Sheller JR, Nadel JA. Barbiturates depress vagal motor pathway to ferret trachea at ganglia. J Appl Physiol 1982; 53:253-7. 6. Blackman JG, McCaig DJ. Studies on an isolated innervated preparation of guinea-pig trachea. Br J Pharmacol 1983; 80:703-10. 7. Armour CL, Johnson PRA, Marthan R, Black JL. Prostaglandin F2« augments the response to parasympathetic fibre stimulation in an isolated innervated preparation of rabbit trachea. J Auton Pharmacol 1988; 8:248-55. 8. Skoogh B-E, Svedmyr N.132-adrenoceptorstimulation inhibits ganglionic transmission in ferret trachea (abstract). Am Rev Respir Dis 1984; 129:A232. 9. Ullman A, Lofdahl C-G, Petterson G, Svedmyr N, Skoogh B-E. Parasympathetic ganglionic transmission demonstrated in an isolated human bronchus: a case report (abstract). Am Rev Respir Dis 1988; 137:AI99. 10. Lundberg JM, Lundblad L, Martling C-R, Saria A, Stjarne P, Anggard A. Coexistence of multiple peptides and classic transmitters in airway neurons: functional and pathophysiological aspects. Am RevRespir Dis 1987; 136(Suppl:16-22).
11. Palmer JBD, Cuss FMC, Mulderry PK, et al. Calcitonin gene-related peptide is localised to human airway nerves and potently constricts human airway smooth muscle. Br J Pharmacol 1987; 91: 95-101. 12. van Koppen CJ, Blackesteijn WM, Klaassen ABM, de Miranda JFR, Beld AJ, van Ginneken CAM. Autoradiographic visualization of muscarinic receptors in pulmonary nerves and ganglia. Neurosci Lett 1987; 83:237-40. 13. Bloom JW, Halonen M, Yamamura HI. Characterization of muscarinic cholinergic receptor subtypes in human peripheral lung. J Pharmacol Exp Ther 1988; 244:625-32. 14. Walters EH, O'Byrne PM, Fabbri LM, Graf PD, Holtzman MJ, Nadel JA. Control of neurotransmission by prostaglandins in canine trachealis smooth muscle. J Appl Physiol1984; 57: 129-34. 15. Daniel E, Davis C, Sharma V. Effects of endogenous and exogenous prostaglandins in neurotransmission in canine trachea. Can J Physiol Pharmacol 1987; 65:1433-41. 16. Inoue Y, Ito Y, Takeda K. Prostaglandininduced inhibition of acetylcholine release from neuronal elements of cat tracheal tissue. J Physiol (Lond) 1984; 349:553-70. 17. Black JL, Armour CL, Johnson PRA. The direct and modulatory effects of PGE2 in rabbit and human isolated airways (abstract). Am Rev Respir Dis 1988; 137:A97. 18. Aizawa H, Miyazaki N, Sigematsu N, Suzuki H, Ito Y. Electrical and mechanical properties of human bronchial smooth muscle (abstract). Am Rev Respir Dis 1988; 137:A377. 19. Leff AR, Munoz NM, Tallet J, Cavigelli M, David AC. Augmentation of parasympathetic contraction in tracheal and bronchial airways by PGF 2« in situ. J Appl Physiol 1985; 58:1558-64. 20. Armour CL, Black JL, Johnson PRA. A role for inflammatory mediators in airway hyperresponsiveness. In: Armour CL, Black JL, eds. Mechanisms in asthma: pharmacology, physiology and management. New York:Alan R. Liss, 1988;99-108. 21. Tamaoki J, Sekizawa K, Graf PD, Nadel JA. Cholinergic neuromodulation by PGD 2 in canine smooth muscle. J Appl Physiol1987; 63:1396-1400. 22. Serio R, Daniel EE. Thromboxane effects on canine trachealis neuromuscular function. J Appl Physiol 1988; 64:1979-88. 23. Lundberg JM, Martling C-R, Saria A. Substance P and capsaicin-induced contraction of human bronchi. Acta Physiol Scand 1983; 119:49-53. 24. Advenier C, Naline E, Drapeau G, Regoli D. Relative potencies of neurokinins in guinea-pig trachea and human bronchus. Eur J Pharmacol1987; 139:133-7. 25. Black JL, Johnson PRA, Armour CL. Potentiation of the contractile effects of neuropeptides in human bronchus by an enkephalinase inhibitor. Pulmon Pharmacol 1988; 1:21-3. 26. Sekizawa K, Tamaoki J, GrafPD, Nadel JA. Modulation of cholinergic neurotransmission by vasoactive intestinal peptide in ferret trachea. J Appl Physiol 1988; 64:2433-7.
27. Martin JG, Wang A, Reid S, Zacour M. Vasoactive intestinal peptide and cholinergic neurotransmission in an isolated innervated guineapig tracheal preparation (abstract). Am Rev Respir Dis 1988; 137:AI97. 28. Tanaka DT, Grunstein MM. Effect of substance P on neurally mediated contraction of rabbit airway smooth muscle. J Appl Physiol 1986: 60:458-63. 29. Sekizawa K, Tamaoki J, Nadel JA, Borson DB. Enkephalinase inhibitor potentiates substance P-and electrically-induced contraction in ferret trachea. J Appl Physiol 1987; 63:1401-5. 30. Barnes PJ, MacLagan J, Meldrum LA. Effects of tachykinins on cholinergic neural responses in guinea-pig trachea. Br J Pharmacol 1987; 90: 138P. 31. Minette PA, Barnes PJ. Prejunctional inhibitory muscarinic receptors on cholinergic nerves in human and guinea-pig airways.J Appl Physiol1988; 64:2532-7. 32. Tamaoki J, Graf PD, Nadel JA. Effect of y-aminobutyric acid on neurally mediated contraction of guinea-pig trachea1issmooth muscle. J Pharmacol Exp Ther 1987; 243:86-90. 33. Shirakawa J, Tanujama K, Tanaka C. y-Aminobutyric acid-induced modulation of ACh release from the guinea-pig lung. J Pharmacol Exp Ther 1987; 243:364-9. 34. Grundstrom N, Andersson RGG, Wikberg JES. Prejunctional alphas-adrenoceptors inhibit contraction of tracheal smooth muscle by inhibiting cholinergic neurotransmission. Life Sci 1981; 28:2981-6. 35. McCaig OJ. Effects of sympathetic stimulation and applied catecholamines on mechanical and electrical responses to stimulation of the vagus nerve in guinea-pig isolated trachea. Br J Pharmacol1987; 91:385-94. 36. Danser AHJ, van den Ende R, Lorenz RR, Flavahan NA, Vanhoutte PM. Prejunctional 131 adrenoceptors inhibit cholinergic transmission in canine bronchi. J Appl Physiol 1987; 62:785-90. 37. Rhoden KJ, Meldrum LA, Barnes PJ. Inhibition of cholinergic neurotransmission in human airways by 132-receptors. J Appl Physiol 1988; 65:700-5. 38. Black J, Armour C, Johnson P, Vincenc K. The calcium dependence of histamine, carbachol, and KCI-induced contraction in human airways in vitro. Eur J Pharmacol 1986; 125:159-68. 39. Marthan R, Armour CL, Johnson PRA, Black JL. The calcium channel agonist BAY K8644 enhances the responsiveness of human airway muscle to KCl and histamine but not to carbachol. Am Rev Respir Dis 1987; 135:185-9. 40. Marthan R, Martin C, Amedee T, Mironneau J. Calcium channel currents in isolated smooth muscle cellsfrom human bronchus. J Appl Physiol1989; 66:1706-14. 41. Allen SL, Boyle JP, Contijo J, Foster RW,Morgan GP, Small RC. Electrical and mechanical effects of BRL 34915in guinea-pig isolated trachealis. Br J Pharmacol 1986; 89:395-405.
