- Email: [email protected]
Barlow replie
316 only to potency but also to enantioselectivity. In this respect it is not surprising that the azaanalogue of hyosciamine5, which has a significantly different structure, does not fit any of the sets. not
FULVIO
GUALTIERI
Dcpnrtafenf of Pllennncer~firol Science. Ultiwrsity of 4orc~~. Via G. Cappotzi 9. 50121 Florem-e.
Itnly.
References I Barlow,R. B. (1990t
5 Barlow, R. 8. (1973) I. Med. Ckew. 16, ln37-103R 6 Lehmann, P. A., de Miranda, ). F R. and AriPns, E. J. (1976) Prgq. Drrrz RES. 18, 101-142 7 Gualtieri. F., Romanelli, M. N. and Teodori, E. (1990) C~z~r~iity2, 79-84
i-remfs
P~r~r~f~ffro~.
Sri. 11, MS-150 2 Pfeiffer, C. C. (1956) Science 124, 29-30 3 Lehmann, P. A. (1986) Trends ~l~~rnrncof. Sri. 7. 2Sl-285 4 Barlow, R. 6.. Franks, F. M. and Pearson, j. D. M. (1973) 1. Med. Clteor. 16, 439-446
Barlow replies: Fulvio Gualtieri is certainly justified in asking the results to define the sets, but the rules of the game must be statistical: can the pooled results be broken down statistically into two populations? Otherwise the selection is arbitrary and there are real dangers in selecting
hteractions between mast cells and nerves
Neurogenicinflammation The review ‘Modulation of neurogenie inflammation’ by Barnes et al. (Tips, May 1990)’ provokes many thoughts about mechanisms of inflammation. An aspect hardly mentioned in the article, however, is the participation of mast cells in neurogenic inflammation and in other axon reflexes. In addition to histamine and (in rodents) 5-I-IT, mast cell granules contain proteolytic enzymes that can catalyse the formation of bradykinin’. This or a closely similar peptide has been isolated from perfusates of skin during antidromic vasodilatation, and is probably more important than histamine or 5-HT in mediating the arteriolar azon reflex flare around sites of minor injury in human3 and rat’ skin. in the skin, mast cells discharge their granules at sites of physical injury or chemical irritation, probably in response to PGE, released from injured cells5. Degranulation of mast cells also takes place at sites remote from the original insult, at the efferent limb of an axon reflex’. The degranulation of mast cells that follows chemical iniiation of the surface of the skin can be prevented by pretreatment of animals with capsaicin?, indicating the involvement of tachykinin-secreting nociceptive axons. In rats that have been depleted of mast cells, axon reflex vasodilatation and neurogenic inflammation’ are suppressed but not
completely prevented. Mast cells contribute to the spread of neurogenie inflammation, because in addition to their vascular actions histamine and bradykinin stimulate nociceptive axons and initiate other axon reflexes’. Degranulation of mast cells induced by activity in nerve8 is not confined to the skin, having also been observed in the trachea and bronchi of the rat followin% stimulation of the vagus nerve1 . Vagal stimulation also causes vasodilatation, bronchoconstriction and increased vascular and epithelial permeability. These responsesll and the mast cell degranulation1° are prevented by prior treatment with capsaicin. Barnes’**2 has suggested that axon reflexes contribute to the propagation of bronchoconstriction in asthma, a condition in which mast cellderived mediators play a considerable part13. In~ammation of the gut’ may also involve axon reflex degranuiation of mast cells, which are contacted by unmyelinated nerve fibres in the mucosa’4. Indeed, mast cells are present in all the YFans in which antidromic vasocillatation or neurogenic inflammation has been demonstrated. As Barnes et al.’ point out, a drug that selectively antagonizes a single mediator of neurogenic inflammation has little therapeutic potential. Substances that protect
sets simply because you obtain linear correlations, improved especially with small numbers of results’. His approach still leaves unanswered the corollary to Pfeiffer’s rule - does the activity of t-he weaker enantiomer have to be determined by the activity of the stronger one? RICHARD
8. BARLOW
Reference 1 Barlow, R. B. (1981) I. P/tune.
Phnracol.
33.4fG-461
mast cells against diverse degranulation-inducing stimuli will prevent the introduction of several mediatolr- into the extracellular fluid. ~romoglicate and nedocromil do this in the respiratory system’5 and are useful in the management of asthma and allergic rhinitis. Drugs to protect mast cells in the skin, urinary tract and gut might reiieve the neurogenic components of a wide variety of inflammatory disorders. JOHN
A. KIERNAN
Depnrtwrent
of Anotoory, 7’Ite Universi!y of Western Otrtnrio, Lot~dorr, Ontario, N6A SC], Cutrada.
References 1 Banes, P. J., Belvisi, EA.G. and Rogers, 2 3 4 5 6 7 8 9
10 11
I2 13 14 15
D. F. (1990) Trends Pfrnrstnco[. Sci. 11. 185-189 G&r&t, J. R. et al. (1982) Hisfochettt. J. 14, 967-979 Chapman, L. F. (1977) /. Itrvest. Dentmtol. 69,88-97 Kiernan, J. A. (1976) Arch. ~er~ruf~~. Res. 255, l-8 Crunkhom, P. and Willis, A. L. (1971) Br. 1. PhanrmcoI. 41,49-56 Kieman, J. A. (1972) Quart. /. Exp. Pltysiol. 57, 311317 Kiernan, J. A. (1977) Qunrt. I. Exp. Pkyrysfoi. 62, 151-161 Kiernan, J. A. (1975) Qu~rf. 1, Exp. Plzysiol. 60, 123-130 Lembeck, F. (1983) Trertds Newosci. 6, 106-108 Kieman, J. A. Ir~t. Arch. Allergy Appl. Jnmuml. (in press) Lundberg, J. M., Martling, C-R. and Lundblad, L. (1988) K/in. WochettscBr. 66 (Suppl. Xi), 151-160 Barnes, I’. 1. (1986) Eur. I. Respir. Dis. 69 (Suppl. 147), SO-87 Skidmore, I. F. and Vardey, C. J. (1984) Ageafs Acfions (Suppl. la), 33-58 Bienenstock, J. et RI. (1987) 1~. Arch. Allergy Appl. Inrnrur~ol. 82, 238-243 Eady, R. P. (1986) Eur. [. Respir. Dis. 69 (Suppl. 147), 112-119
FULVIO
GUALTIERI
Dcpnrtafenf of Pllennncer~firol Science. Ultiwrsity of 4orc~~. Via G. Cappotzi 9. 50121 Florem-e.
Itnly.
References I Barlow,R. B. (1990t
5 Barlow, R. 8. (1973) I. Med. Ckew. 16, ln37-103R 6 Lehmann, P. A., de Miranda, ). F R. and AriPns, E. J. (1976) Prgq. Drrrz RES. 18, 101-142 7 Gualtieri. F., Romanelli, M. N. and Teodori, E. (1990) C~z~r~iity2, 79-84
i-remfs
P~r~r~f~ffro~.
Sri. 11, MS-150 2 Pfeiffer, C. C. (1956) Science 124, 29-30 3 Lehmann, P. A. (1986) Trends ~l~~rnrncof. Sri. 7. 2Sl-285 4 Barlow, R. 6.. Franks, F. M. and Pearson, j. D. M. (1973) 1. Med. Clteor. 16, 439-446
Barlow replies: Fulvio Gualtieri is certainly justified in asking the results to define the sets, but the rules of the game must be statistical: can the pooled results be broken down statistically into two populations? Otherwise the selection is arbitrary and there are real dangers in selecting
hteractions between mast cells and nerves
Neurogenicinflammation The review ‘Modulation of neurogenie inflammation’ by Barnes et al. (Tips, May 1990)’ provokes many thoughts about mechanisms of inflammation. An aspect hardly mentioned in the article, however, is the participation of mast cells in neurogenic inflammation and in other axon reflexes. In addition to histamine and (in rodents) 5-I-IT, mast cell granules contain proteolytic enzymes that can catalyse the formation of bradykinin’. This or a closely similar peptide has been isolated from perfusates of skin during antidromic vasodilatation, and is probably more important than histamine or 5-HT in mediating the arteriolar azon reflex flare around sites of minor injury in human3 and rat’ skin. in the skin, mast cells discharge their granules at sites of physical injury or chemical irritation, probably in response to PGE, released from injured cells5. Degranulation of mast cells also takes place at sites remote from the original insult, at the efferent limb of an axon reflex’. The degranulation of mast cells that follows chemical iniiation of the surface of the skin can be prevented by pretreatment of animals with capsaicin?, indicating the involvement of tachykinin-secreting nociceptive axons. In rats that have been depleted of mast cells, axon reflex vasodilatation and neurogenic inflammation’ are suppressed but not
completely prevented. Mast cells contribute to the spread of neurogenie inflammation, because in addition to their vascular actions histamine and bradykinin stimulate nociceptive axons and initiate other axon reflexes’. Degranulation of mast cells induced by activity in nerve8 is not confined to the skin, having also been observed in the trachea and bronchi of the rat followin% stimulation of the vagus nerve1 . Vagal stimulation also causes vasodilatation, bronchoconstriction and increased vascular and epithelial permeability. These responsesll and the mast cell degranulation1° are prevented by prior treatment with capsaicin. Barnes’**2 has suggested that axon reflexes contribute to the propagation of bronchoconstriction in asthma, a condition in which mast cellderived mediators play a considerable part13. In~ammation of the gut’ may also involve axon reflex degranuiation of mast cells, which are contacted by unmyelinated nerve fibres in the mucosa’4. Indeed, mast cells are present in all the YFans in which antidromic vasocillatation or neurogenic inflammation has been demonstrated. As Barnes et al.’ point out, a drug that selectively antagonizes a single mediator of neurogenic inflammation has little therapeutic potential. Substances that protect
sets simply because you obtain linear correlations, improved especially with small numbers of results’. His approach still leaves unanswered the corollary to Pfeiffer’s rule - does the activity of t-he weaker enantiomer have to be determined by the activity of the stronger one? RICHARD
8. BARLOW
Reference 1 Barlow, R. B. (1981) I. P/tune.
Phnracol.
33.4fG-461
mast cells against diverse degranulation-inducing stimuli will prevent the introduction of several mediatolr- into the extracellular fluid. ~romoglicate and nedocromil do this in the respiratory system’5 and are useful in the management of asthma and allergic rhinitis. Drugs to protect mast cells in the skin, urinary tract and gut might reiieve the neurogenic components of a wide variety of inflammatory disorders. JOHN
A. KIERNAN
Depnrtwrent
of Anotoory, 7’Ite Universi!y of Western Otrtnrio, Lot~dorr, Ontario, N6A SC], Cutrada.
References 1 Banes, P. J., Belvisi, EA.G. and Rogers, 2 3 4 5 6 7 8 9
10 11
I2 13 14 15
D. F. (1990) Trends Pfrnrstnco[. Sci. 11. 185-189 G&r&t, J. R. et al. (1982) Hisfochettt. J. 14, 967-979 Chapman, L. F. (1977) /. Itrvest. Dentmtol. 69,88-97 Kiernan, J. A. (1976) Arch. ~er~ruf~~. Res. 255, l-8 Crunkhom, P. and Willis, A. L. (1971) Br. 1. PhanrmcoI. 41,49-56 Kieman, J. A. (1972) Quart. /. Exp. Pltysiol. 57, 311317 Kiernan, J. A. (1977) Qunrt. I. Exp. Pkyrysfoi. 62, 151-161 Kiernan, J. A. (1975) Qu~rf. 1, Exp. Plzysiol. 60, 123-130 Lembeck, F. (1983) Trertds Newosci. 6, 106-108 Kieman, J. A. Ir~t. Arch. Allergy Appl. Jnmuml. (in press) Lundberg, J. M., Martling, C-R. and Lundblad, L. (1988) K/in. WochettscBr. 66 (Suppl. Xi), 151-160 Barnes, I’. 1. (1986) Eur. I. Respir. Dis. 69 (Suppl. 147), SO-87 Skidmore, I. F. and Vardey, C. J. (1984) Ageafs Acfions (Suppl. la), 33-58 Bienenstock, J. et RI. (1987) 1~. Arch. Allergy Appl. Inrnrur~ol. 82, 238-243 Eady, R. P. (1986) Eur. [. Respir. Dis. 69 (Suppl. 147), 112-119