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Peptides and classical transmitters in autonomic control of airway function
417
PEPTIDES AND CLASSICAL TRANSMITTERS IN AUTONOMIC CONTROL OF AIRWAY FUNCTION. J.M. LUNDBERG,
S. LACROIX, C.-R. MARTLING & R. MATRAN.
cology, Karolinska Institute,
Department of Pharma-
S-I04 01 Stockholm, Sweden
A population of sensory nerves in the nasal mucosa and lower airways are sensitive to capsaicin and release multiple peptides upon irritation. likely to mediate vasodilatation,
and neurokinin A bronchoconstriction.
Sympathetic
contain NPY which is a potent vasoconstrictor tory actions on acetylcholine adrenergic
CGRP is
substance P plasma protein extravasation noradrenergic
fibres also
agent with prejunctional
inhibi-
and neurokinin A release. NPY may mediate non-
sympathetic vasoconstriction
in the airways. Parasympathetic
nerves contain VIP and PHI which are likely to be involved in atropine resistant vasodilatation and non-adrenergic
bronchodilatation.
PROBLEMS IN THE USE OF NEUROKININ ANTAGONISTS IN ANALYSIS OF NANC RESPONSES OF RABBIT AND SHEEP IRIS SPHINCTER PUPILLAE PREPARATIONS A O MAGBAGBEOLA, G PATERSON and I K M MORTON Department of Pharmacology, King's College London,
Strand, London, WC2R 2LS
The NANC contractile response of the field-stimulated iris sphincter preparation in the presence of guanethidine and atropine is thought to involve release of mediators including neurokinins from capsaicin-sensitive nerves. Putative neurokinin receptor antagonists have been used by several workers to obtain evidence of neurokinin release but have given equivocal results, as responses are reduced, but not abolished. We find, for example, that 10~M [ D ArgO,.D-Pro 2 , D-Trp .7 '9 ' Leu 11 ]-SP ( i- )11 reduces NANC (5Hz) responses by 41% in the rabblt and 66% mn the sheep. However, we have shown in a number of other preparations (eg, Bailey et al, 1986, Br.J.Pharmac. 87:79-85) that such antagonists have some selectivity giving varying pA 2 values depending on agonist, and hence might be expected to show differing degrees of antagonism of NANC responses, depending whether the mediators released were predominantly substance P (SP), neurokinin A (NKA), or neurokinin B (NKB); which are most active on NKI, NK 2 & NK 3 receptors respectively. To explore this, neurokinin receptors of both species were characterised using parallel bioassays of a series of naturally-occurring and subtype selective synthetic tachykinin agonists. Further, pA 2 estimates using a number of agonists were made for putative antagonists including the above-mentioned. Briefly, the results with the agonists showed that the predominant neurokinin receptor in both species was of the NK I subtype,and the antagonists, though blocking NKA quite effectively, were largely inactive against SP and NKB. Consequently such antagonists should be used with caution in assesssing the degree of involvement of neurokinins in the overall NANC response.
PEPTIDES AND CLASSICAL TRANSMITTERS IN AUTONOMIC CONTROL OF AIRWAY FUNCTION. J.M. LUNDBERG,
S. LACROIX, C.-R. MARTLING & R. MATRAN.
cology, Karolinska Institute,
Department of Pharma-
S-I04 01 Stockholm, Sweden
A population of sensory nerves in the nasal mucosa and lower airways are sensitive to capsaicin and release multiple peptides upon irritation. likely to mediate vasodilatation,
and neurokinin A bronchoconstriction.
Sympathetic
contain NPY which is a potent vasoconstrictor tory actions on acetylcholine adrenergic
CGRP is
substance P plasma protein extravasation noradrenergic
fibres also
agent with prejunctional
inhibi-
and neurokinin A release. NPY may mediate non-
sympathetic vasoconstriction
in the airways. Parasympathetic
nerves contain VIP and PHI which are likely to be involved in atropine resistant vasodilatation and non-adrenergic
bronchodilatation.
PROBLEMS IN THE USE OF NEUROKININ ANTAGONISTS IN ANALYSIS OF NANC RESPONSES OF RABBIT AND SHEEP IRIS SPHINCTER PUPILLAE PREPARATIONS A O MAGBAGBEOLA, G PATERSON and I K M MORTON Department of Pharmacology, King's College London,
Strand, London, WC2R 2LS
The NANC contractile response of the field-stimulated iris sphincter preparation in the presence of guanethidine and atropine is thought to involve release of mediators including neurokinins from capsaicin-sensitive nerves. Putative neurokinin receptor antagonists have been used by several workers to obtain evidence of neurokinin release but have given equivocal results, as responses are reduced, but not abolished. We find, for example, that 10~M [ D ArgO,.D-Pro 2 , D-Trp .7 '9 ' Leu 11 ]-SP ( i- )11 reduces NANC (5Hz) responses by 41% in the rabblt and 66% mn the sheep. However, we have shown in a number of other preparations (eg, Bailey et al, 1986, Br.J.Pharmac. 87:79-85) that such antagonists have some selectivity giving varying pA 2 values depending on agonist, and hence might be expected to show differing degrees of antagonism of NANC responses, depending whether the mediators released were predominantly substance P (SP), neurokinin A (NKA), or neurokinin B (NKB); which are most active on NKI, NK 2 & NK 3 receptors respectively. To explore this, neurokinin receptors of both species were characterised using parallel bioassays of a series of naturally-occurring and subtype selective synthetic tachykinin agonists. Further, pA 2 estimates using a number of agonists were made for putative antagonists including the above-mentioned. Briefly, the results with the agonists showed that the predominant neurokinin receptor in both species was of the NK I subtype,and the antagonists, though blocking NKA quite effectively, were largely inactive against SP and NKB. Consequently such antagonists should be used with caution in assesssing the degree of involvement of neurokinins in the overall NANC response.