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Neurokinin receptors and mechanisms in the guinea-pig taenia caeci
76
NEUROKININ RECEPTORS TAENIA CAECI.
AND
MECHANISMS
IN THE
GUINEA-PIG
Judith M.HALL and lan K.M.MORTON. Department
of Pharmacology,
King's College London,
Strand,
London.
WC2R 2LS.
Neurokinin receptors mediating contraction of the guinea-pig ileum have been extensively studied, where agonists have both a direct action on the smooth muscle mediated by NK I receptors, and an indirect action via acetylcholine release (I) mediated by NK 3 receptors. In contrast, far less information is available regarding tachykinin (TK) actions on the anatomically adjacent taenia caeci, where SP appears by several criteria only to have a direct action on the smooth muscle. Relative activities of naturally occuring TKs suggest a predominant NK I receptor population in this tissue (2), which is also supported by the activity of the synthetic analogue substance P methyl ester (activity 0.38 relative to substance P). However, studies using newer subtype selective agonists revealed some inconsistencies. Thus the L- and D-isomers of [GIpS,L-ProS]-SP(6-11) (septide) were essentially equiactive, and succ- [Asp6,MePhe 8 ] -SP(6-11) (senktide) had an activity c. 0.07 relative to substance P, which suggests some contribution from NK 3 receptors. Mechanistic studies in the taenia caeci contrasted neurokinin receptors with muscarlnic receptors throughout and, in all cases, the peptides showed a lower maximal response. This was true for contractile responses in normal Krebs' medium, and also in high-K + depolarising medium used in experiments designed to estimate Ca2+-mobilisation and/or involvement of receptor-operated Ca 2+ channels (ROCs) in the contractile mechanism (3). Similar differences in maximal effect was found in experiments measuring stimulated [JH]phosphatidylinosltol hydrolysis, where the maximal effect measured with a number of TKs including senktide was considerably less (c. 20%) than that of carbachol. Differences between the coupling mechanisms of NK and muscarinic receptors was suggested by+ experiments in high-K + medium using 88Rb-efflux to estimate changes in K -permeability. Here, even high concentrations of TKs (I00 ~M) had no discernable effect on tissues in which carbachol (i0 ~M) caused pronounced K+- channel opening. In summary, the predominant neurokinin receptor in the taenia caeci, as in the ileum, appears to be of the NK I subtype, although the possibility of some contribution from an NK 3 receptor population is likely. Coupling of NK receptors to contraction involves essentially similar mechanisms to those used by other stimulatory agonists, namely Ca z+ entry through voltage-operated channels, release of intracellular Ca 2+ via phosphatidylinositol hydrolysis and/or Ca 2+ entry through ROCs. Whether the difference in maximal responses between the neurokinin and the muscarinic receptor systems reflects differences in coupling efficiency or receptor number is under investigation. We thank the M R C for a studentship to JMH, and Dr.S.P.Watson for assistance and advice with the biochemical studies.
l. Fosbraey P, Featherstone
RL, Morton IKM (1984)N.-S.Arch. Pharmac 326:111-115.
2.Morton IKM, Hall JM (1987) In: Henry JL Neurokinins. Springer-Verlag, NY, pp138-140. 3.Hall JM and Morton IKM (1987) ibid, pp135-137.
et
al
(eds)
Substance
P
and
NEUROKININ RECEPTORS TAENIA CAECI.
AND
MECHANISMS
IN THE
GUINEA-PIG
Judith M.HALL and lan K.M.MORTON. Department
of Pharmacology,
King's College London,
Strand,
London.
WC2R 2LS.
Neurokinin receptors mediating contraction of the guinea-pig ileum have been extensively studied, where agonists have both a direct action on the smooth muscle mediated by NK I receptors, and an indirect action via acetylcholine release (I) mediated by NK 3 receptors. In contrast, far less information is available regarding tachykinin (TK) actions on the anatomically adjacent taenia caeci, where SP appears by several criteria only to have a direct action on the smooth muscle. Relative activities of naturally occuring TKs suggest a predominant NK I receptor population in this tissue (2), which is also supported by the activity of the synthetic analogue substance P methyl ester (activity 0.38 relative to substance P). However, studies using newer subtype selective agonists revealed some inconsistencies. Thus the L- and D-isomers of [GIpS,L-ProS]-SP(6-11) (septide) were essentially equiactive, and succ- [Asp6,MePhe 8 ] -SP(6-11) (senktide) had an activity c. 0.07 relative to substance P, which suggests some contribution from NK 3 receptors. Mechanistic studies in the taenia caeci contrasted neurokinin receptors with muscarlnic receptors throughout and, in all cases, the peptides showed a lower maximal response. This was true for contractile responses in normal Krebs' medium, and also in high-K + depolarising medium used in experiments designed to estimate Ca2+-mobilisation and/or involvement of receptor-operated Ca 2+ channels (ROCs) in the contractile mechanism (3). Similar differences in maximal effect was found in experiments measuring stimulated [JH]phosphatidylinosltol hydrolysis, where the maximal effect measured with a number of TKs including senktide was considerably less (c. 20%) than that of carbachol. Differences between the coupling mechanisms of NK and muscarinic receptors was suggested by+ experiments in high-K + medium using 88Rb-efflux to estimate changes in K -permeability. Here, even high concentrations of TKs (I00 ~M) had no discernable effect on tissues in which carbachol (i0 ~M) caused pronounced K+- channel opening. In summary, the predominant neurokinin receptor in the taenia caeci, as in the ileum, appears to be of the NK I subtype, although the possibility of some contribution from an NK 3 receptor population is likely. Coupling of NK receptors to contraction involves essentially similar mechanisms to those used by other stimulatory agonists, namely Ca z+ entry through voltage-operated channels, release of intracellular Ca 2+ via phosphatidylinositol hydrolysis and/or Ca 2+ entry through ROCs. Whether the difference in maximal responses between the neurokinin and the muscarinic receptor systems reflects differences in coupling efficiency or receptor number is under investigation. We thank the M R C for a studentship to JMH, and Dr.S.P.Watson for assistance and advice with the biochemical studies.
l. Fosbraey P, Featherstone
RL, Morton IKM (1984)N.-S.Arch. Pharmac 326:111-115.
2.Morton IKM, Hall JM (1987) In: Henry JL Neurokinins. Springer-Verlag, NY, pp138-140. 3.Hall JM and Morton IKM (1987) ibid, pp135-137.
et
al
(eds)
Substance
P
and