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Astor Grumann-Júnior, Marcos Antônio Dias, Ricardo Vieira Alves, Joel E. Boteon, João Batista Calixto; Mechanisms Mediating Substance P–Induced Contraction in the Rat Iris In Vitro. Invest. Ophthalmol. Vis. Sci. 2000;41(7):1861-1870.
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purpose. To determine some of the mechanisms by which substance P (SP) induces
contraction in the isolated rat iris.
methods. Rings of rat iris were mounted in a 5-ml organ chamber containing Krebs
solution at 37°C under basal tension of 75 mg, and isometric tension
results. Substance P produced graded contraction in the rat iris, being
approximately 40-fold more potent than carbachol. Peptidase inhibitors
(captopril, phosphoramidon, thiorphan) did not affect the SP
response. The SP contraction was dependent on external Ca2+ by a mechanism resistant to both nifedipine and ω-conotoxin GVIA.
Atropine and tetrodotoxin significantly shifted the SP response to the
right (three- and fivefold, respectively). Neither phorbol nor
genistein altered the SP-induced contraction, whereas staurosporine
caused a weak inhibition. Indomethacin, pyrilamine, guanethidine, 8–37
calcitonin gene–related peptide (CGRP) fragment, and N G-nitro-l-arginine methyl ester
had no effect on SP response. All the natural tachykinin agonists
caused concentration-dependent contraction in rat iris with similar
maximal responses. The NK3 selective agonist
senktide caused graded contraction, being approximately
150-fold more active than the NK2 selective agonist[β
-ala] NKA. The NK1 selective agonist SP
methyl ester induced a small contraction. The NK3 and
NK2 antagonists SR 142801 and SR 48968 shifted the SP
response to the right. Schilds plots gave pA2 (negative logarithm of the molar concentration of antagonist causing a
twofold rightward displacement of the concentration response curves)
values of 9.37 and 7.97 and slopes of 0.70 and 1.02, respectively.
conclusions. Substance P produces a potent contraction in the isolated rat iris that
seems to depend on the neural release of acetylcholine by
tetrodotoxin-sensitive mechanisms. Its response relies largely on
external Ca2+, through mechanisms independent of activation
of L- or N-type Ca2+ channels, and is probably mediated via
activation of NK3 and NK2 receptors.
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