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Mechanisms Mediating Substance P–Induced Contraction in the Rat Iris In Vitro

From the Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil.

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 was recorded.

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 -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 [ß-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.