RESUMO
We have reported previously that bradykinin (BK) induces potent and reproducible concentration-dependent contractions of the pig iris sphincter (PIS) muscle in vitro through the activation of BK B(2) receptors. Here we attempted to investigate additional mechanisms by which BK induces contraction of the PIS in vitro. BK-mediated contraction of the PIS relied largely on the external Ca2+ influx by a mechanism sensitive to the L-, N- and P-type of Ca2+ channel selective blockers. Likewise, BK-induced contraction of the PIS was greatly inhibited by the CGRP-(8-37), NK(2) or NK(3) receptor antagonists (SR 48968, SR 142801), and to a lesser extent by the NK(1) antagonist (FK 888). Capsaicin desensitization of PIS or capsazepine pre-incubation also significantly reduced BK-mediated contraction in the PIS. Furthermore, KT 5720 or GF 109203X (the protein kinase A and C inhibitors, respectively) also significantly inhibited BK-mediated contraction. Taken together, these results indicate that BK-mediated contraction of the PIS seems to be mediated primarily by the release of CGRP and tachykinins from sensory nerve fibers, and relies largely on extracellular Ca2+ influx via activation of L-, N- and P-type of Ca2+ channels. Finally, these responses are mediated by activation of both protein kinase A- and C-dependent mechanisms.
Assuntos
Bradicinina/farmacologia , Capsaicina/análogos & derivados , Iris/fisiologia , Contração Muscular/efeitos dos fármacos , Animais , Benzamidas/farmacologia , Bradicinina/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Cálcio/metabolismo , Cálcio/farmacologia , Canais de Cálcio/fisiologia , Capsaicina/farmacologia , Carbazóis/farmacologia , Conotoxinas/farmacologia , Dipeptídeos/farmacologia , Relação Dose-Resposta a Droga , Ácido Egtázico/farmacologia , Técnicas In Vitro , Indóis/farmacologia , Iris/efeitos dos fármacos , Maleimidas/farmacologia , Nicardipino/farmacologia , Fragmentos de Peptídeos/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases , Proteínas Quinases/metabolismo , Pirróis/farmacologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia , Receptores de Droga/antagonistas & inibidores , Receptores de Droga/fisiologia , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores da Neurocinina-2/fisiologia , Receptores da Neurocinina-3/antagonistas & inibidores , Receptores da Neurocinina-3/fisiologia , Suínos , Taquicininas/fisiologia , ômega-Agatoxina IVA/farmacologiaRESUMO
The generation of hyperalgesia by Phoneutria nigriventer venom was investigated in rats using the paw pressure test, through the intraplantar injection of the venom. Hyperalgesia was significantly inhibited by N-[2-(4-chlorophenyl) ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide (capsazepine), a vanilloid receptor antagonist, by the local administration of pGlu-Ala-Asp-Pro-Asn-Lys-Phe-Tyr-Pro (spiro-gamma-lactam) Leu-Trp-NH(2) (GR82334) or of Phenyl-CO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH(2) (GR94800), inhibitors of tachykinin NK(1) and NK(2) receptors, respectively, or by the local injection of dizocilpine (MK 801), (+/-)-2-amino-5-phosphonopentanoic acid ((+/-)-AP-5), or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), antagonists of NMDA and non-NMDA excitatory amino acid receptors. The correlation between hyperalgesia and the inflammatory response induced by the venom was also investigated. The venom-induced edematogenic response was not modified by the pharmacological treatments. These results suggest that hyperalgesia induced by P. nigriventer venom is mediated by stimulation of capsaicin-sensitive neurons, with activation of peripheral tachykinin NK(1) and NK(2) receptors and of both the NMDA and AMPA receptors. Distinct mechanisms are involved in the development of hyperalgesia and edema induced by the venom.
Assuntos
Capsaicina/análogos & derivados , Hiperalgesia/metabolismo , Receptores de Glutamato/fisiologia , Receptores de Taquicininas/fisiologia , Venenos de Aranha/toxicidade , Animais , Capsaicina/farmacologia , Capsaicina/uso terapêutico , Edema/induzido quimicamente , Edema/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Membro Posterior , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Masculino , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/fisiologia , Receptores de Droga/antagonistas & inibidores , Receptores de Glutamato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Receptores da Neurocinina-1/efeitos dos fármacos , Receptores da Neurocinina-1/fisiologia , Receptores da Neurocinina-2/efeitos dos fármacos , Receptores da Neurocinina-2/fisiologia , Receptores de Taquicininas/antagonistas & inibidoresRESUMO
The role of NK-1 and NK-2 receptors on the pulmonary response to capsaicin in guinea pigs was evaluated using intravenous infusion of selective nonpeptide antagonists of NK 1 (CP 96345, 300 nmol/kg, and SR 140333, 300 nmol/kg) and NK-2 (SR 48968, 100 nmol/kg) neurokinin receptors. Maximal values of pulmonary dynamic elastance (Edyn) and pulmonary resistance (RL) after capsaicin infusion were significantly lower in the presence of SR 48968 (p < .005). Morphometric analysis of lungs obtained by quick-freezing showed significant attenuation of airway contraction and peribronchiolar edema formation in the presence of NK-2 antagonist (p < .001). When compared to guinea pigs that received only capsaicin, animals that received SR 140333 or CP 96345 showed lower values of Edyn, RL, airway contraction, and peribronchiolar edema, but only the difference in Edyn values was significant. The combination of NK-1 and NK-2 antagonists was not more effective than NK-2 antagonist alone in attenuating capsaicin effects. The results suggest that airway effects of capsaicin are mainly mediated by activation of NK-2 receptors although NK-1 receptors may also play a role.