Action of Bradykinin in the Submucosal Plexus of Guinea Pig Small Intestine

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Abstract
Intracellular recording methods with “sharp” microelectrodes were used to study actions of bradykinin (BK) on electrical behavior of morphologically identified neurons and the identification and localization of BK receptors in the submucosal plexus of guinea pig small intestine. Exposure to BK depolarized the membrane potential and elevated excitability in submucosal neurons with AH-type electrophysiological behavior and Dogiel II multipolar morphology and in neurons with S-type electrophysiological behavior and uniaxonal morphology. BK-evoked depolarizing responses were associated with increased neuronal input resistance in AH-type neurons and decreased input resistance in S-type neurons. The selective B2 BK receptor antagonists HOE-140 (icatabant acetate) and WIN64338 [(S)-4[2-bis(cyclohexylamino)methyleneamino]-3-(2-napthalenyl)-1-oxopropylamino]benzyl tributyl phosphonium chloride hydrochloride], but not the selective B1 receptor antagonists des-arg10-HOE-140 and des-arg9-leu8-BK, suppressed the BK-evoked responses. The selective B2 receptor agonist Kallidin, but not the selective B1 receptor agonist des-arg9-BK mimicked the excitatory action of BK. Western blot analysis and reverse transcription-polymerase chain reaction confirmed the expression of B2 receptor protein and mRNA. Binding studies with a fluorescently labeled BK2 antagonist found expression of B2 receptors on a majority of the ganglion cells. B2 receptors occupied 82% of the neurons that expressed immunoreactivity for neuropeptide Y, 75% of the neurons that expressed vasoactive intestinal peptide, 84% of the neurons that expressed substance P, 71% of the neurons that expressed choline acetyltransferase, and all neurons that expressed calbindin immunoreactivity. The results suggest that the B2 receptor mediates the excitatory action of BK on submucosal plexus neurons. Pathophysiological significance of the excitatory actions on secretomotor neurons might be stimulated mucosal secretion and the secretory diarrhea associated with intestinal inflammatory states.