Cholinergic and VIP-ergic pathways mediate histamine H2 receptor-induced cyclical secretion in the guinea pig colon

Abstract

Previous studies demonstrated neurally mediated recurrent increases in short-circuit current (Isc) suggestive of anion secretion in guinea pig distal colon. To determine the neural pathways involved, segments of distal colon from guinea pigs were mounted in flux chambers. In muscle-stripped or whole thickness preparations, serosal addition of the histamine H2 receptor agonist, dimaprit, caused cyclical increases in Isc, which were reduced by the chloride channel blocker, N-phenylanthranilic acid, but not by the sodium channel blocker amiloride. Dimaprit stimulated release of [3H]acetylcholine and vasoactive intestinal polypeptide (VIP) from submucosal/mucosal sheets. Dimaprit caused recurrent increases in Isc, which were significantly decreased by mecamylamine, a nicotinic receptor antagonist, and nearly abolished by the muscarinic antagonist, atropine (M3 > M1 = M2). The muscarinic antagonist, 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP, M3 > M1), was more potent than pirenzepine (M1 > M3) in reducing recurrent increases in Isc. Dimaprit- and electrically evoked secretion were inhibited by the VIP antagonists [4Cl-D-Phe6, Leu17]VIP and VIP hybrid. The results suggest the involvement of VIP-ergic and cholinergic neurons utilizing nicotinic and muscarinic synapses in mediating secretion.

Activation of adenosine low-affinity A3 receptors inhibits the enteric short interplexus neural circuit triggered by histamine

“…The H2 receptor agonist dimaprit elicits a stereotypic cyclical motor response characterized by coordinated secretion and contraction in the guinea pig distal colon. Motor responses are triggered by activation of H2 receptors that are sensitive to blockade by cimetidine (19,22,23); once triggered they continue for hours without desensitization, and this is consistent with the underlying recurrent excitation of enteric neurons that occurs with continuous exposure to histamine. Wood and colleagues (21,(32)(33)(34)(35) hypothesized that release of histamine from mast cells during gut inflammation and its actions in the ENS contribute to the observed pathobiology.…”

“…Histamine H2 receptor-induced cyclical secretion involves cholinergic and VIP-ergic pathways in the submucous plexus (23). An H2 receptor-activated chloride conductance is involved in the excitability of myenteric neurons (60), and these receptors could contribute to the short interplexus reflex but do not trigger it; since severing the interplexus connections prevents the coordinated response and results exclusively in a neurosecretomotor response, it is evident that the response is triggered at submucous neurons and then spreads to the myenteric plexus via the short interplexus neural circuit.…”

“…The I sc represents the algebraic sum of net fluxes of actively transported ions. Changes in Isc to dimaprit or carbachol were previously shown to represent chloride secretion (19,(21)(22)(23). The difference between peak responses and baseline I sc before drug addition was used to calculate changes in Isc.…”

L-Type Ca2+ Channels in the Enteric Nervous System Mediate Oscillatory Cl- Secretion in Guinea Pig Colon

“…Cholinergic transmission within the ENS has been demonstrated by functional and electrophysiological studies (Kuwahara et al 1987;Diener et al 1989;Cooke et al 1995). Our laboratory has been investigating the cellular mechanisms whereby low (0.2-1 mM) concentrations of Ba 2+ induce atropine (a cholinergic antagonist)-sensitive oscillatory Cl − secretion in the guinea pig distal colon.…”

“…Thus, changes in amplitude and frequency of the repetitive firing, respectively, may reflect the amount of Ach release and the excitability of the submucosal neurons. It is therefore valid to estimate the Ca 2+ channel activity of the submucosal cholinergic neurons and/or the crypt cells by using a mucosasubmucosa preparation mounted in Ussing chambers (Kuwahara et al 1987;Diener et al 1989;Cooke et al 1995;Nishikitani et al 2002;Kokubo et al 2005), although the data are obtained via indirect methods.…”