The Role of Histamine H 1 , H 2 and H 3 Receptors on Enteric Ascending Synaptic Transmission in the Guinea Pig Ileum 1

The role of histamine H1-, H2and H3-receptors was studied on neural transmission in ascending excitatory pathways of the guinea pig ileum. A two-compartment (oral and anal compartments) bath was used: ascending neural pathways were activated by electrical stimulation in the anal compartment and the resulting contraction of the circular muscle in the oral compartment was recorded. Drugs were applied in the anal compartment and each agonist was evaluated in the presence of the antagonists of the other two receptors. In the presence of cimetidine (10 mM) and thioperamide (1 mM), histamine (0.03–3 mM) depressed the nerve-mediated contractions (5–70% inhibition, P ,.05–.01). The inhibitory effect of histamine was antagonized by mepyramine. At the higher concentrations (10 and 30 mM), histamine elicited contractions of the circular muscle in the oral compartment, and these were abolished by mepyramine (1 mM) and tetrodotoxin (0.6 mM). The H2 agonists dimaprit (30 and 100 mM) and amphamine (0.1–300 mM) produced small contractions of the circular muscle in the oral compartment. These contractile responses were abolished by tetrodotoxin (0.6 mM) and cimetidine (10 mM). The H3 agonist R-amethylhistamine (0.001–1 mM) inhibited (2–58%, P ,.05) the nerve-mediated contractions. This inhibitory effect was antagonized by the H3 antagonist thioperamide. These results indicate that 1) histamine, acting at H1 receptors, at lower concentrations depresses synaptic transmission, although at higher concentrations activates the enteric excitatory ascending pathway; 2) activation of H2 receptors by H2 agonists stimulates the enteric excitatory ascending pathways and 3) activation of H3 receptors inhibits synaptic transmission. Histamine is widely distributed within mammalian tissues in both neural and nonneural compartments and there is evidence that in the central nervous system, it has a role as primary transmitter or neuromodulator (Schwartz et al., 1991). However, histamine is contained in mast cells and basophils in the wall of the intestine (Burks, 1994) and there is evidence that when it is released during hypersensitivity reactions to allergens, it may mediate neural events (Wood, 1992). Three classes of histamine receptors, H1, H2 and H3 have been identified in vertebrates (Hill, 1990) and all three are present in the guinea pig small intestine (Leurs et al., 1991; Bertaccini and Coruzzi, 1995). Histamine contracts the longitudinal muscle in the guinea pig small intestine. These contractions are mediated by the H1 receptor subtype, because they can be antagonized by mepyramine (Zavecz and Yellin, 1982; Trzeciakowski, 1987) and are likely to be due to a direct action on the smooth muscle. There is ample evidence that histamine stimulates the enteric neurons. A tetrodotoxin-sensitive release of acetylcholine via H2 receptors and of tachykinins has been demonstrated (Barker and Ebersole, 1982; Rubinstein and Cohen, 1985). In addition H2 agonists have been shown to increase the amplitude of electrically evoked contractions of the longitudinal muscle (Zavecz and Yellin, 1982). Thus it is likely that histamine activates the longitudinal muscle excitatory motor neurons. Histamine also produces a tetrodotoxin sensitive contraction of the circular muscle in the guinea pig small intestine indicating that it stimulates excitatory motorneurons to the circular muscle (Harry, 1963). Histamine, acting via H1and H2-receptors produces slow depolarization of guinea pig myenteric neurons that is associated with increase in the input resistance, augmented excitability and repetitive spike discharge (Nemeth et al., 1984; Tamura and