Signal transducing mechanisms coupled to histamine H3 receptors and alpha-2 adrenoceptors in the guinea pig duodenum: possible involvement of N-type Ca++ channels

The signaling pathways following histamine H, receptor activation by (R)alpha-methylhistamine (MHA) have been examined in the isolated guinea pig duodenum, in which selective excitation of cholinergic neurons was induced by electrical field stimulation (EFS). The effect of MHA on electrically evoked contractions was compared with that induced by the alpha-2 adrenoceptor agonist clonidine (CLON). The inhibitory effect of MHA on EFS-induced contractions was significantly reduced by increasing Ca++ content in the nutrient fluid from 2.5 to 5 mM and by the Ca++ agonist Bay K 8644 (10(-8) M); conversely, the effect of MHA was significantly enhanced by lowering Ca++ content in the medium (from 2.5 to 1.25 mM) and by the N-type Ca++ channel blocker omega-conotoxin (CTX) (10(-8) M). The L-type Ca++ channel blocker nifedipine (NIF) (10(-7) M) did not modify the effect of MHA, although it significantly reduced both EFS- and exogenous acetylcholine (ACH)-induced contractions. Similar to MHA, the inhibitory effect elicited by CLON was enhanced by low external Ca++ and by CTX, but it was slightly affected by the compound Bay K 8644 (10(-7) M) or by high Ca++ concentrations (5 mM) and it was unaffected by NIF. 4-Aminopyridine (4-AP) (10(-4) M) reduced the effects of both MHA and CLON. The present data indicate that histamine H-3 receptor activation in electrically stimulated duodenum is closely associated with a restriction of Ca++ access into the nerve terminal through N-type Ca++ channels; the same mechanism appears to be responsible for the inhibitory effect induced by alpha-2 adrenoceptor activation. Slight differences in the reversing effect of compound Bay K 8644 or of high Ca++ concentrations indicate that the two receptor systems are influenced differently by Ca++ availability at presynaptic nerve ending membranes.