TY - JOUR
T1 - Pharmacological characterization of histamine receptors mediating cyclic AMP accumulation in the mouse vas deferens. Sensitivity to H1 and H2 receptor agonists and antagonists
AU - Vohra, M. M.
AU - Rautanen, P. K.
PY - 1982
Y1 - 1982
N2 - Histamine (10-6-10-2 M) caused a concentration-dependent increase in the accumulation of endogenous cyclic AMP in mouse vas deferens of about 3 times the basal level. This effect was mimicked by dimaprit and 4-methylhistamine, two known H2 receptor agonists, and, to a lesser extent, by 2-thiazolylethylamine, a relatively selective H1 receptor agonist. The slopes of the percentage of maximal increase in cyclic AMP accumulation versus log molar concentration curves for the H2 agonists differ significantly from that for histamine. The rank order and relative potencies of the tested H2 agonists were as follows: histamine (100%) > dimaprit (64%) > 4-methylhistamine (31%). The effect of 10-2 M (but not of 10-3 M) 2-thiazolylethylamine on cyclic AMP accumulation was markedly depressed in the presence of 1 μM propranolol. Cyclic AMP accumulation elicited by 10-3 M 2-thiazolylethylamine was significantly lower than that caused by histamine, indicating that the intrinsic activity of 2-thiazolylethylamine relative to histamine was considerably lower; therefore, its relative potency as an H2 agonist could not be defined. Stimulation of cyclic AMP accumulation caused by histamine was antagonized by cimetidine 3.5-140 μM), an H2 receptor antagonist, in a concentration-related manner, but not by mepyramine (0.1-1.0 μM), an H1 receptor antagonist. The slope of the Schild plot for cimetidine against histamine-induced cyclic AMP accumulation was not significantly different from unity, confirming that cimetidine causes a competitive inhibition of histamine response. The calculated pA2 value of cimetidine against histamine was 5.40. 2-Thiazolylethylamine-stimulated cyclic AMP accumulation was also antagonized by cimetidine (35 μM) but was unaffected by mepyramine (1.0 μM). On the basis of these findings, it is concluded that the stimulant effect of histamine and selective H1 and H2 receptor agonists on cyclic AMP accumulation in mouse vas deferens is mediated via activation of a histamine H2 receptor in the preparation. Although the potency profile of the various H2 agonists as determined in the present study is similar to that reported for typical H2 receptor-containing systems such as guinea pig atrium, the calculated pA2 value of cimetidine in mouse vas deferens is lower than that reported in guinea pig atrium. In this regard, 2-thiazolylethylamine seems to act as a partial agonist. Furthermore, the maximal increase in cyclic AMP accumulation elicited by 2-thiazolylethylamine, unlike that elicited by histamine, was significantly depressed by propranolol (1.0 μM), indicating that the effect of 2-thiazolyl-ethylamine at the highest concentration on cyclic AMP accumulation might in part be secondary to the release of norepinephrine from the endogenous stores.
AB - Histamine (10-6-10-2 M) caused a concentration-dependent increase in the accumulation of endogenous cyclic AMP in mouse vas deferens of about 3 times the basal level. This effect was mimicked by dimaprit and 4-methylhistamine, two known H2 receptor agonists, and, to a lesser extent, by 2-thiazolylethylamine, a relatively selective H1 receptor agonist. The slopes of the percentage of maximal increase in cyclic AMP accumulation versus log molar concentration curves for the H2 agonists differ significantly from that for histamine. The rank order and relative potencies of the tested H2 agonists were as follows: histamine (100%) > dimaprit (64%) > 4-methylhistamine (31%). The effect of 10-2 M (but not of 10-3 M) 2-thiazolylethylamine on cyclic AMP accumulation was markedly depressed in the presence of 1 μM propranolol. Cyclic AMP accumulation elicited by 10-3 M 2-thiazolylethylamine was significantly lower than that caused by histamine, indicating that the intrinsic activity of 2-thiazolylethylamine relative to histamine was considerably lower; therefore, its relative potency as an H2 agonist could not be defined. Stimulation of cyclic AMP accumulation caused by histamine was antagonized by cimetidine 3.5-140 μM), an H2 receptor antagonist, in a concentration-related manner, but not by mepyramine (0.1-1.0 μM), an H1 receptor antagonist. The slope of the Schild plot for cimetidine against histamine-induced cyclic AMP accumulation was not significantly different from unity, confirming that cimetidine causes a competitive inhibition of histamine response. The calculated pA2 value of cimetidine against histamine was 5.40. 2-Thiazolylethylamine-stimulated cyclic AMP accumulation was also antagonized by cimetidine (35 μM) but was unaffected by mepyramine (1.0 μM). On the basis of these findings, it is concluded that the stimulant effect of histamine and selective H1 and H2 receptor agonists on cyclic AMP accumulation in mouse vas deferens is mediated via activation of a histamine H2 receptor in the preparation. Although the potency profile of the various H2 agonists as determined in the present study is similar to that reported for typical H2 receptor-containing systems such as guinea pig atrium, the calculated pA2 value of cimetidine in mouse vas deferens is lower than that reported in guinea pig atrium. In this regard, 2-thiazolylethylamine seems to act as a partial agonist. Furthermore, the maximal increase in cyclic AMP accumulation elicited by 2-thiazolylethylamine, unlike that elicited by histamine, was significantly depressed by propranolol (1.0 μM), indicating that the effect of 2-thiazolyl-ethylamine at the highest concentration on cyclic AMP accumulation might in part be secondary to the release of norepinephrine from the endogenous stores.
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M3 - Article
C2 - 6130470
AN - SCOPUS:0020444674
SN - 0026-895X
VL - 22
SP - 602
EP - 608
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 3
ER -