A postsynaptic inhibitory histamine H2-receptor in the mouse isolated vas deferens

Abstract

The effect of histamine on adrenergic neurotransmission in the mouse isolated vas deferens preparation was investigated. Concentrations of histamine ranging from 0.2 to 650 microM depressed, in a dose-related manner, not only the contractile response elicited by field stimulation but also the response caused by the addition of exogenous noradrenaline and acetylcholine. However, the release of [3H]-NA evoked by field stimulation or by high K+ remained unchanged in the presence of these concentrations of histamine. The inhibitory effect of histamine on the contractile responses caused by various stimuli was reduced or completely antagonized by cimetidine, a histamine H2-receptor antagonist but not by mepyramine, a conventional antihistamine. The inhibitory effect of histamine was found to be inversely proportional to both the Ca2+ concentration in the bathing medium and to the frequency of field stimulation. Further, the inhibitory effect of histamine was markedly reduced when Mg2+ was omitted from the bathing medium. It is concluded that the mouse vas deferens preparation contains a post-junctional inhibitory H2-receptor. The stimulation of H2-receptors by histamine inhibits the contractile response of the vas deferens, possibly by decreasing the availability of Ca2+ required for contraction by depressing the influx of Ca2+.

Genetic heterogeneity of histamine H2‐receptors in the mouse vas deferens

“…Secondly, it is possible that in some strains but not in others, pre-as well as postsynaptic H2-receptors are present which may exert an inhibitory effect by reducing neurotransmitter output, in the manner of clonidine (Starke et al, 1975) or morphine (Henderson & Hughes, 1976). Extracellular calcium concentration is clearly a potent modifier of histamine sensitivity, as found here, and previously reported by Vohra (1979). However, this variable did not affect the strain distribution patterns of the antagonist potency of cimetidine, clearly implicating the H2-receptor itself as the site of genetic modification.…”

“…First, the evidence currently available would suggest that histamine exerts at least some of its inhibitory effects on the mouse vas deferens by restricting calcium influx into postsynaptic tissue (Marshall, 1978;Vohra, 1979); thus, it is possible that strain differences in histamine sensitivity could arise through t : differences in either calcium utilisation by smooth muscle or in membrane components other than the H2-receptor responsible for modifying rates of calcium entry. Secondly, it is possible that in some strains but not in others, pre-as well as postsynaptic H2-receptors are present which may exert an inhibitory effect by reducing neurotransmitter output, in the manner of clonidine (Starke et al, 1975) or morphine (Henderson & Hughes, 1976).…”

“…Such studies as are available in drugs display a wide variation, both between and the literature would indicate that genetic variability within species in their beneficial pharmacological in the characteristics of receptor populations may be effects, and also in their propensity to cause adverse considerable. The investigations of Henderson & reactions. There is considerable evidence that some Hughes (1976), Waterfield et al (1978) and Szerb & of this variability can be attributed to genetic factors Vohra (1979) have produced convincing evidence operating at the level of pharmacokinetic (i.e. 'prethat the sensitivity of mouse vas deferens to both receptor') events (Idle & Smith, 1979; Al-Dabbagh endogenous and exogenous opiate agonists displays et al., 1981), however, relatively little attention has marked inter-strain variability.…”

“…This experimental system was selected as a model for the study of the influence of genetic factors on receptor function on a number of criteria. The mouse vas deferens appears to be unique in displaying only H2-receptormediated effects to histamine (Marshall, 1978;Vohra, 1979), vasa deferentia from other species (rat, rabbit and guinea-pig) all display varying proportions of mutually antagonistic H1-and H2-receptor mediated effects (Vohra, 1981). The mouse tissue thus provides an opportunity to examine the histamine H2-receptor under conditions relatively free of other variables.…”

“…The mouse tissue thus provides an opportunity to examine the histamine H2-receptor under conditions relatively free of other variables. However, the response to histamine is markedly influenced by extracellular calcium concentration (Vohra, 1979), and thus a study of the response to histamine in isolation could give rise to spurious 'receptor' differences actually due to, for example, differences in the utilization of calcium by smooth muscle. A full characterization of the histamine H2-receptor-mediated response thus requires the determination of parameters related to receptor affinity for both an agonist and an antagonist.…”