An Inhibitory Role for Noradrenaline in the Mouse Vas Deferens

Abstract

1 Noradrenaline (0.1-3.0 gM) inhibited the twitch responses to single pulse field stimulation of the isolated vas deferens of the mouse. The higher concentrations of noradrenaline (ca. 0.3-3.0 gM) were required to make the tissue contract. 2 Phentolamine (10 ,UM) abolished the contractor response to higher concentrations of noradrenaline and antagonized the inhibitory effect of lower concentrations on the twitch response. 3 Propranolol (10IM) potentiated both the contractor and the inhibitory effect ofnoradrenaline on the twitch response.4 Isoprenaline (0.1-3.0 uM) and salbutamol (1.0-3.0 gM) both inhibited the twitch response. Their effects were antagonized by propranolol (10 jiM), but not by practolol (10 jiM). SThe effects of uptakel and uptake2 blocking agents were determined. Cocaine (10 gM) reduced the size of the twitch response in 2 out of 4 experiments. Imipramine (0.18 ,uM) also reduced the size of the twitch, as did oestradiol (3.7 gM) and a combination of cocaine and oestradiol.6 Contractor responses to exogenous noradrenaline showed tachyphylaxis, but when this was not very marked, the response could be shown to be potentiated by uptake blocking agents. 7 The inhibitory effect of noradrenaline on the twitch response was greatly potentiated by cocaine (10 gM) and much less so by oestradiol (3.7 gM).8 It is concluded that the transmitter responsible for the twitch response is either an unknown substance released from the sympathetic neurone, or noradrenaline acting upon a receptor with none of the characteristics of known a-or fi-adrenoceptors. In either case, noradrenaline can inhibit the output, probably by stimulation of presynaptic a-adrenoceptors.

Effects of Metoclopramide and Isoprenaline in the Rat Vas Deferens; Interactions With Α‐adrenoceptors

“…These propranolol-resistant effects of isoprenaline were antagonized by metoclopramide and phentolamine and the pA2 values obtained (5.3 and 7.7) were identical to those obtained when clonidine was used as the agonist, indicating that isoprenaline (>0.5 gM) may activate presynaptic a-adrenoceptors. Interestingly, isoprenaline (0.5 to 1 riM) hyperpolarizes rat sympathetic ganglia prep-arations by an action which is antagonized by phentolamine but not by propranolol (Brown & Caulfield, 1979), an effect on 'a2'-adrenoceptors (Berthelson & Pettinger, 1977;Langer, 1977 (Vizi et al, 1973;Jenkins et al, 1977). Metoclopramide, by acting as an antagonist at these receptors, would prevent the inhibition, thereby augmenting the contraction.…”

“…Although the nature of the neurotransmitter(s) in the vas deferens is unresolved (Ambache & Zar, 1971;Swedin, 1971;Jenkins, Marshall & Nasmyth, 1977;McGrath, 1978), it is believed that the inhibitory effects of clonidine on the responses of rat vas deferens to field stimulation result from inhibition of neurotransmitter release. Thus, the degree of inhibition is dependent upon pulse frequency and upon the Ca2+ concentration of the medium (Drew, 1978) and clonidine inhibits noradrenaline release from the mouse vas deferens following low frequency stimulation (Marshall, Nasmyth & Shepperson, 1977).…”

The EFFECTS OF 4‐AMINOPYRIDINE ON THE ISOLATED VAS DEFERENS AND ITS EFFECTS ON THE INHIBITORY PROPERTIES OF ADENOSINE, MORPHINE, NORADRENALINE AND Γ‐AMINOBUTYRIC ACID

“…These agonists have in common that their site of action in depressing the size of the electricallyevoked twitch is presynaptic (Henderson et al, 1972;Henderson & Hughes, 1976;Clanachan, Johns & Paton, 1977;Jenkins et al, 1977;Marshall, Nasmyth, Nicholl & Shepperson, 1978, Bowery et al, 1979Stone, 1981). Amyl nitrite however, is known to have direct relaxant effects on smooth muscle, and phentolamine reduces twitch height by a postsynaptic blockade of neurally released noradrenaline (Henderson et al, 1972;Jones & Spriggs, 1975).…”

“…This possibility has now been investigated more directly in the isolated vas deferens of the mouse, in which adenosine depresses transmitter release. Adenosine has been compared with morphine, noradrenaline and y-aminobutyric acid (GABA) which also depress transmitter release in the mouse vas (Henderson, Hughes & Kosterlitz, 1972;Jenkins, Marshall & Nasmyth, 1977;Bowery, Doble, Hill, Hudson, Shaw & Turnbull, 1979) and wth nitrites, thought to relax smooth muscle directly, and phentolamine which blocks transmitter action postsynaptically (Jones & Spriggs, 1975).…”

Postjunctional inhibition of contractor responses in the mouse vas deferens by rat and human calcitonin gene‐related peptides (CGRP)

“…Therefore, the mouse vas deferens has been used as a model system as the twitch response can be inhibited in a variety of ways by drugs influencing adrenergic mechanisms. For example, responses of the mouse vas deferens to field stimulation can be inhibited by indirect acting sympathomimetics (Marshall et al, 1978b), neuronal uptake blocking drugs (Jenkins et al, 1977), 2-or Padrenoceptor agonists (Marshall et al, 1978a;Jenkins et al, 1977) and adrenergic neurone blocking agents (Marshall et al, 1980). All these possible mechanisms of action for CGRP have been eliminated as the peptide did not alter either the uptake of [3H]-noradrenaline, or its basal or stimulated release and the twitch inhibition was not antagonized by the 2-adrenoceptor antagonist idazoxan or by propranolol.…”