Desensitization by Noradrenaline of Responses to Stimulation of Pre‐ and Postsynaptic Adrenoceptors

Abstract

The effect of exposing isolated preparations of rat aortic strip, rat atria and mouse vas deferens to perfusions of Krebs solution containing various concentrations of noradrenaline on their sensitivity to the drug has been determined. The responses evoked by stimulation of postsynaptic adrenoceptors in all the tissues and presynaptic α‐adrenoceptors in the mouse vas deferens were diminished by the perfusion of noradrenaline through the organ bath for 30 min. The concentration of noradrenaline required to produce desensitization was higher in the mouse vas deferens than in the other tissues and more was required to desensitize the chronotropic responses than the inotropic responses in rat isolated atria. The inclusion of cocaine (10−5m) in the bathing solution to block uptake1 increased the sensitivity of most tissues to noradrenaline. With the possible exception of the response to stimulation of presynaptic receptors in the mouse vas deferens, desensitization was somewhat increased in its presence. When uptake2 was blocked by oestradiol (10−5m), it was not possible to desensitize the contractor responses of the aortic strip and vas deferens to exogenous noradrenaline, nor the inotropic response of the atria to the drug. However, oestradiol failed to block the desensitization of chronotropic responses and responses to stimulation of presynaptic receptors in the vas deferens. Blockade of monoamine oxidase (MAO) with iproniazid (7.2 × 10−4m) or with pargyline (5 × 10−4 m) did not affect the desensitization process in the aortic strip. Blockade of catechol‐O‐methyltransferase (COMT) with U‐0521 (5.3 × 10−5m) greatly increased desensitization in the aortic strip and desensitization of inotropic responses in the atria. It had no effect on desensitization of chronotropic responses. Its effect on responses in the mouse vas deferens was not determined. The perfusion of methoxamine at concentrations about 1000 times higher than those of noradrenaline also produced desensitization in the aortic strip. The desensitization of presynaptic receptors in the mouse vas deferens was shown to be specific and that of the responses to postsynaptic receptor stimulation to be non‐specific. It is concluded that responses to adrenoceptor stimulation may be desensitized by accumulation of noradrenaline inside the cells bearing the receptors and that the desensitization is caused by noradrenaline itself not by a metabolite. Desensitization may also be caused without accumulation of noradrenaline in uptake2 and for some receptors these may not be alternative mechanisms.

Noradrenaline desensitizes β‐ but not α‐adrenoceptor mediated cardiac responses in vitro

“…Noradrenaline is an endogenous agonist at both aand P-adrenoceptors and might be expected to desensitize cardiac tissues to this a-adrenoceptor agonist. Noradrenaline in vitro desensitizes the postjunctional a-adrenoceptor-mediated responses of vas deferens from guinea-pigs (Takeyasu et al, 1982) and mice (Ball et al, 1982). In addition, elevated plasma noradrenaline levels reduce the density of a-adrenoceptor binding sites in rat renal cortex and lung (Snavely et al, 1983).…”

“…In addition, elevated plasma noradrenaline levels reduce the density of a-adrenoceptor binding sites in rat renal cortex and lung (Snavely et al, 1983). In the cardiovascular system, noradrenaline has also been shown to desensitize the a-adrenoceptor responses of the mouse aorta (Ball et al, 1982). Although vascular a,-adrenoceptor responses in vivo are not affected by elevating plasma noradrenaline levels (Deighton, Hamilton, Howie & Reid, 1989), this may not reflect the effects of altered synaptic noradrenaline concentrations.…”

Activation and desensitization of presynaptic α2‐adrenoceptors after inhibition of neuronal uptake by antidepressant drugs in the rat vas deferens

“…In this context, desensitization of presynaptic M2-adrenoceptors after the in vitro exposure to NA has been demonstrated in Crews & Smith (1980). various functional preparations (Langer & Dubocovich, 1977;Ball et al, 1982).…”

“…Modified from Crews & Smith (1980). various functional preparations (Langer & Dubocovich, 1977;Ball et al, 1982).…”

Functional analysis of desensitization of the β‐adrenoceptor signalling pathway in rat cardiac tissues following chronic isoprenaline infusion

“…We therefore examined β‐AR signalling in the heart following infusion of rats with isoprenaline (400 μg kg −1 h −1 ) or vehicle for 2 weeks. Since the extent of β‐AR desensitization differs between atrial and ventricular preparations ( Chess‐Williams, 1993 ; Butterfield & Chess‐Williams, 1993 ) and between inotropic and chronotropic responses ( Kaumann & Birnbaumer, 1976 ; Ball et al ., 1982 ; Herepath & Broadley, 1990 ; Butterfield & Chess‐Williams, 1993 ; Russell et al ., 1994 ), we examined chronotropic responses of spontaneously beating right atria and the inotropic responses of electrically driven left atria and left and right ventricular papillary muscles to agents acting at several points of the β‐AR‐cyclic AMP signalling pathway.…”