Clonidine and presynaptic adrenoceptor theory

Abstract

1The effects of clonidine, a presumed selective presynaptic x2-adrenoceptor agonist or partial agonist, were examined in guinea-pig atria. 2 Split left atrial preparations were stimulated transmurally at 2Hz with 100 pulses of 0.5 ms duration and the efflux of 3H-transmitter determined. 3 Clonidine inhibited efflux at 3 x 10-8M to 3 x 10 7M by about 30%. Yohimbine, at a concentration (10-6M) which caused a 3 fold increase in the release of 3H-transmitter during field stimulation, did not alter the ability of clonidine to inhibit transmitter efflux. 4 At 10-6M clonidine alone had no significant effect on the stimulation-induced efflux of 3H-transmitter, but in the presence of yohimbine (10-'M), inhibited efflux by over 50%.5 The inhibitory effect of noradrenaline (10-6M) on 3H-transmitter efflux was antagonized by clonidine at 10-6M but not at 10-8M, although neither concentration of clonidine alone inhibited transmitter efflux. 6 The present findings indicate that the effects of clonidine on the efflux of noradrenaline from sympathetic nerves cannot be accommodated within the currently held view that the compound is an agonist or partial agonist on presynaptic M2-adrenoceptors. It appears that clonidine has multiple sites of action few of which are antagonized by a concentration of the prototypical presynaptic antagonist yohimbine, which enhances efflux 3 fold.

Inhibition of Adenylate Cyclase in Bovine Ciliary Process and Rabbit Iris Ciliary Body to Alpha2-Adrenergic Agonists

“…These data establish the oa-adrenergic selectivity of the lofexidine inhibitory effect. Alpha2-adrenoceptors are not only present on adrenergic nerve terminals as presynaptic autoreceptors, but are also found as postsynaptic receptors (18). Results obtained by Bausher et al, (8) and our previous observations that an intact sympathetic innervation to the eye was not required for cc2-adrenergic agonists to reduce IOP (19), suggest that oa-adrenoceptors, which mediate the results described above, may be postsynaptic.…”

Release of [3H]‐noradrenaline from the sympathetic nerves to bovine mesenteric lymphatic vessels and its modification by α‐agonists and antagonists

“…Thus both the non-selective a-antagonist phentolamine and the more selective a2-antagonists yohimbine and rauwolscine were effective in potentiating evoked release of 3H, while release was significantly reduced by clonidine, xylazine and noradrenaline itself. Both clonidine and xylazine are considered to be relatively selective a2-agonists (Langer, 1981), although some doubt has recently been expressed concerning the specificity of clonidine (Baker et al, 1984;Kalsner, 1985). Similarly, prazosin and phenylephrine were also effective in altering evoked release, but only at the lower of the two frequencies used.…”

Characterization of the Subtype of Presynaptic (α2-Adrenoceptors Modulating Noradrenaline Release in Cat and Bovine Cerebral Arteries

“…However, this effect was not observed in cat cerebral arteries in which clonidine acts as a full agonist. The partial a-agonist action o f clonidine, among other actions, has been reported (Kalsner 1985 ; Docherty 1989; McGrath et a1 1989).…”

“…However, in bovine cerebral arteries, the stimulated noradrenaline secretion was reduced by B-HT 920, but not by clonidine, even at high concentration, showing a lack of intrinsic activity in this tissue. Both the incapacity (Kalsner 1985;Kawasaki et a1 1989) and the ability of clonidine (Sakakibora et a1 1982;Gothert et a1 1984;Kalsner 1985;Ellis et a1 1990) and B-HT 920 (Gothert et a1 1984;Hentrich et a1 1986) to inhibit the stimulated [3H]noradrenaline release in different tissues, including blood vessels, have been reported; the potency of the latter agonist is greater than the former (Gothert et a1 1984;Hentrich et a1 1986;Balfagon & Marin 1989; Sanchez-Merino et a1 1990), as occurs in our vascular preparation. This major effect of B-HT 920 could be related to a greater selectivity and efficacy at the level of a2-adrenoceptors (Hammer et a1 1980;.…”