Clonidine and presynaptic adrenoceptor theory

1 The effects of clonidine, a presumed selective presynaptic α 2 ‐adrenoceptor agonist or partial agonist, were examined in guinea‐pig atria. 2 Split left atrial preparations were stimulated transmurally at 2 Hz with 100 pulses of 0.5 ms duration and the efflux of 3 H‐transmitter determined. 3 Clonidine inhibited efflux at 3 × 10 −8 M to 3 × 10 −7 M by about 30%. Yohimbine, at a concentration (10 −6 M) which caused a 3 fold increase in the release of 3 H‐transmitter during field stimulation, did not alter the ability of clonidine to inhibit transmitter efflux. 4 At 10 −6 M clonidine alone had no significant effect on the stimulation‐induced efflux of 3 H‐transmitter, but in the presence of yohimbine (10 −6 M), inhibited efflux by over 50%. 5 The inhibitory effect of noradrenaline (10 −6 M) on 3 H‐transmitter efflux was antagonized by clonidine at 10 −6 M but not at 10 −8 M, 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 α 2 ‐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.