Comparative assay of neuronal uptake and autoinhibitory feedback in guinea-pig and rat atria.

1. The roles of neuronal uptake and autoinhibitory feedback were studied in guinea-pig and rat isolated right atria. Tachycardia was used as a measure of noradrenaline concentration at the post-junctional beta-adrenoreceptors in response to electrical field stimulation, 1-16 pulses at 1 Hz, or to exogenous noradrenaline. 2. The EC50 values for noradrenaline concentration-response curves were similar (7.3, -log M) in the two species when neuronal uptake was inhibited by desipramine (DMI, 1 microM). In the absence of DMI, however, the EC50 values were different for the rat (7.0) and guinea-pig (6.3). 3. DMI (0.01-1 microM) caused a substantial increase in half-response time (t 1/2), an integrated measure of tachycardia, in the rat during field stimulation but only caused modest increases in the guinea-pig atria. Following pretreatment with the irreversible alpha 2-adrenoceptor antagonist benextramine, the t 1/2 values were substantially raised in guinea-pig atria with no further change to t 1/2 in the rat atria. 4. The existence of presynaptic inhibitory alpha 2-adrenoceptors in the rat was established using clonidine which caused parallel rightward shifts of field stimulation-tachycardia curves. 5. These results suggest that in the guinea-pig atria blockade of both autoinhibitory feedback and neuronal uptake cause a very large increase in tachycardia compared with blockade of either system alone. In rat atria the most important modulation is from neuronal uptake, which suggests that in this species autoinhibitory feedback is of little consequence.