Abstract
The effects of clonidine, a presumed selective presynaptic alpha 2-adrenoceptor agonist or partial agonist, were examined in guinea-pig atria. Split left atrial preparations were stimulated transmurally at 2 Hz with 100 pulses of 0.5 ms duration and the efflux of 3H-transmitter determined. Clonidine inhibited efflux at 3 X 10(-8)M to 3 X 10(-7)M by about 30%. Yohimbine, at a concentration (10(-6)M) 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. At 10(-6)M clonidine alone had no significant effect on the stimulation-induced efflux of 3H-transmitter, but in the presence of yohimbine (10(-6)M), inhibited efflux by over 50%. The inhibitory effect of noradrenaline (10(-6)M) on 3H-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. 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 alpha 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.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Baker D. J., Drew G. M., Hilditch A. Presynaptic alpha-adrenoceptors: do exogenous and neuronally released noradrenaline act at different sites? Br J Pharmacol. 1984 Mar;81(3):457–464. doi: 10.1111/j.1476-5381.1984.tb10098.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Furchgott R. F., Garcia P. S., Wakade A. R., Cervoni P. Interactions of bretylium and other drugs on guinea-pig atria: evidence for inhibition of neuronal monoamine oxidase by bretylium. J Pharmacol Exp Ther. 1971 Nov;179(2):171–185. [PubMed] [Google Scholar]
- Kalsner S. Evidence against the unitary hypothesis of agonist and antagonist action at presynaptic adrenoceptors. Br J Pharmacol. 1982 Oct;77(2):375–380. doi: 10.1111/j.1476-5381.1982.tb09308.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kalsner S., Quillan M. A hypothesis to explain the presynaptic effects of adrenoceptor antagonists. Br J Pharmacol. 1984 Jun;82(2):515–522. doi: 10.1111/j.1476-5381.1984.tb10788.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kalsner S. Single pulse stimulation of guinea-pig vas deferens and the presynaptic receptor hypothesis. Br J Pharmacol. 1979 Jun;66(2):343–349. doi: 10.1111/j.1476-5381.1979.tb13686.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kalsner S., Suleiman M., Dobson R. E. Adrenergic presynaptic recpetors: an overextended hypothesis? J Pharm Pharmacol. 1980 Apr;32(4):290–292. doi: 10.1111/j.2042-7158.1980.tb12914.x. [DOI] [PubMed] [Google Scholar]
- Kalsner S. Yohimbine and prolongation of stimulation pulse duration alter similarly 3H-transmitter efflux in heart: an alternative to the negative feedback hypothesis. Br J Pharmacol. 1983 Aug;79(4):985–992. doi: 10.1111/j.1476-5381.1983.tb10545.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Medgett I. C., McCulloch M. W., Rand M. J. Partial agonist of clonidine on prejunctional and postjunctional alpha-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol. 1978 Oct;304(3):215–221. doi: 10.1007/BF00507961. [DOI] [PubMed] [Google Scholar]
- Stjärne L. Clonidine enhances the secretion of sympathetic neurotransmitter from isolated guineq-pig tissues. Acta Physiol Scand. 1975 Jan;93(1):142–144. doi: 10.1111/j.1748-1716.1975.tb05801.x. [DOI] [PubMed] [Google Scholar]
- Stone T. W., Taylor D. A. Antagonism by clonidine of neuronal depressant responses to adenosine, adenosine-5'-monophosphate and adenosine triphosphate. Br J Pharmacol. 1978 Nov;64(3):369–374. doi: 10.1111/j.1476-5381.1978.tb08659.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sullivan A. T., Drew G. M. Pharmacological characterisation of pre- and postsynaptic alpha-adrenoceptors in dog saphenous vein. Naunyn Schmiedebergs Arch Pharmacol. 1980 Nov;314(3):249–258. doi: 10.1007/BF00498546. [DOI] [PubMed] [Google Scholar]