Summary
The influence of clonidine on presynaptic α-adrenoceptors (mediating inhibition of noradrenaline release) and postsynaptic α-adrenoceptors (mediating smooth muscle contraction) was compared in superfused strips of the rabbit pulmonary artery.
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1.
On smooth muscle α-receptors, clonidine acted as a partial agonist. Its intrinsic activity was 0.32 of that of noradrenaline, the EC50 3.8×10−7 M, and the pA2 value of phentolamine against clonidine 7.56.
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2.
The spontaneous outflow of tritium from arteries preincubated with 3H-noradrenaline was not changed by clonidine and phentolamine. Clonidine decreased, and phentolamine increased, tritium overflow evoked by transmural sympathetic nerve stimulation. The inhibition caused by clonidine was greater at a low (2 Hz) than at a high stimulation frequency (8 Hz). Phentolamine shifted the dose-response curve for clonidine to the right. The presence of noradrenaline in the biophase during stimulation complicated the calculation of drug-presynaptic receptor interaction constants; however, evidence is presented that the intrinsic activity of clonidine was similar to that of noradrenaline, its EC50 below 3.7×10−8 M, and the pA2 value of phentolamine against clonidine above 6.27.
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3.
The combined contractile effect of low concentrations of clonidine (3×10−9 to 10−7 M) and of low frequencies of sympathetic nerve stimulation (0.25–2 Hz) was smaller than the effect of stimulation alone: the combined effect of low concentrations and high frequencies (4–32 Hz) did not differ from the effect of stimulation alone. The combined effect of 3×10−6 M clonidine and low frequencies of stimulation was greater, that of 3×10−6 M clonidine and high frequencies smaller than the effect of stimulation alone.
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4.
In the rabbit pulmonary artery, the apparent affinity of clonidine to presynaptic α-receptors is at least ten times higher than its apparent affinity to postsynaptic α-receptors, probably because of differences in pre-and postsynaptic binding sites. When impulses reach noradrenergic nerve endings at physiological rates, low concentrations of clonidine, due to their preferential presynaptic effect, reduce overall postsynaptic adrenoceptor activation; the consequence is α-sympathomimetic inhibition of neurogenic vasoconstriction.
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Starke, K., Montel, H., Gayk, W. et al. Comparison of the effects of clonidine on pre-and postsynaptic adrenoceptors in the rabbit pulmonary artery. Naunyn-Schmiedeberg's Arch. Pharmacol. 285, 133–150 (1974). https://doi.org/10.1007/BF00501149
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DOI: https://doi.org/10.1007/BF00501149