Comparison of the effects of clonidine on pre-and postsynaptic adrenoceptors in the rabbit pulmonary artery
- 79 Downloads
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.
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.
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.
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.
Key wordsRabbit Pulmonary Artery Clonidine α-Adrenoceptors Noradrenaline Release Vasoconstriction
Unable to display preview. Download preview PDF.
- Ariëns, E. J. (ed.): Molecular pharmacology. The mode of action of biologically active compounds, Vol. I. New York-London: Academic Press 1964Google Scholar
- Bevan, J. A.: Some characteristics of the isolated sympathetic nerve-pulmonary artery preperation of the rabbit. J. Pharmacol. exp. Ther. 137, 213–218 (1962)Google Scholar
- Constantine, J. W., McShane, W. K.: Analysis of the cardiovascular effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (catapres). Europ. J. Pharmacol. 4, 109–123 (1968)Google Scholar
- Dubocovich, M. L., Langer, S. Z.: Negative feed-back regulation of noradrenaline release by nerve stimulation in the perfused cat's spleen: Differences in potency of phenoxybenzamine in blocking the pre-and post-synaptic adrenergic receptors. J. Physiol. (Lond.) 237, 505–519 (1974)Google Scholar
- Farnebo, L. O., Hamberger, B.: Catecholamine release and receptors in brain slices. In: E. Usdin and S. S. Snyder (eds.): Frontiers in catecholamine research, pp. 589–593. New York-Toronto-Oxford-Sydney-Braunschweig: Pergamon Press 1973Google Scholar
- Folkow, B.: Nervous control of the blood vessels. Physiol. Rev. 35, 629–663 (1955)Google Scholar
- Furchgott, R. F.: The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory. In: H. Blaschko and E. Muscholl (eds.): Catecholamines. Handbook of experimental pharmacology Vol. XXXIII, pp. 283–335. Berlin-Heidelberg-New York: Springer 1972Google Scholar
- Häggendal, J.: Regulation of catecholamine release. In: E. Usdin and S. S. Snyder (eds.): Frontiers in catecholamine research, pp. 531–535. New York-Toronto-Oxford-Syndey-Braunschweig: Pergamon Press 1973Google Scholar
- Hughes, J.: Inhibition of noradrenaline release by lysergic acid diethylamide. Brit. J. Pharmacol. 49, 706–708 (1973)Google Scholar
- Kirpekar, S. M., Furchgott, R. F., Wakade, A. R., Prat, J. C.: Inhibition by sympathomimetic amines of the release of norepinephrine evoked by nerve stimulation in the cat spleen. J. Pharmacol. exp. Ther. 187, 529–538 (1973)Google Scholar
- Langer, S. Z.: The regulation of transmitter release elicited by nerve stimulation through a presynaptic feed-back mechanism. In: E. Usdin and S. S. Snyder (eds.): Frontiers in catecholamine research, pp. 543–549. New York-Toronto-Oxford-Sydney-Braunschweig: Pergamon Press 1973Google Scholar
- Nedergaard, O. A., Schrold, J.: Release of 3H-noradrenaline from incubated and superfused rabbit pulmonary artery. Acta physiol. scand. 89, 296–305 (1973)Google Scholar
- Salt, P. J.: Inhibition of noradrenaline uptake2 in the isolated rat heart by steroids, clonidine and methoxylated phenylethylamines. Europ. J. Pharmacol. 20, 329–340 (1972)Google Scholar
- Starke, K.: Regulation of catecholamine release: α-Receptor mediated feed-back control in peripheral and central neurones. In: E. Usdin and S. S. Snyder (eds.): Frontiers in catecholamine research, pp. 561–565. New York-Toronto-Oxford-Sydney-Braunschweig: Pergamon Press 1973Google Scholar
- Starke, K., Altmann, K. P.: Inhbition of adrenergic neurotransmission by clonidine: An action on prejunctional α-receptors. Neuropharmacology 12, 339–347 (1973)Google Scholar
- Starke, K., Montel, H.: Lokale Rückkopplungssteuerungen der Noradrenalinfreisetzung als mögliche Angriffspunkte antihypertensiver Pharmaka. Therapiewoche 23, 4263–4264 (1973)Google Scholar
- Starke, K., Montel, H.: Local feed-back mechanisms controlling the release of noradrenaline: Possible sites of action of antihypertensive drugs. In: A. Distler and H. P. Wolff (eds.): Hypertension, pp. 218–228. Stuttgart: Thieme 1974aGoogle Scholar
- Starke, K., Montel, H.: Influence of drugs with affinity for α-adrenoceptors on noradrenaline release by potassium, tyramine and dimethylphenylpiperazinium. Europ. J. Pharmacol. 27, 273–280 (1974b)Google Scholar
- Starke, K., Wagner, J., Schümann, H. J.: Adrenergic neuron blockade by clonidine: Comaprison with guanethidine and local anesthetics. Arch. int. Pharmacodyn. 195, 291–308 (1972)Google Scholar
- Stjärne, L.: Mechanisms of catecholamine secretion. In: E. Usdin and S. S. Snyder (eds.): Frontiers in catecholamine research, pp. 491–496. New York-Toronto-Oxford-Sydney-Braunschweig: Pergamon Press 1973Google Scholar
- Su, C., Bevan, J. A.: The release of H3-norepinephrine in arterial strips studied by the technique of superfusion and transmural stimulation. J. Pharmacol. exp. Ther. 172, 62–68 (1970)Google Scholar