Summary
The possible involvement of cardiac presynaptic α2-adrenoceptors in the acute negative chronotropic effect of intravenous clonidine and four selected analogues was tested in pentobarbitone-anaesthetized normotensive rats by establishing the following parameters: 1) the peripheral presynaptic activity (inhibition of tachycardia to stimulation of the spinal cord in pithed rats); 2) central hypotensive potency in intact rats (decrease in mean arterial pressure); 3) overall bradycardiac activity in intact rats (decrease in cardiac frequency); 4) sympathetic bradycardia in bilaterally vagotomized rat; and 5) vagal bradycardia in β-blocked rats. The lipophilicity of the imidazolidines (log P′) was measure in the octanol/buffer (pH=7.4) reference system at 37°C. Central hypotensive activity as well as vagal bradycardiac potency correlated with the ability to penetrate the central nervous system, as indicated by the overall lipophilic behavior (log P′) of the compounds. In contrast, brain penetration was not a prerequisite for the provocation of bradycardia in bilaterally vagotomized rats. This sympathetic bradycardia resembled peripheral presynaptic inhibition. The hydrophilic — poor brain-penetrating — substances already induced maximal sympathetic bradycardia at doses which did not induce hypotension or vagal bradycardia. The lipophilic drugs, however, only showed a preferentially sympathetic bradycardiac effect over vagal bradycardia at low doses. In intact pentobarbitone-anaesthetized rats, the log dose-bradycardiac response curves of the hydrophilic imidazolidines displayed a bisigmoidal character in contrast to their lipophlic analogues, i.e. at the lower dose-range of the hydrophilic drugs, bradycardia in intact rats resembled peripheral presynaptic inhibition, whereas a contribution of increased vagal activity only was significant after maximal sympathoinhibition was achieved. These data provide evidence for the view that the bradycardiac action of clonidine in pentobarbitone-anaesthetized normotensive rats is due, at least in part, to the functional role of cardiac presynaptic α2-adrenoceptors. The stimulation of these receptors will inhibit the sympathetic neurotransmission in the heart.
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References
Armstrong LM, Boura ALA (1973) Effects of clonidine and guanethidine on peripheral sympathetic nerve function in the pithed rat. Br J Pharmacol 47:850–852
Armstrong JM, Cavero I, Lefèvre-Borg F (1980) Some agents that stimulate presynaptic α2-adrenoceptors produce bradycardia in pentobarbitone anaesthetized rats by an action on peripheral cardiac sympathetic nerves. Br J Pharmacol 70:169P
Armstrong JM, Cavero I, Lefèvre-Borg F (1981) Comparison of the bradycardia produced by oxymetazoline and clonidine in urethane and pentobarbitone anaesthetized rats. Br J Pharmacol 72:107P-108P
Berthelsen S, Pettinger WA (1977) A functional basis for classification of α-adrenergic receptors. Life Sci 21:595–606
Cavero I, Dennis T, Levèvre-Borg F, Perrot P, Roach AG, Scatton B (1979) Effect of clonidine, prazosin and phentolamine on heart rate and coronary sinus catecholamine concentration during cardioaccelerator nerve stimulation in spinal dogs. Br J Pharmacol 68:321–332
Cavero I, Levèvre-Borg F, Roach AG (1977) Differential effects of prazosin on pre- and postsynaptic α-adrenoceptors in the rat and dog. Br J Pharmacol 61:469P
Docherty JR, McGrath JC (1979a) An analysis of some factors influencing α-adrenoceptor feed-back at the sympathetic junction in the rat heart. Br J Pharmacol 66:55–63
Docherty JR, McGrath JC (1979b) Inhibition of sympathetic transmission in the rat heart by clonidine: The roles of stimulation frequency, endogenous feedback and noradrenaline re-uptake. Naunyn Schmiedeberg's Arch Pharmacol 309:225–233
Doxey JC, Everitt J (1977) Inhibitory effects of clonidine on responses to sympathetic nerve stimulation in the pithed rat. Br J Pharmacol 61:559–566
Doxey JC, Hersom AS (1980) The relationship between the selectivity of agonists for presynaptic and their cardiovascular responses in the anaesthetized rat and their cardiovascular responses in the anaesthetized rat. Br J Pharmacol 70:171P-172P
Drew GM (1976) Effects of α-adrenoceptor agonists and antagonists on pre-and postsynaptically located α-adrenoceptors. Eur J Pharmacol 36:313–320
Hoefke W, Kobinger W, Walland A (1975) Relationship between activity and structure in derivatives of clonidine. Arzneim Forsch 25:786–793
Kobinger W (1978) Central α-adrenergic systems as targets for hypotensive drugs. Rev Physiol Biochem Pharmacol 81:39–100
Kobinger W, Pichler L (1975) Investigation into some imidazoline compounds with respect to peripheral α-adrenoceptor, stimulation and depression of cardiovascular centres. Naunyn Schmiedeberg's Arch Pharmacol 291:175–191
Kobinger W, Pichler L (1980) Relationship between central sympathoin-hibitory and peripheral pre- and postsynaptic α-adrenoceptors as evaluated by different clonidine-like, substances in rats. Naunyn Schmiedeberg's Arch Pharmacol 315:21–27
KobingerW, Walland A (1971) Involvement of adrenergic receptors in central vagus activity. Eur J Pharmacol 16:120–122
Kobinger W, Walland A (1972a) Evidence for a central activation of a vagal cardiodepressor reflex by clonidine. Eur J Pharmacol 19:203–209
Kobinger W, Walland A (1972b) Facilitation of vagal reflex bradycardia by an action of clonidine on central α-adrenoceptors. Eur J Pharmacol 19:210–217
Kobinger W, Walland A (1973) Modulating effect of central adrenergic neurons on a vagally mediated cardioinhibitory reflex. Eur J Pharmacol 22:344–350
Pichler L, Kobinger W (1978) Presynaptic activity at peripheral adrenergic sites and blood pressure effect of α-adrenoceptor stimulating drugs. Eur J Pharmacol 52:287–295
Roach AG, Dennis T, Scatton B, Cavero I (1979) Contribution of cardiac presynaptic α-adrenoceptors to the clonidine-induced bradycardia in dogs. In: Langer SZ, Strake K, Dubocovich ML (eds) Presynaptic Receptors, Adv in the Biosciences, vol 18. Pergamon Press, Oxford, p 53
Roach AG, Levèvre F, Cavero I (1978) Effects of prazosin and phentolamine on cardiac presynaptic α-adrenoceptors in the cat, dog, and rat. Clin Exp Hypertension 1:87–101
Robson RD, Antonaccio MJ, Saelens JK, Liebman J (1978) Antagonism by mianserin and classical α-adrenoceptor blocking drugs of some cardiovascular and behavioral effects of clonidine. Eur J Pharmacol 47:431–442
Schmitt H (1977) The pharmacology of clonidine and related products. In: Gross F (ed) Handbuch der experimentellen Pharmacologie, vol 39. Springer, Berlin Heidelberg New York, p 299
Scriabine A, Stavorski JM (1973) Effect of clonidine on cardiac acceleration in vagotomized dogs. Eur J Pharmacol 24:101–104
Scriabine A, Sweet CS, Ludden CT, Stavorski JM, Wenger HC, Bohidar NR (1977) Some cardiovascular, effects of St-91 and clonidine. Eur J Pharmacol 43:333–341
Timmermans PBMWM, Brands A, van Zwieten PA (1977) Lipophilicity and brain disposition of clonidine and structurally related imidazolidines. Naunyn Schmiedeberg's Arch Pharmacol 300:217–226
Timmermans PBMWM, Fluitman PHM, Mackaay JCJ, van Zwieten PA (1978) Hypotensive and bradycardic effects of classical alpha-sympathomimetic drugs upon intravenous administration to pentobarbitone-anaesthetized rats. Arch Int Pharmacodyn 231:98–103
Timmermans PBMWM, Schoop AM, Kwa HY, van Zwieten PA (1981) Characterization of α-adrenoceptors participating in the central hypotensive and sedative effects of clonidine using yohimbine, rauwolscine and corynanthine. Eur J Pharmacol 70:7–15
van Zwieten PA (1980) Pharmacology of centrally acting hypotensive drugs. Br J Clin Pharmacol 10:13S-20S
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de Jonge, A., Timmermans, P.B.M.W.M. & van Zwieten, P.A. Participation of cardiac presynaptic α1-Adrenoceptors in the bradycardiac effects of clonidine and analogues. Naunyn-Schmiedeberg's Arch. Pharmacol. 317, 8–12 (1981). https://doi.org/10.1007/BF00506249
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DOI: https://doi.org/10.1007/BF00506249