Cardiac postjunctional supersensitivity to β-agonists after chronic chemical sympathectomy with 6-hydroxydopamine
The sensitivity to sympathomimetic amines of isolated atria removed from sham-injected and 6-hydroxydopamine-treated (6-OHDA) guinea-pigs was examined in the presence of an extraneuronal uptake blocker and an α-adrenoceptor antagonist. Three weeks of pretreatment with 6-OHDA resulted in leftwards shifts of the dose-response curves for the positive chronotropic and inotropic responses of right and left atria to isoprenaline. The responses to the partial agonist salbutamol were also potentiated after 6-OHDA pretreatment, revealed as an increase in the maximum response relative to isoprenaline.
The supersensitivity was post-synaptic in origin and independent of changes in disposition or metabolism, since it was observed with agonists immune to neuronal uptake and O-methylation, and in the presence of extraneuronal uptake inhibition by metanephrine. It was also specific for the β-adrenoceptor, no supersensitivity to histamine being found. In the right atria, the supersensitivity was partially masked by an opposing depressant effect after 6-OHDA pretreatment which was observed with histamine.
Dissociation constants (KA) for the left atrial inotropic responses to orciprenaline were determined by use of the antagonist Ro 03-7894. Atria from 6-OHDA-pretreated animals were supersensitive to orciprenaline, but the KA value did not differ from that after sham injection. It could therefore be concluded that the increase in sensitivity was not due to an increase in affinity for the β-adrenoceptor.
Key wordsGuinea-pig atria 6-Hydroxydopamine Supersensitivity β-Adrenoceptor Agonist affinity
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- Baker SP, Posner P (1983) The effect of beta-adrenoceptor antagonist Ro 03-7894 on rat atrial tension development and (−)-[3H]dihydroalprenolol binding to cardiac and lung membranes. Life Sci 33:459–466Google Scholar
- Besse JC, Furchgott RF (1976) Dissociation constants and relative efficacies of agonists acting on alpha adrenergic receptors in rabbit aorta. J Pharmacol Exp Ther 197:66–78Google Scholar
- Biswas B, Jonsson G (1981) Reversal of noradrenaline denervation-induced increase of β-adrenoceptor binding in rat neocortex by noradrenaline infusion. Eur J Pharmacol 69:341–348Google Scholar
- Broadley KJ, Lumley P (1977) Selective reserpine-induced supersensitivity of the positive inotropic and chronotropic response to isoprenaline and salbutamol in guinea-pig isolated atria. Br J Pharmacol 59:51–60Google Scholar
- Broadley KJ, McNeill JH (1983) Dissociation constants (K A) and relative efficacies of sympathomimetic amines in isolated atria during hypothermia-induced supersensitivity. Can J Physiol Pharmacol 61:572–580Google Scholar
- Broadley KJ, Williams RG (1983) Temperature-induced changes in dissociation constants (K A) of agonists at cardiac β-adrenoceptors determined by use of the irreversible antagonist Ro 03-7894. Br J Pharmacol 79:517–524Google Scholar
- Brus R, Hees ME, Jacobowitz D (1970) Effect of 6-hydroxydopamine and thyroxine on chronotropic response to norepinephrine. Eur J Pharmacol 10:323–327Google Scholar
- Culling W, Penny WJ, Lewis MJ, Middleton K, Sheridan DJ (1984) Effects of myocardial catecholamine depletion on cellular electrophysiology and arrhythmias during ischaemia and reperfusion. Cardiovasc Res 18:675–682Google Scholar
- Fleming WW (1975) Supersensitivity in smooth muscle. Introduction and historical perspective. Fed Proc 34:1969–1970Google Scholar
- Furchgott RF (1966) The use of beta-haloalkylamines in the differentiation of receptors and in the determination of dissociation constants of receptor-agonist complexes. Adv Drug Res 3:21–55Google Scholar
- Furchgott RF, Bursztyn P (1967) Comparison of dissociation constants and of relative efficacies of selected agonists acting on parasympathetic receptors. Ann NY Acad Sci 144:882–898Google Scholar
- Harden TK, Wolfe BB, Sporn JR, Poulos BK, Molinoff PB (1977) Effects of 6-hydroxydopamine on the development of the beta-adrenergic receptor/adenylate cyclase system in rat cerebral cortex. J Pharmacol Exp Ther 203:132–143Google Scholar
- Haeusler G, Haefely W, Thoenen H (1969) Chemical sympathectomy of the cat with 6-hydroxydopamine. J Pharmacol Exp Ther 170:50–61Google Scholar
- Iversen LL (1965) The inhibition of noradrenaline uptake by drugs. Adv Drug Res 2:1–48Google Scholar
- Kajiyama H, Obara K, Nomura Y, Segawa T (1982) The increase of cardiac β1-subtype of β-adrenergic receptors in adult rats following neonatal 6-hydroxydopa treatment. Eur J Pharmacol 77:75–77Google Scholar
- Kostrezewa RM, Jacobowitz DM (1974) Pharmacological actions of 6-hydroxydopamine. Pharmacol Rev 26:199–275Google Scholar
- Krstew E, McPherson GA, Malta E, Molenaar P, Raper C (1984) Is Ro 03-7894 an irreversible antagonist of β-adrenoceptor sites? Br J Pharmacol 82:501–508Google Scholar
- Nadeau RA, De Champlain J, Tremblay GM (1971) Supersensitivity of the isolated rat heart after chemical sympathectomy with 6-hydroxydopamine. Can J Physiol Pharmacol 49:36–44Google Scholar
- Nicholson CD, Broadley KJ (1978) Irreversible β-adrenoceptor blockade of atrial rate and tension responses. Eur J Pharmacol 52:259–269Google Scholar
- Nicholson CD, Broadley KJ, Burden DT, Natoff IL (1979) The in vivo examination of the irreversible β-adrenoceptor antagonist Ro 03-7894 on cardiac rate and contractility. Clin Exp Pharmacol Physiol 6:599–609Google Scholar
- Nomura Y, Kajiyama H, Segawa T (1980) Hypersensitivity of cardiac β-adrenergic receptors after treatment of rats with 6-hydroxydopa. Eur J Pharmacol 66:225–232Google Scholar
- Pointon SE, Banerjee SP (1979) Alpha- and beta-adrenergic receptors of the rat salivary gland. Biochim Biophys Acta 584:231–241Google Scholar
- Rankin A, Broadley KJ (1982) Comparison of the apparent irreversible β-adrenoceptor antagonist Ro 03-7894 with propranolol in cardiac ventricular muscle by pharmacological and radioligand binding techniques. Biochem Pharmacol 31:1325–1332Google Scholar
- Sporn JR, Harden TK, Wolfe BB, Molinoff PB (1976) β-adrenergic receptor involvement in 6-hydroxydopamine-induced supersensitivity in rat cerebral cortex. Science 194:624–625Google Scholar
- Williams RG, Broadley KJ (1983) Determination of agonist affinity for cardiac β-adrenoceptors during reserpine-induced supersensitivity. Eur J Pharmacol 87:95–105Google Scholar
- Yamada S, Yamamura HI, Roeske WR (1980) Alterations in cardiac autonomic receptors following 6-hydroxydopamine treatment in rats. Mol Pharmacol 18:185–192Google Scholar