Library

Notes: Summary Cardiovascular alterations in hypo- and hyperthyroidism have been ascribed to changes of noradrenergic neurotransmission. In the present study the influence of thyroid hormones on adrenoceptors in the rat heart was further characterized. The effect of artificial hypothyroidism (induced by feeding 6-propyl-2-thiouracil, PTU) and hyperthyroidism (induced by daily injections of triiodothyronine, T3) on myocardial adrenoceptor binding, catecholamines, some physiological responses, and their interdependence was examined. 1. The density of myocardial β-adrenergic binding sites (3H-dihydroalprenolol, 3H-DHA) was reduced after PTU (by 38%) and enhanced after T3 treatment (by up to 82%). The increase was dose- and time-dependent and reversible within 4 days. No changes of the affinity of 3H-DHA to its binding sites were observed. Only L-T3 and L-T4 proved to be active, D-T3 and reverse T3 had no effect. The rise in β-adrenoceptor density caused by T3 was prevented by concomitant administration of cycloheximide, indicating its dependence on protein synthesis. 2. The density of myocardial α 1-adrenergic binding sites (3H-prazosin) was significantly reduced in the PTU group (by up to 28%) and even more distinctly by T3 treatment (by up to 50%). K D values remained unaltered. 3. The noradrenaline content and turnover of rat hearts was significantly reduced by T3-induced hyperthyroidism. PTU treatment had no influence on content and turnover of noradrenaline. Plasma noradrenaline as well as adrenaline levels in freely moving rats were increased by PTU treatment 9- and 5-fold, respectively. In T3-injected animals no significant changes were measured. 4. The density of adrenoceptors is known to be inversely correlated with catecholamine levels in several organs. Neither α- nor β-adrenoceptor changes in the myocardium of dysthyroid rats could be attributed to such a homologous regulation, since they still occurred after chemical sympathectomy with 6-hydroxydopamine and adrenalectomy. 5. Hypertrophy of the heart due to T3 could not be explained by prolonged β-adrenergic stimulation because it was not inhibited by 6-hydroxydopamine or high doses of propranolol. A T3-induced tachycardia was recorded in pithed and in intact rats. It was not reduced to normal levels by the β-adrenoceptor antagonist sotalol and, thus, was independent of sympathetic influence. Hypothyroid pithed rats displayed a marked bradycardia, whereas in intact hypothyroid animals a normal heart rate was measured at rest. Obviously, an enhanced availability of catecholamines which seems to reflect an increased release and/or a central nervous compensatory mechanism was responsible for the maintenance of the normal heart rate. 6. In pithed rats the β-adrenoceptor-mediated increase in heart rate was attenuated by PTU treatment. The isoprenaline dose-response curve was shifted to the right, the maximal response was reduced. After T3 injections, the sensitivity to isoprenaline was not affected, but the maximal heart rate that could be obtained was increased. These results are compatible with the β-adrenoceptor changes described above. It is concluded that cardiovascular signs of hypo- and hyperthyroidism can only be explained by a complex interaction of several factors. Beside the changes of adrenoceptor density and an altered sensitivity to noradrenaline, a central nervous regulation and subsequent changes of catecholamine release as well as effects independent of the sympathetic nervous system have to be considered.

Notes: Summary Several neuroleptic drugs enhance the release and the turnover of noradrenaline in the central nervous system and in peripheral organs. The present study demonstrates the effect of long term treatment (18 days) with atypical neuroleptic drugs (clozapine, thioridazine, and sulpiride) on β-adrenoceptor density in the cerebral cortex and in the myocardium of rats. 1. Clozapine and thioridazine significantly reduced the number of 3H-dihydroalprenolol (DHA)-binding sites by 24 and 21%, respectively, in a crude cortical membrane fraction, and by 28 and 24% in myocardial membranes. 2. Sulpiride failed to alter the maximal number of binding sites in the cortex and in the myocardium. 3. The affinity of 3H-DHA to its binding sites remained unchanged by treatment with neuroleptic drugs. 4. Desipramine, which is known to reduce cerebral β-adrenoceptors during chronic administration, was tested as reference compound. It proved to be more effective in this regard than clozapine and thioridazine in the cortex, but failed to reduce 3H-DHA binding in the myocardium. 5. Acute treatment with desipramine, clozapine, and thioridazine had no effect on 3H-DHA binding in the cerebral cortex. The decrease in β-adrenoceptor density after long term treatment with neuroleptics may be ascribed to an increased concentration of noradrenaline at the receptor site due to antagonism at presynaptic α2-adrenoceptors and inhibition of noradrenaline reuptake.

Notes: Summary Lithium (Li) at a concentration, which exerts prophylactic effects in affective disorders is known to alter noradrenaline turnover and the β-adrenoceptor-dependent cAMP accumulation. In the present study the action of chronic Li administration (at least 5 weeks) on agonist and antagonist binding to adrenoceptors and on the regulation of adrenoceptors was investigated in rat cerebral cortex. Li treatment caused a small but significant decrease in the number of β-adrenoceptor binding sites by 10% (3H-dihydroalprenolol binding) leaving the number of α1- and α2-adrenoceptor binding sites (3H-prazosin and 3H-rauwolscine, respectively) unchanged. The affinity of the radioligands as well as the affinity of agonists to these binding sites were not altered. The up-regulation of β-adrenoceptor binding sites produced by repeated reserpine injections was inhibited by 32% in rats treated concomitantly with Li, although the noradrenaline depleting effect of reserpine was not impaired. In contrast, Li treatment had no effect on the up-regulation of β-adrenoceptor binding induced by 6-OH-dopamine, nor did it alter the β-adrenoceptor down-regulation following chronic administration of desipramine. The up-regulation of α1-adrenoceptor binding sites caused by reserpine or 6-OH-dopamine also remained unaffected by Li. It is concluded that chronic Li has limited effects on cortical adrenoceptors and their regulation. The inhibition of β-adrenoceptor up-regulation caused by reserpine may reflect an action of Li on non-adrenergic systems rather than a general “stabilizing” effect on adrenoceptors proposed previously.