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Notes: Summary We used novel highly subtype-selective antagonists to study whether α1A- and/or α1B-adrenoceptors mediate the stimulation of inositol phosphate generation by noradrenaline in rat cerebral cortex. Phentolamine (10 μM) and prazosin (100 nM) completely abolished the stimulated inositol phosphate generation. The α1A-selective antagonists 5-methyl-urapidil (100 nM) and (+)− and (−)-niguldipine (10 nM) caused only weak inhibition or none at all although these concentrations occupied α1A-adrenoceptors almost completely. In contrast, pretreatment with the irreversible α1B-selective chloroethylclonidine reduced the noradrenaline-stimulated inositol phosphate generation by 76 ± 8%. These data demonstrate that α1B-adrenoceptors couple to inositol phosphate generation; the signal transduction system of α1A-adrenoceptors remains unclear.

Notes: Summary The mechanism responsible for the antihypertensive effect of urapidil is not yet completely understood. Its vasodilator action has been attributed to an antagonism at vascular α1-adrenoceptors. However, it has been suggested that a central action contributes to the hypotensive effect. Recently, three potent analogues of urapidil have been described which also lower blood pressure by a central mechanism. 5-Hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype have been implicated with the central control of cardiovascular function. In the present study, the affinities of these urapidil derivatives (5-acetyl, 5-formyl- and 5-methylurapidil) for 5-HT receptors were investigated using 3H-8-hydroxy-2-(di-n-propylamino)tetralin (3H-8-OH-DPAT), 125I-iodocyanopindolol (125I-ICYP) and 3H-ketanserin for labelling 5-HT1A, 5-HT1B and 5-HT2 binding sites, respectively. 3H-Prazosin and 3H-clonidine were used as selective α1- and α2-adrenoceptor radioligands, respectively. Urapidil and its analogues produced half-maximum inhibition of 3H-8-OH-DPAT binding at concentrations of 4 × 10−9 mol/l to 4 × 10−7 mol/l with the following order of potency: urapidil 〈 5-acetyl- 〈 5-formyl- 〈 5-methyl-urapidil. Thus, 5-methyl-urapidil is one of the most potent ligands at 5-HT1A recognition sites known to date. The IC50 values of urapidil and its derivatives for 3H-prazosin binding were in the range of 5 × 10−8 mol/l to 8 × 10−7 mol/l (order of potency: urapidil 〈 5-formyl- 〈 5-acetyl- ≤ 5-methyl-urapidil). The affinity of these analogues for 5-HT1B, 5-HT2 and α2-adrenergic recognition sites was distinctly lower. Urapidil and its congeners clearly discriminate between 5-HT- and between α-receptor subtypes. It is postulated that the high affinity for 5-HT1A receptors as well as for α1-adrenoceptors is relevant to the hypotensive properties of these compounds.

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 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.