Radio-isotopic labelling of cardiac pre- and postsynaptic alpha-adrenoceptors

RADIO-ISOTOPIC LABELLING OF CARDIAC PRE- AND POSTSYNAPTIC ALPHA-ADRENOCEPTORS. P. Guicheney, C. Levy-Marchal & P. Meyer. INSERM U7, Hopital Necker, 75015 Paris, France. Pharmacological experiments suggest the existence of two varieties of alpha-adrenoceptors in heart. Postsynaptic receptors are located in the plasma membrane of target-cells, the alpha-adrenergic effect being triggered by their interaction with adrenaline and noradrenaline (NA). Presynaptic alpha-adrenoceptors are situated in the membrane of nerve endings and their occupancy by NA results in a reduction of the release of this neurotransmitter from nerve endings. ARC 239, prazosin and WB 4101 exhibit preferential affinities for postsynaptic receptors while yohimbine and clonidine bind preferentially to presynaptic receptors. Using these preferential compounds and 3H-dihydroergocryptine (3H-DHE) as ligand, we demonstrated the presence of these two types of alphaadrenoceptors in rat cardiac membranes. The binding of H-DHE to presynaptic receptors shows a markedly positive cooperativity (Hill n = 2.88, with initial and final apparent Kds of 23 and 0.83 nM), while the binding to postsynaptic receptors follows the law of mass action (KD25OC = 1.67 t 0.37 nM). Experiments on catecholaminergic neuron destruction by neonatal 6-hydroxydopamine treatment are in progress.

COMPARATIVE STUDIES ON THE INTERACTION OF SEVERAL BENZOATE DERIVATIVES WITH OUABAIN TOXICITY IN ISOLATED HEARTS. K. Giittler, W. Klaus and F. Koster. Institute of Pharmacology, University of Cologne, W.-Germany In extension of previous studies on the antagonistic action of salicylate (SAL) to myocardial ouabain toxicity (K. Giittler et al., NaunynSchmiedeberg's Arch. Pharmacol. 302, (Suppl.), R34, 1978) we compared the influence of some chemical analo@s (acetyls'alicylate=ASA, 3,5-dichlorosalicylate=DCS) on this and some other parameters of myocardial function. Isolated electrically driven guinea pig hearts were perfused with Tyrode solution at a congtant rate. Contractile force and perfusion pressure as well as the a-v K -difference were monitored continuously. After addition of a toxic concentration of ouabain (0.8)1M) the time until appearance of ventricular arrhythmias was determined both in presence and in absence of the maximum tolerable concentrations of the above substances (0.5 mM SAL and ASA, 0.05 mM DCS). The contractile force was either not influenced (DCS) or slightly enhanced ( SAL, ASA ) by these pretreatments, whereas the coronary resistance was uniformly increased ( 20 % ). The time course and the maximum of the inotropic ouabain effects were identical under all conditions. However, the appearance of arrhythmias was delayed appreciably in the presence of ASA (7.83 t 0.37 min), SAL (9.82 t 0.53 min) and DCS (10.87 t 1.05 min) as compare3 to the control value T4.4 + 0.37 mjn).This change in ouabain toxicity was not correlated to the.myocardial K balance. the antitoxic activity is a common property of all benzoate derivaThus, tives tested, but the underlying mechanism still remains to be elucidated.