INHIBITION OF NORADRENALINE RELEASE VIA PRESYNAPTIC 5-HT1D-ALPHA RECEPTORS IN HUMAN ATRIUM

In segments of human right atrial appendages preincubated with [H-3]no radrenaline and superfused with physiological salt solution containing desipramine and corticosterone, we determined the effects of 5-hydrox ytryptamine (5-HT) receptor agonists and antagonists on tritium overfl ow evoked by transmural electrical stimulation (2 Hz). Tritium overflo w was inhibited by 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryp tamine (5-MeOT), 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole succinate (RU 24969) and sumatriptan. Yohimbine and oxymetazoline (in the presence of idazoxan) also inhibited tritium overflow. The inhibi tory potency of the drugs was significantly correlated with their affi nity for 5-HT1D receptors in human brain and for cloned human 5-HT1D a lpha and 5-HT1D beta receptors, but not with their affinity for 5-HT1B , 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5A, 5-HT5B and 5- HT7 receptors. The potency order 5-CT >5-HT >5-MeOT is opposite to the order of affinities reported for 5-HT6 binding sites. The preferentia l S-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (up to 0.3 mu M) and the selective 5-HT4 receptor agonist cisapride (up to 1 mu M) failed to inhibit tritium overflow. L-694,247, a potent 5-HT1 D beta receptor agonist, did not inhibit tritium overflow, but counter acted the inhibitory effect of 5-HT. Ketanserin at a concentration whi ch should block 5-HT1D alpha but not 5-HT1D beta receptors and methiot hepin at a concentration which may be assumed to block both 5-HT1D alp ha and 5-HT1D beta receptors antagonized the inhibitory effect of 5-HT . Propranolol and ondansetron did not modify the 5-HT-induced inhibiti on of release. In conclusion, noradrenaline release in human right atr ial appendages is inhibited via 5-HT receptors which are located on th e noradrenergic axon terminals. These inhibitory presynaptic 5-HT rece ptors belong to the 5-HT1D subfamily. The ability of ketanserin to ant agonize the inhibitory effect induced by activation of these receptors suggests that they can be subclassified as 5-HT1D alpha.