Pharmacology of amezinium, a novel antihypotensive drug. IV. Biochemical investigations of the mechanism of action.

The possible sites of action of 4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, were investigated in biochemical experiments. 1. In vivo in mice, amezinium inhibits the uptake of 3H-noradrenaline into heart and adrenals (among other tissues). The Ki for this inhibition determined in vitro with rat atria is 1.3 x 10(-7) mol/l. As is shown with synaptosomes amezinium exhibits a predilection for the noradrenaline transport, the uptake of dopamine and serotonin being also inhibited, but less so. 2. Amezinium itself is taken up into synaptosomes. This transport follows Michaelis-Menten kinetics, showing the same dependence on Na+ and K+ as uptake 1 of noradrenaline, and is also inhibited by desipramine and cocaine. 3. Storage of 3H-amezinium in rat atria in vivo is almost completely inhibited by pretreatment with 6-hydroxy-dopamine and by approx. 50% inhibited by pretreatment with reserpine. This indicates that amezinium is at least partly stored in the neuronal granules. 4. Amezinium inhibits MAO-A in rat heart homogenate with a Ki of 3 x 10(-6) mol/l and MAO-B in liver homogenate with a Ki of 3 x 10(-4) mol/l; the inhibition is reversible. 5. Even high doses of amezinium do not deplete catecholamines in the heart or adrenals of the rat. The role of the various sites of action is discussed and the effect of amezinium interpreted as the result of noradrenaline release with simultaneous inhibition of intraneuronal and extraneuronal MAO-A and of uptake 1.