Pharmacology of amezinium, a novel antihypotensive drug. III. Studies on the mechanism of action.

Pharmacological studies on the mechanism of action of 4-amino-6-methoxy-1-phenyl-pyridazinim methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, are presented. 1. Amezinium increases the arterial blood pressure and heart rate of anaesthetized animals and of pithed rats by stimulating vascular alpha- and cardiac beta 1-adrenoceptors. The action was not modified by ganglionic blockade with hexamethonium. The alpha-adrenergic blocking drug phentolamine antagonized the blood pressure increasing effect and the beta-adrenergic blocking drug propranolol antagonized the heart rate increasing effect. 2. Noradrenaline depletion by pretreatment with reserpine reduced the pressor effect of amezinium to approximately the same extent as it reduced the effect of tyramine. It completely abolished the heart rate increasing effect. Under these conditions, high doses of amezinium reduced the heart rate. 3. Amezinium is taken up by adrenergic neurones. Inhibition of uptake 1 with desipramine reduced the pressor effect of amezinium and of tyramine. 4. Being a substrate of uptake 1, amezinium also inhibited noradrenaline and tyramine uptake. Consequently, it enhanced the pressor effect of exogenous noradrenaline and increased the contractions of the nictitating membrane following preganglionic stimsipramine reduced the pressor effect of amezinium and of tyramine. 4. Being a substrate of uptake 1, amezinium also inhibited noradrenaline and tyramine uptake. Consequently, it enhanced the pressor effect of exogenous noradrenaline and increased the contractions of the nictitating membrane following preganglionic stimsipramine reduced the pressor effect of amezinium and of tyramine. 4. Being a substrate of uptake 1, amezinium also inhibited noradrenaline and tyramine uptake. Consequently, it enhanced the pressor effect of exogenous noradrenaline and increased the contractions of the nictitating membrane following preganglionic stimulation (endogenous noradrenaline). It diminished the effect of indirectly acting sympathomimetic drugs (tyramine). It did not modify the action of the sympathomimetic drugs methoxamine and isoprenaline, which are not subject to uptake 1. 5. Amezinium inhibits monoamine oxidase (MAO). As a result of being concentrated in sympathetic neurones via uptake 1 amezinium causes specific inhibition of intraneuronal MAO; this was demontrated by enhanced restoration of the effects of tyramine and amezinium by noradrenaline infusion in reserpinized animals. The effective doses of amezinium here were lower than the doses necessary to inhibit tyramine and to exert a pressor effect. This is in accordance with the blood pressure increasing effect of amezinium itself by amezinium pretreatment and noradrenaline-infusion. 6. Pretreatment with a MAO inhibitor (nialamide) enhanced the pressor effect of amezinium, probably by also inhibiting extraneuronal MAO...