On the adrenergic neuron blocking activity of 1-methyl-3-keto-4-phenylquinuclidinium bromide (MA540) during acute and chronic administration.
The quaternary quinuclidine derivative 1-methyl-3-keto-4-phenylquinuclidinium bromide (MA540) antagonized rabbit ileum and cat nictitating membrane responses to postganglionic sympathetic stimulation in a manner similar to guanethidine, indicating adrenergic neuron blocking activity. The potency of MA540 in relation to guanethidine varied according to the experimental procedure employed for assay, being equal to, less and greater than that of the reference agent in the rabbit ileum, and the acute and chronic nictitating membrane, respectively. Preferential blockade of nictitating membrane responses to both lower and higher frequencies of sympathetic stimulation were found with MA540 and guanethidine, depending on the dose used in acute experiments, or on the number of daily administrations in chronic tests. Significant tolerance to the adrenergic impairment induced by MA540 and guanethidine was not apparent in membranes subjected to supramaximal sympathetic stimulation, but was evident in membranes under the influence of normal sympathetic tone in unanesthetized cats. This phenomenon appeared much earlier with guanethidine than with the quinuclidine derivative. Tolerance was correlated neither with norepinephrine supersensitivity nor with catecholamine depletion, which was evaluated indirectly through measurement of membrane responses to tyramine. The results of this study indicate that MA540 may be a useful antihypertensive agent, possessing some advantages over guanethidine.
D000818:Animals; D002415:Cats; D004361:Drug Tolerance; D004558:Electric Stimulation; D005260:Female; D006145:Guanethidine / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy; D007082:Ileum / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009541:Nictitating Membrane / Q000187:drug effects; D009638:Norepinephrine; D011812:Quinuclidines / Q000494:pharmacology*; D011817:Rabbits; D013564:Sympathetic Nervous System / Q000187:drug effects; D013565:Sympatholytics; D014439:Tyramine
D011812:Quinuclidines; D013565:Sympatholytics; D009638:Norepinephrine; D014439:Tyramine; D006145:Guanethidine