Selective blockade of muscarinic M2 receptors in vivo by the new antagonist tripitramine.

The antimuscarinic effects of tripitramine (1, 1, 24--tris[[5, 11-dihydro-6-oxo-6H-pyrido [2,3-b][1,4]- benzodiazepin-11-yl)carbonyl]methyl]-8, 17-dimethyl-1, 8, 17, 24-tetraazatetracosane tetraoxalate), a member of a series of polymethylene tetraamines with in vitro cardioselectivity, were assessed in two in vivo preparations: anaesthetized and pithed rats. The well-known M2 selective antagonist methoctramine was used in a comparative study. Tripitramine (0.0202 mumol/kg i.v.) proved to be a potent antagonist at cardiac M2 receptors that mediate the decrease in heart rate in the pithed rat; the same dose of this antagonist in the anaesthetized rat did not significantly affect the depressor action of methacholine mediated by vascular M3 receptors. In the pithed rat, this dose did not affect the ganglionic M1 receptor-mediated tachycardia and pressor response to muscarine or McN-A-343. These in vivo data are consistent with the in vitro findings and confirm that tripitramine is a more potent and selective muscarinic M2 receptor antagonist than methoctramine.