SELECTIVE BLOCKADE OF MUSCARINIC M(2) 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 M(2) selective antagonist methoctramine was used in a comparative study. Tripitramine (0.0202 mu mol/kg i.v.) proved to be a potent antagonist at cardiac M(2) receptors that mediate the dec rease in heart rate in the pithed rat; the same dose of this antagonis t in the anaesthetized rat did not significantly affect the depressor action of methacholine mediated by vascular M(3) receptors. In the pit hed rat, this dose did not affect the ganglionic M(1) receptor-mediate d tachycardia and presser 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 M(2) receptor a ntagonist than methoctramine.