CARDIAC EFFECTS OF 4-METHYL-2-AMINOPYRIDINE AND SOME OF ITS ISOMERS

¹ Department of Pharmacology and Toxicology and The Cardiopulmonary Research Laboratory, University of Wisconsin, Madison, Wisconsin

The effects of 4-methyl - 2 - aminopyridine (4M2AP) and its 3-methyl-, 5-methyl- and 6-methyl-isomers were determined on isolated auricles (atria) and papillary muscles of the cat and heart-lung preparations of the dog. All compounds exhibited positive inotropic and chronotropic activities which were most marked in the case of 4M2AP. Effective doses of 4M2AP restored competence in the failing heart-lung preparation of the dog for periods of 1 hour or longer. No evidence of the development of any refractoriness to the cardiostimulant actions of these pyridine derivatives could be demonstrated. Their effects on papillary muscles or auricles were not significantly altered by atropine or ganglionic blocking agents (nicotine, hexamethonium, tetraethylammonium, d-tubocurarine).

Experiments in which the responsiveness of the papillary muscle to 4M2AP, TMA and amphetamine in various orders of exposure and concentration was studied suggest that these agents act at a common site but differ in terms of their affinities for receptors at this site.

Administration of reserpine to cats markedly reduced the concentration of their myocardial catecholamines and abolished the responsiveness of papillary muscles and auricles to 4M2AP and its isomers. 1-(3,4-I)ichlorophenyl)-2-isopropyl-aminoethanol hydrochloride (DC1) blocked the cardiostimulant effects of these pyridine derivatives on all the cardiac preparations studied. Trimethyl-(2-(2,6-xylyloxy)-propyl) ammonium chloride (SKF-6890A), in doses which failed to alter the cardiostimulant responses to epinephrine, also blocked the positive inotropic effects of 4M2AP and its isomers on the papillary muscle and the positive inotropic and chronotropic action of these compounds on the auricles. These findings suggest that 4M2AP and its isomers cause the release of catecholamines from either sympathetic nerve endings and/or other storage Sites.