Abstract

The inotropic and chronotropic effects of pyridine, 2MP, 3MP, 4MP, 2,6DMP and 2AP and their N-oxide analogs were studied on the isolated papillary muscle and auricles of the cat and on the heart-lung preparation of the dog.

The action of pyridine and its methyl derivatives on the papillary muscle was characterized by a transient negative inotropic effect followed by a much more prolonged positive inotropic response. The former was not abolished by atropine or nicotine. The monomethyl derivatives exhibited approximately equal positive inotropic activity but addition of a second methyl group to the pyridine ring (2,6DMP) significantly enhanced this activity. Only positive inotropic responses were effected by 2AP which was more potent in this respect than pyridine or its methyl derivatives. The enhanced contractile amplitude of the papillary muscle produced by pyridine and all its derivatives was prevented by DCI, SKF-6890A, or pretreatment of the animals with reserpine. These results indicate that the positive inotropic responses to these compounds are effected by a release of catecholamines.

Only 2AP and 2,6DMP elicited positive inotropic and chronotropic responses by isolated auricles. These responses were blocked by DCI, SKF-6890A and were not apparent with auricles from reserpinized cats. Pyridine and its monomethyl derivatives exhibited only negative inotropic and chronotropic activities. The inotropic effects were occasionally, but not consistently, blocked by atropine but not by nicotine.

In the hypodynamic heart-lung preparation of the dog 2,6DMP produced a transient negative inotropic effect, not prevented by atropine, followed by a restoration of competence.

The N-oxide analogs of pyridine and its derivatives elicited only positive inotropic responses. Each compound was less potent than its pyridine analog. The dimethyl derivative of pyridine-N-oxide was significantly more potent than the monomethyl derivatives, all of which possessed about the same degree of activity. Positive chronotropic responses of cat auricles to PNO and its derivatives were either weak or absent.

Results presented indicate that the positive inotropic effects of PNO and its derivatives do not involve a cardiac adrenergic mechanism and catecholamine release but a more direct one on cardiac tissue.