THE INOTROPIC ACTIONS OF QUATERNARY AMMONIUM COMPOUNDS

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

The cardiac effects of a series of quaternary ammonium compounds were studied on the papillary muscle of the cat and the heart-lung preparation of the dog. Tetramethylammonium displayed muscarinic activity and, after atropine, transitory positive inotropic activity in both preparations. Tetraethylammonium was devoid of muscarinic activity and effected only positive inotropic responses. Tetra-n-propylammonium produced effects qualitatively similar to those produced by tetraethylammonium but was less active than the latter. Tetra-n-butylammonium caused a biphasic response, i.e., an initial positive inotropic effect then a negative inotropic effect which was not blocked by atropine.

The inotropic effects of trimethylethylammonium were qualitatively similar effects to those of tetramethylammonium but it was only one-third as active as the latter. Dimethyldiethylammonium inhibited contractility only slightly or not at all in nonatropinized preparations but had a significant positive inotropic effect after atropinization. Triethylmethylammonium displayed no muscarinic activity and approached tetraethylammonium in its capacity to produce a positive inotropic effect.

Lower analogues of alkyltrimethylammonium, having n-alkyl chains containing up to four or five carbons, exhibited muscarinic activity (maximal in the butyl derivative) and higher analogues displayed positive inotropic activity on nonatropinized papillary muscles. On the atropinized papillary muscle, all members of this series effected a positive inotropic response, being greatest in the hexyl member. In the heart-lung preparation, all members of the alkyltrimethylammonium series, except the octyl member, produced a muscarinic effect and maximal activity was found in the pentyl member. In the atropinized hypodynamic heart-lung preparation, all members of the series, except the heptyl and octyl compounds, improved cardiac performance. Maximal activity was exhibited by the hexyl member. Octyltrimethylammonium increased the contractile amplitude of the papillary muscle but failed to produce this effect in the hypodynamic heart-lung preparation.

Phenyltrimethylammonium, benzyltrimethylammonium and -phenethyltrimethylammonium evoked a marked positive inotropic response in the papillary muscle and this response was more pronounced after atropinization. In the heart-lung preparation positive inotropic activity predominated in the case of the phenyl and phenethyl analogues whereas a muscarinic response predominated in the case of benzyltrimethylammonium. However, all of these compounds displayed marked positive inotropic activity in the atropinized hypodynamic heart-lung preparation, the phenyl analogue being the most potent.

Successive replacement of methyl groups by ethyl radicals in phenyltrimethylammonium enhanced positive inotropic activity slightly but at the same time resulted in a decreased duration of action. Meta-hydroxylation enhanced the positive inotropic activity of the phenyltrialkylammonium compounds studied.