CARDIOVASCULAR AND OXYTOCIC ACTIONS OF A SERIES OF QUINOLINE DERIVATIVES

¹ Department of Physiology and Pharmacology, Graduate School of Medicine, University of Pennsylvania, Philadelphia, Pa.

The cardiovascular and oxytocic actions of a series of compounds related to quinoline were investigated. The 3-quinolinecarboxamide derivatives (Group A) exhibited little activity of either type. The tetrahydro-3-quinolinecarboxamides (Group B) had slight hypotensive activity of brief duration but were relatively strong oxytocics. Their mechanism of action appears to differ from that of ergonovine. The 3-carbamylquinolinium halides (Group C) possessed relatively strong hypotensive but no oxytocic activity. The most active derivative, 1-methyl-3-[N-(1-carboethoxyethylcarbamyl)] quinoliium iodide (McN-259-15), was studied in detail.

Five mgm./kgm. of McN-259 i.v. in dogs usually produced a rapid, prolonged fall in blood pressure accompanied by brief tachycardia and apnea. The pressure returned to normal over a period of thirty minutes to two hours, but circulatory reflexes were depressed for longer periods. The initial rapid vasodepression was attributed to an action on some structure of the head or neck, since it could be elicited by the intra-carotid injection of small doses and was largely abolished by section of the spinal cord at C-3 but not by antihistamiics. The prolonged phase of hypotension appeared to be due to histamine-liberation, since it showed tachyphylaxis, considerable individual variation, was accompanied by increased peripheral flow, and was prevented or reversed by antihistaminics. The prolonged phase was not significantly modified by ganglionic blockade, section of the vagi above and below the nodose ganglia, or spinal transection. The drug was ineffective when perfused through the carotid sinus—body circulation, and did not inhibit cholinesterase, mono- or diamine oxidase in pharmacological concentrations.

Assays for histamine-like activity, employing the isolated guinea pig uterus, were performed on the whole blood of five dogs following repeated i.v. injections of McN-259. The rise in blood histamine-equivalent closely paralleled the degree of fall in mean arterial pressure in all cases; however, the former returned to control levels long before the return of pressure to normal.

Species variation was indicated by the considerably smaller response obtained in cats and rabbits. The actions of McN-259 are compared with those of other histamine-liberators described in the literature.