Abstract

The pharmacological properties of McN-A-343, 4-(m-chlorophenylcarbamoyloxy)-2-butynyl-trimethylammonium chloride, are described. This agent produced a small depressor response followed by a large pressor response in chloralose-anesthetized dogs or cats with doses as small as 8 µg/kg, i.v., and progressively greater pressor responses at large dose levels until maximal responses were observed at doses of 200 to 300 µg/kg, i.v.

Such pressor activity was not reduced, but was usually augmented by C-6 and similar compounds, and was antagonized by Dibozane, an adrenergic blocking agent. Reserpine pretreatment antagonized the pressor but not the depressor action of McN-A-343. Bretylium treatment affected these responses in a manner qualitatively comparable to that observed with reserpine pretreatment. Increase in force of cardiac contraction and increase in cardiac rate due to McN-A-343 were blocked by bretylium.

The depressor activity and, surprisingly, the pressor activity of this substance were selectively blocked by atropine. In an attempt to explain the nature of this blockade, it was shown that McN-A-343 caused contraction of the nictitating membrane when given intravenously. On this basis, the possibility was entertained that McN-A-343 might be a ganglionic stimulant. This was verified by the demonstration that the material caused a contraction of the nictitating membrane when injected intraarterially to the ganglion in small amounts and by the finding that the contraction was abolished by ganglionic extirpation, postganglionic section, or small amounts of atropine administered intraarterially to the ganglion. It was also concluded that sympathetic ganglionic stimulation was responsible for the observed pressor responses, since the pressor activity of McN-A-343 was abolished by bilateral sympathectomy and adrenalectomy.

It was shown also that McN-A-343 was without detectable activity in isolated cat or rabbit hearts, and was less than 1/200 as active as ACh in producing contraction of isolated rabbit jejunal strips. Blood-flow experiments, carried out in the dog femoral bed, indicated that this material caused a direct penipheral dilator effect which was selectively antagonized by atropine.

Although McN-A-343 was approximately as active as ACh in producing contracture of the isolated frog rectus muscle, it was found to be unable to produce a rapid twitch response in mammalian skeletal muscle when administered intraarterially, a response readily demonstrated with ACh. Contrary to expectations, nicotine was also found to be inactive in this respect.

It is concluded that the pressor activity of McN-A-343 is due to ganglionic stimulation; furthermore, it appears to act selectively on sympathetic ganglia. Activation of cholinoceptive sites at vascular smooth muscle is probably the basis of the transient depressor response. Antagonism by atropine of the action of McN-A-343 at ganglionic sites indicates the presence of receptor areas or ganglion cells distinct from those which are selectively activated by ACh and blocked by C-6. Evidence presented here suggests that these receptor areas may be of physiological importance in the maintenance of sympathetic tonus.