THE SYMPATHOMIMETIC ACTION OF BRETYLIUM ON ISOLATED ATRIA AND AORTIC SMOOTH MUSCLE

¹ Department of Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, New York

The ability of bretylium to block the response to sympathetic nerve stimulation was demonstrated with isolated atrial preparations (kitten and guinea pig).

Bretylium produced contraction of aortic strips from normal rabbits and had a marked positive inotropic effect on electrically driven left atria from normal guinea pigs. These sympathomimetic effects of bretylium were antagonized by cocaine.

Reserpinized atria and aortic strips did not respond to bretylium. Bretylium potentiated the response to norepinephrine (NE) on neserpinized atnia by 10-fold and on aortic strips by 2-fold.

Incubation of reserpinized aortic strips and atnia with sufficient NE for short periods, followed by washout, led to restoration of essentially normal response to bretylium (so-called "repletion" experiments). Restored responsiveness to bretylium was lost on prolonged exposure to bretylium, but could be restored again by reincubation with NE.

Restoration of the hretyliumn response in reserpinized atria was a function of both the concentration of NE in the incubating medium and the duration of exposure to it. At romm temperature maximal restoration was obtained following an incubation with 10^-7 NE for from 2 to 5 mitutes. The minimal concentration of NE which could partially restore the bretylium response at room temperature was of the order of 5 x 10^-10 to 10^-9, even though this concentration of NE produced no detectable inotnopic effect itself.

If bretylium, tyramine or cocaine was present in suitable concentrations during the period of incubation with NE, the restoration of bretylium response in reserpinized tissues was blocked.

In reserpinized atria, the bretylium response was restored by epinephrine, dopamine and l-dopa. Tyrosine failed to restore the response. Epinephrine and dopamine were less effective than NE but were better than l-dopa.

The left atrium of a guinea pig subjected to cardiac sympathectomy 6 days earlier was found to be hypersensitive to NE, and almost completely insensitive to bretylium. Responsiveness to bretylium could not be restored by incubating the atrium with high concentrations of NE.

The behavior of bretylium as an indirectly acting sympathomimetic agent and as a potentiating agent for NE is satisfactorily explained by an hypothesis previously developed to account for the behavior of tyramine.