STUDIES ON VERATRUM ALKALOIDS. XXXIX. INTERACTION OF VERATRAMINE AND ACCELERATING AGENTS ON THE PACEMAKER OF THE HEART

¹ Department of Pharmacology, Harvard Medical School, Boston, Massachusetts

The action of veratramine on the pacemaker of isolated guinea-pig and rabbit atria was studied under three different experimental conditions: a) its negative chronotropic action was determined on spontaneously beating atria, b) its rate-decreasing effect was studied on atria accelerated by norepinephrine or histamine, and c) the response to norepinephrine and histamine was determined in the presence of veratramine.

The depression by veratramine of the response of the atrial pacemaker to norepinephrine is not selective, since the response to equieffective concentrations of histamine was equally depressed. Since norepinephrine and histamine are known to act on different receptors of the atrial pacemaker, a pharmacological antagonism is unlikely.

In spontaneously beating atrial preparations the magnitude of the negative chronotropic action of veratramine was highly significantly related to the heart rate: the higher the atrial rate, the greater was the response to veratramine. The same relationship holds for the atrial maker stimulated by norepinephrine or histamine. The regression line calculated for this relation was an extension of the regression line determined for spontaneously beating preparations.

Since the final rate observed in the presence of both veratramine and norepinephrine (or histamine) was not influenced by the sequence of drug administration, it is evident that the reduction by veratramine of the response of the atrial pacemaker to norepinephrine is the result of a physiobogical antagonism, i.e., of the interaction of a rate-decreasing agent (the response to which was found to be highly dependent on heart rate) with a rate-increasing agent (the response to which was found to be independent of heart rate).

It is concluded that the various actions of veratramine under study have the same basic mechanism: a negative chronotropic effect which increases with increasing activity of the pacemaker. It appeared to be of no importance whether the activity of the pacemaker was induced by rate-increasing drugs or by changing the temperature from 30° to 37°C. Furthermore, the position of the regression line relating the rate-decreasing effect of veratramine to heart rate provides an explanation of various phenomena reported in the literature.