CONCERNING THE MECHANISM OF ACTION OF METHYLPHENIDATE ON THE RESPONSES OF RABBIT VASCULAR TISSUE TO NOREPINEPHRINE

¹ Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont

Methylphenidate (10^-6 M) augmented norepinephrine-induced contractions of rabbit aortic strips. Concentrations of 10^-5 M and greater antagonized norepinephrine-induced contractions in a concentration-dependent manner. Similar results were elicited in the isolated, perfused rabbit ear when methylphenidate was added to the perfusion fluid. Methylphenidate at 10^-5 M and greater antagonized in a concentration-dependent manner 5-hydroxytryptamine- and histamine-induced contractions in rabbit aortic strips. High concentrations of methylphenidate during exposure of strips to phenoxybenzamine interfered with the development of nonequilibrium blockade against norepinephrine, histamine and 5-hydroxytryptamine. The capacity of angiotensin II amide to contract rabbit aortic strips and constrict the vessels of the isolated perfused rabbit ear was enhanced by methylphenidate.

Rabbit aortic strips exposed to dl-norepinephrine-7-H³ hydrochloride took up and bound norepinephrine as an increasing function of concentration in the range between 6 x 10^-9 M and 2 x 10^-7 M. The difference between the "uptake" and the "bound" norepinephrine, i.e., the diffusible fraction of the norepinephrine taken up, increased with increasing concentration. Uptake and binding of norepinephrine increased with time over a 30-minute period. Uptake and binding were not linearly correlated with strip weight, nor with the magnitude of contraction.

Methylphenidate depressed the uptake and binding of norepinephrine. It did not change the magnitude of the diffusible fraction. Uptake and binding of radioactivity in the presence of methylphenidate were not linearly correlated with magnitude of contraction.

It is concluded that the antagonism exerted by methylphenidate against responses of aortic strips to norepinephrine is similar to adrenergic blockade. Although the potentiation of the responses of aortic strips to norepinephrine which is produced at lower concentrations of methylphenidate is associated with depression of uptake and binding of radioactivity by the strips, it is not clearly established that they are causally related.