Pergolide block of the cloned Kv1.5 potassium channels

Pergolide mesylate, an ergot-derivative dopamine receptor agonist, is prescribed for the management of patients with Parkinson's disease. Pergolide caused vasoconstriction in a pulmonary artery. Kv1.5 channel is highly expressed in pulmonary arterial smooth muscle cells, where it plays an important role as a determinant of vascular tone. In the present study, we investigated the effects of pergolide on Kv1.5 stably expressed in Chinese hamster ovary cells using the whole-cell patch-clamp technique. The Kv1.5 block by pergolide was concentration-, time-, voltage-, and use-dependent. Pergolide blocked Kv1.5 currents in a concentration-dependent manner, with an IC50 value of 15.4 mu M and a Hill coefficient of 1.7. The activation and inactivation of Kv1.5 were significantly accelerated by pergolide in a concentration-dependent manner. The apparent association and dissociation rate constants were 0.43 mu M-1 s(-1) and 8.34 s(-1), respectively, with a K (D) value of 19.1 mu M. Pergolide slowed deactivation kinetics of Kv1.5, resulting in a tail crossover phenomenon. The block of Kv1.5 by pergolide was voltage-dependent, increasing significantly at test potentials from -10 to +10 mV, whereas the current was reduced slightly with a shallower voltage dependence in the range between +20 and +50 mV (delta = 0.34). There was a significant hyperpolarizing shift in the voltage dependence of steady-state inactivation of Kv1.5. Pergolide produced a use-dependent Kv1.5 block at 1 and 2 Hz, and also slowed the time course for recovery from inactivation. These results suggest that pergolide has an affinity for the open and inactivated states of Kv1.5 channels.