The effects of quinidine and its chiral isolates on erg-1sm potassium current and correlation with gastrointestinal augmentation.
Smooth-muscle erg 1 (erg1-sm) potassium channel has been recently reported to participate in the modulation of gastrointestinal contractility. Because quinidine inhibits cardiac potassium channel and as a result augments gastrointestinal contractility, it was thought that quinidine may affect erg1-sm. Studies were undertaken to evaluate the effects of quinidine and its chiral isolates on gastrointestinal erg1-sm potassium current and correlate these effects with colon contractility. Chiral separation (high-performance liquid chromatography technique), mass spectrometry, and optical rotation determination were performed to obtain chiral isolates needed for experiments. The erg1-sm potassium channel was expressed in Xenopus oocytes, and the two-electrode patch clamp technique was employed for recording. An isolated rat colon preparation was employed to measure changes in contractility. As a result of chiral separation, two peaks were obtained with elution times of 8.31 and 8.66 minutes, both with a molecular weight of 324; the optical rotations of racemate isolates X and Y were: +258 degrees, +/-0 degrees; and +217 degrees, respectively. The percentage changes in amplitudes of colon contraction (from baseline) were determined at different concentrations of quinidine and for the two isolates in five experiments in each group. Quinidine 0.1, 1, and 10 microM increased contractility by 79 +/- 34, 125 +/- 42, and 217 +/- 51 (P < or = 0.05); for isolate X, the values were 70 +/- 20, 115 +/- 32, and 272 +/- 32 (P < or = 0.05), and for isolate Y the values were 22 +/- 12, 46 +/- 17, and 59 +/- 22. The inhibition of erg1-sm currents by quinidine was 19 +/- 4, 21 +/- 5, and 48 +/- 6 (P < or = 0.05), respectively; that by isolate X was 20 +/- 4, 23 +/- 5, and 39 +/- 7 (P < or = 0.05), and that by isolate Y was 22 +/- 4, 21 +/- 4, and 31 +/- 6. One chiral isolate and quinidine markedly augmented contractility, whereas quinidine and the two chiral isolates inhibited the erg1-sm potassium currents to a similar extent. These results suggest that erg1-sm inhibition does not explain gastrointestinal contractile augmentation caused by the quinidine racemate and its chiral isolates.
Cvetanovic
Ivana
I
Department of Pharmacology and Medicine, Rush University Medical Center, Chicago, Illinois, USA. Ivanacvetanovic@yahoo.com
Lin
Congrong
C
Ranade
Vasant
V
Keshavarzian
Ali
A
Somberg
John
J
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects*; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011802:Quinidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014982:Xenopus laevis
D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels; D011802:Quinidine