Inhibition of potassium currents by the sigma receptor ligand (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine in sympathetic neurons of the mouse isolated hypogastric ganglion

Abstract

The actions of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)3-PPP] on sympathetic neurons of the mouse isolated hypogastric ganglion were studied using the current clamp and single electrode voltage clamp techniques. In neurons studied under current clamp (+)3-PPP ( 10 −5 to 3 × 10 −4 M ) evoked a concentration-dependent depolarization, which was fully reversible on washout of the drug. The depolarization was associated with an increase in membrane input resistance. At membrane potentials between −43 and −65mV the amplitude of the depolarization was inversely related to the membrane potential. (+)3-PPP had no effect on membrane potential at potentials negative to −65mV. The effect of (+)3-PPP on the M-current was studied in cells voltage clamped at −40 mV and stepped to −60 mV for 300–500 ms. The slow current relaxations seen during and after the voltage step are largely due to the M-current. (+)3-PPP ( 3 × 10 −5 to 3 × 10 −4M ) inhibited the M-current and produced an inward current in a concentration-dependent manner. (−)3-PPP ( 3 × 10 −5 M ) had similar effects, but was less potent than (+)3-PPP. (+)3-PPP ( 3 × 10 −5 M ) also inhibited the A-current and a calcium-dependent potassium current, but to a lesser degree than the M -current. Inhibition of the M-current by (+)3-PPP was not antagonized by atropine ( 10 −6M ), sulpiride ( 10 −6M ), or by the putative sigma antagonists 1, 3-di-O-tolylguanidine ( 3 × 10 −6and10 −5M ) and rimcazole ( 3 × 10 −6Mand10 −5M ). It is concluded that (+)3-PPP depolarizes sympathetic neurons of the mouse isolated hypogastric ganglion by inhibiting the M-current. (+)3-PPP also inhibits the A-current and calcium-dependent potassium current. Through these actions (+)3-PPP may increase evoked neurotransmitter release and potentiate neurogenic twitch contractions of the mouse isolated vas deferens, as previously reported.