NS-4591 is a potent synthetic activator of KCa3.1 and KCa2 channels. It has an effective concentration of 0.01-5 μM. NS-4591 does not seem to affect KCa1.1 or NaV channels but does cause a small reduction in CaV currents and a prominent reduction in delayed rectifier KV channel. In whole-cell patch-clamp experiments conducted, NS-4591 doubled IK-mediated currents at a concentration of 45±6 nM while 530±100 nM was required for doubling of SK3-mediated currents. The effect of NS-4591 was also examined in acutely dissociated bladder primary afferent neurons and NS-4591 was shown to inhibit the number of action potentials generated by suprathreshold depolarizing pulses. NS-4591 reduces the amplitude of detrusor twitches in a concentration dependent manner. in vivo experiments in rats and cats have demonstrated that 30 mg/kg inhibits bladder hyper activity induced by capsaicin and acetic acid. NS-4591 might prove to be an important agent for the treatment of bladder hyperactivity.
