The pharmacological properties of K~+ currents from rabbit isolated aortic smooth muscle cells

摘要

1 Using the whole-cell patch-clamp technique, the effects of several K~+ channel blocking drugs on K~+ current recorded from rabbit isolated aortic smooth muscle cells were investigated. 2 Upon depolarization from -80 mV, outward K~+ current composed of several distinct components were observed: a transient, 4-aminopyridine (4-AP)-sensitive component (I_t) and a sustained component (I_(sus), comprising a 4-AP-sensitive delayed rectifier current (I_(K(V))), and a noisy current which was sensitive to tetraethylammonium (TEA), and probably due to Ca~(2+) -activated K~+ current (I_(K(Ca))). 3 Several drugs in clinical or experimental use have as part of their action an inhibitory effect on specific K~+ channels. Because of their differential K~+ channel blocking effects, these drugs were used in an attempt to characterize further the K~+ channels in rabbit aortic smooth muscle cells. Imipramine, phencyclidine, sotalol and amitriptyline failed to block selectively any of the components of K~+ current, and were thus of little value in isolating individual channel contributions. Clofilium showed selective block of I_(K(V)) in the presence of TEA, but only at low stimulation frequencies (0.07 Hz). At higher frequencies (1 Hz) of depolarization, both I_t, and I_(K(V)) were suppressed to a similar extent. Thus, the blocking action of clofilium was use-dependent. 4 The voltage-dependent inactivation of I_t and the delayed rectifier were very similar although a brief (100 ms) pre-pulse to -30 mV could preferentially inactivate I_t. Together with the non-selective blocking effects of the K~+ channel blockers, similarities in the activation and inactivation of these two components suggest that they may not exist as separate ionic channels, but as distinct kinetic states within the same K~+ channel population. 5 The effects of all of these drugs on tension were examined in strips of rabbit aorta. The non-specific K~+ channel blockers caused only minor increases in basal tension. TEA and 4-AP by themselves caused significant increases in tension and were even more effective when applied together. There appeared to be no correlation between the effects of the drugs tested on tension and their actions on currents recorded from isolated myocytes. Thus tension studies are an inappropriate means of investigating the mechanism of action of these drugs, and studies on ionic currents in isolated myocytes cannot easily predict drug actions on intact tissues.