Pharmacological evidence for a key role of voltage-gated K+ channels in the function of rat aortic smooth muscle cells

* The role of voltage-dependent (IKv) and large conductance Ca2+-activated (BKCa) K+ currents in the function of the rat aorta was investigated using specific BKCa and KV channel inhibitors in single rat aortic myocytes (RAMs) with patch-clamp technique and in endothelium-denuded aortic rings with isometric tension measurements. * The whole-cell K+ currents were recorded in RAMs dialysed with 200 and 444 nM Ca2+ and in perforated-patch configuration. Electrophysiological analysis demonstrated that IKv appeared at −40 mV, while BKCa (isolated using 1 μM paxilline) were seen positive to −20 mV in all conditions. * Voltage-dependent characteristics, but not maximal conductance, of IKv was significantly altered in increased [Ca2+]i. Correolide (1 μM) (a KV1 channel blocker) did not inhibit the IKv, whereas millimolar concentration of TEA (IC50=3.1±0.6 mM, n=5) and 4-aminopyridine (4-AP, IC50=5.9±1.9 mM, n=7) suppressed IKv. These results and immunocytochemical analysis suggest the KV2.1 channel to be a molecular correlate for IKv. * In nonstimulated aortic rings 1–5 mM TEA and 4-AP (inhibitors of IKv), but not paxilline (1 μM), caused contraction. The frequency of contractile responses to TEA and 4-AP was increased in the presence of 10 mM KCl, which itself did not significantly affect the aortic basal tone. * Phenylephrine (15–40 nM) induced sustained tension with superimposed slow oscillatory contractions (termed OWs). OWs were blocked by diltiazem, ryanodine and cyclopiazonic acid, suggesting the involvement of L-type Ca2+ channels and ryanodine-sensitive Ca2+ stores in this process. * TEA and 4-AP, but not IbTX, paxilline or correolide, increased the duration and amplitude of OWs, indicating that IKv is involved in the control of oscillatory activity. * In conclusion, our findings suggest that the KV2.1-mediated IKv, and not BKCa, plays an important role in the regulation of the excitability and contractility of rat aorta. British Journal of Pharmacology (2004) 143, 303–317. doi:10.1038/sj.bjp.0705957