Bupivacaine blocks BKCa channels by a fast open mechanism in human vascular smooth muscle cells.

MARTIN P; ENRIQUE N; ROLDAN PALOMO AR; REBOLLEDO A; MILESI V

Sicilia

Workshop; EMBO/FEBS Lecture Course on Channels and Transporters, International School of Biophysics; 2011

Local anesthetics are used in a wide range of clinical situations to prevent acute pain. It is known that bupivacaine is able to block voltage activated Na+ and K+ channels and in the last years it has been reported to block some members of K2P K+ channel family. The mechanism of action of this drug on K+ channels has been less studied than in Na+. Nilsson et al. (Biophys J 95(11):5138-52, 2008) suggest that bupivacaine blocks the N-type inactivating K+ channels Shaker and Kv 3.4 by blocking the channels exclusively in the open state. However, there are no reports about  bupivacaine effects on other kind of K+ channels, such as the large conductance Ca2+-activated K+ channels (BKCa). We used the patch-clamp technique on freshly enzimatically isolated human umbilical artery cells to record K+ currents in the whole-cell and inside-out configurations. Our results show that bupivacaine produced a significant blocking effect on whole-cell currents mainly carried by BKCa channels (we characterized these currents in a previous work: Milesi et al., J Soc Gynecol Investig 10(6):339-46, 2003). Moreover, in inside-out patches presenting one or more copies of single BKCa, we observed that bupivacaine induced a fast blocking effect characterized by an apparent reduction in unitary conductance. The blocking effect was also present when the channel was activated by 1 µM of Ca2+. BKCa channels are widely expressed in vascular smooth muscle and are related to important vascular regulation mechanisms like myogenic tone, agonist induced vasoconstriction, and endothelium dependent vasorelaxation, among others. Hence, this new finding should be further explored to fully understand bupivacaine effects in human subjects.