Reverse-mode Na+/Ca2+ exchange is an important mediator of venous contraction.

The Na(+)/Ca(2+) exchanger (NCX) is a bi-directional regulator of cytosolic Ca(2+), causing Ca(2+) efflux in forward-mode and Ca(2+) influx in reverse-mode. We hypothesized that reverse-mode NCX is a means of Ca(2+) entry in rat aorta (RA) and vena cava (RVC). NCX protein in RA and RVC was confirmed by immunoprecipitation. To assess NCX function, isometric contraction and intracellular Ca(2+) was measured in RA and RVC rings in response to low extracellular Na(+), endothelin-1 (ET-1), and KCl, in the presence or absence of the NCX antagonist KB-R7943. In RVC, low extracellular Na(+) caused vasoconstriction and an increase in intracellular Ca(2+) that was attenuated by 10μM KB-R7943. KB-R7943 (10 μM) attenuated maximal contraction to ET-1 in RVC (53 ± 9% of control), but not RA (91±1% of control). KB-R7943 (10 μM) reduced the maximal contraction to KCl in RA (48 ± 5%) and nearly abolished it in RVC (9 ± 2%), suggesting that voltage-dependent Ca(2+) influx may be inhibited by KB-R7943 as well. However, the L-type Ca(2+) channel inhibitor nifedipine (1 μM) did not alter ET-1-induced contraction. Our findings suggest that reverse-mode NCX is an important mechanism of Ca(2+) influx in RVC but not RA, especially during ET-1-induced contraction. Also, the effects of KB-R7943 on ET-1-induced contraction of RA and RVC are predominantly mediated by reverse-mode NCX inhibition and not due to off-target inhibition of Ca(2+) channels.