Involvement of Na⁺/Ca²⁺exchanger in endothelial NO production and endothelium-dependent relaxation

Abstract

Endothelial nitric oxide (NO) synthase (eNOS) is controlled by Ca(2+)/calmodulin and caveolin-1 in caveolae. It has been recently suggested that Na(+)/Ca(2+) exchanger (NCX), also expressed in endothelial caveolae, is involved in eNOS activation. To investigate the role played by NCX in NO synthesis, we assessed the effects of Na(+) loading (induced by monensin) on rat aortic rings and cultured porcine aortic endothelial cells. Effect of monensin was evaluated by endothelium-dependent relaxation of rat aortic rings in response to acetylcholine and by real-time measurement of NO release from cultured endothelial cells stimulated by A-23187 and bradykinin. Na(+) loading shifted the acetylcholine concentration-response curve to the left. These effects were prevented by pretreatment with the NCX inhibitors benzamil and KB-R7943. Monensin potentiated Ca(2+)-dependent NO release in cultured cells, whereas benzamil and KB-R7943 totally blocked Na(+) loading-induced NO release. These findings confirm the key role of NCX in reverse mode on Ca(2+)-dependent NO production and endothelium-dependent relaxation.

Na+-K+ pump activation inhibits endothelium-dependent relaxation by activating the forward mode of Na+/Ca2+ exchanger in mouse aorta

“…We found that KB-R7943 at low concentrations (up to 10 M) did not change ATP-induced Ca 2ϩ transients in MAECs, which is consistent with the finding that KB-R7943 at 1 M did not inhibit EDR (25). In addition, we found that the subtype of NCX in MAECs is NCX1.…”

“…This mechanism may enable endothelial cells to release an appropriate amount of NO by regulating increases in [Ca 2ϩ ] i . On the other hand, as shown in this study, the reverse mode of NCX increases [Ca 2ϩ ] i and evokes EDR in Na ϩ -loaded conditions (6,25,28). In pathophysiological situations such as under oxidative stress, excessive Na ϩ entry via redox-activated cation channels has been observed (2,8).…”

“…On the other hand, we previously reported that Na ϩ -K ϩ pump activation inhibits Ca 2ϩ mobilization in endothelial cells and thereby endothelium-dependent relaxation (EDR) (26). NCX is thought to contribute to endothelium-dependent control of vascular contractility (6,25,28). These results support the involvement of the reverse mode of NCX in Ca 2ϩ mobilization in endothelial cells.…”

“…These data suggest that the reverse mode of NCX does not contribute to EDR under physiological conditions, since KB-R7943 inhibits the reverse mode of NCX1 at low concentration (IC 50 ϭ 1.2-2.4 M) (13). The reverse mode of NCX may contribute EDR in pathophysiological conditions such as Na ϩ -loaded conditions or hyponatremia (Ͻ100 mM) (25). On the other hand, KB-R7943 inhibited EDR at a high concentration (Ͼ10 M).…”

Acute effects of glucose and insulin on vascular endothelium

“…These proteins are localised in the plasmalemmal caveolae in close proximity to eNOS and participate in the control of sub-plasmalemmal intracellular Ca 2+ , which is of particular importance for modulation of eNOS activity [34,35]. The high affinity/low capacity PMCA is the principal Ca 2+ removal system in vascular endothelium [36].…”