Sodium Channel Nav1.3 Is Expressed by Polymorphonuclear Neutrophils during Mouse Heart and Kidney Ischemia In Vivo and Regulates Adhesion, Transmigration, and Chemotaxis of Human and Mouse Neutrophils In Vitro

Abstract

Background Voltage-gated sodium channels generate action potentials in excitable cells, but they have also been attributed noncanonical roles in nonexcitable cells. We hypothesize that voltage-gated sodium channels play a functional role during extravasation of neutrophils. Methods Expression of voltage-gated sodium channels was analyzed by polymerase chain reaction. Distribution of Nav1.3 was determined by immunofluorescence and flow cytometry in mouse models of ischemic heart and kidney injury. Adhesion, transmigration, and chemotaxis of neutrophils to endothelial cells and collagen were investigated with voltage-gated sodium channel inhibitors and lidocaine in vitro. Sodium currents were examined with a whole cell patch clamp. Results Mouse and human neutrophils express multiple voltage-gated sodium channels. Only Nav1.3 was detected in neutrophils recruited to ischemic mouse heart (25 ± 7%, n = 14) and kidney (19 ± 2%, n = 6) in vivo. Endothelial adhesion of mouse neutrophils was reduced by tetrodotoxin (56 ± 9%, unselective Nav-inhibitor), ICA121431 (53 ± 10%), and Pterinotoxin-2 (55 ± 9%; preferential inhibitors of Nav1.3, n = 10). Tetrodotoxin (56 ± 19%), ICA121431 (62 ± 22%), and Pterinotoxin-2 (59 ± 22%) reduced transmigration of human neutrophils through endothelial cells, and also prevented chemotactic migration (n = 60, 3 × 20 cells). Lidocaine reduced neutrophil adhesion to 60 ± 9% (n = 10) and transmigration to 54 ± 8% (n = 9). The effect of lidocaine was not increased by ICA121431 or Pterinotoxin-2. Conclusions Nav1.3 is expressed in neutrophils in vivo; regulates attachment, transmigration, and chemotaxis in vitro; and may serve as a relevant target for antiinflammatory effects of lidocaine.

Potential Impact of Local Anesthetics Inducing Granulocyte Arrest and Altering Immune Functions on Perioperative Outcome

“…This result is in line with several other studies which have investigated the influence of local anesthetics on PMNs. 4,5,27 Migration ceased at concentrations of 1.58 mmol/L and above. Surprisingly in this study, lidocaine at lower concentrations of up to 1.42 mmol/L increased PMN migration.…”

“…29 Furthermore, higher concentrations of lidocaine led to reduced migration, matching several other studies. [4][5][6]16 Migration stopped at concentrations beyond 1.42 mmol/L. This occurrence may be due to an overwhelming inactivation of the NaV 1.3 channel and the non-canonical effects exerted by local anesthetics, 4,5,7,16 or due to an increase in intracellular calcium concentration, as has been observed in investigations into the effect of LAs on tumor cell lines and muscle cells, [30][31][32] though these investigations require further elucidation.…”

“…[1][2][3] In recent years, several studies have shown significant immunomodulation with LAs caused by interactions with polymorphonuclear granulocytes (PMNs). Although PMNs are considered to be electrically non-excitable, the predominant mechanisms [4][5][6][7][8] for the modulations are thought to be the inactivation of voltage-gated sodium channel 1.3 (NaV 1.3), non-canonical effects such as the blocking of inflammatory mediators, antiapoptotic effects or reduced vascular adhesion, and trans-endothelial migration capacity. The amide type LAs bupivacaine and lidocaine are on the WHO's list of essential drugs 9,10 and may also have antitumor effects for several tumor entities.…”

The role of Mean Platelet Volume/platelet count Ratio and Neutrophil to Lymphocyte Ratio on the risk of Febrile Seizure

“…Third, recent studies have reported that the voltage-gated sodium channels can comprise a family of nine alpha subunits (referred to as NaV1.1 through NaV1.9), which are variably expressed in leukocytes. A subset of neutrophils recruited to the site of injury has been demonstrated to express NaV1.3 sodium channels 68 , 69 . Na V 1.3 channels can recover from inactivation rapidly and sustain high-frequency firing 70 .…”

New Insights into the Type II Toxins from the Sea Anemone Heteractis crispa

“…Even though tetrodotoxin (TTX)-sensitive brain-type sodium channel isoforms Na V 1.1-Na V 1.3 and Na V 1.6 are the main channels expressed in the CNS, their participation in other physiological processes is still under investigation. Recent data provide evidence that Na V 1.1, Na V 1.3, and Na V 1.6 play an important role in action potential propagation in the cardiomyocyte and in excitation-contraction coupling [37,38]. However, further research is needed to verify if the strong toxic effect of the RTX-III toxin comes solely from the modulation of Na V 1.3 channels.…”