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Assessment of the role of ion channels in flow- induced dilation mechanisms of a carotid artery in low salt and high salt fed Tff3−/−/C57BL/6N mice and their wild type controls

The Abstract Methods: Male, ten-weeks-old transgenic Tff3−/ −/C57BL/6N (Tff3−/−) knockout mice and WT/C57BL/6N (WT) (parental strain) healthy mice were divided in LS (0.4% NaCl in rodent chow) and HS (4% NaCl in rodent chow fed for 1 week) groups. After anaesthesia, mice were decapitated and carotid arteries were isolated and pressurized for 60’at 80 mmHg to assess basal diameter and then subjected to flow at pressure gradients Δ100-Δ180 mmHg. FID was determined in the presence of antagonists of large conductance Ca2+-activated K+-channel (iberiotoxin), ATP-sensitive potassium channels (glibenclamide) and TRPV4 (RN-1734). Data were analysed using Two-way ANOVA tests ; p<0.05 was considered significant. Results: FID was similar between the Tff3−/−_LS and Tff3−/−_HS groups, while FID was reduced in WT_ HS mice compared to the WT_LS group. FID was also reduced in Tff3−/−_LS compared to WT_LS mice. In the Tff3-/-_ LS group, iberiotoxin and glibenclamide reduced FID at ∆180 mm Hg, while had no effect in the Tff3-/-_HS group. In the WT_LS group all inhibitors reduced FID at ∆140-180 mm Hg while had no effect in the WT_HS. Discussion: HS diet causes impaired responses to FID in WT mice but not in Tff3−/− mice. In Tff3−/− mice on LS diet Ca2+- activated K+- channel and ATP- sensitive potassium channels have a significant role in FID. In WT_ mice on LS diet, beside Ca2+-activated K+- channel and ATP- sensitive potassium channels, TRPV4 contributes to FID. In Tff3−/− and WT mice on HS diet, applied antagonists have no effect on FID. Conclusion: Genetic modification as well as dietary intake significantly affect the mechanisms of FID by altering the ion channels' engagement. Funding and financial support: This study was supported by the Croatian Science Foundation under the project IP-2014-09-6380 (V-ELI Athero), VIF- 2018-MEFOS-09-1509 grant and Faculty of Medicine Osijek Institutional grant #IP-1-MEFOS2019 and #IP-1-MEFOS2020 (2019, 2020 ; PI Ines Drenjančević). Ethical Committee: All experimental procedures conformed to the European Guidelines for the Care and Use of Laboratory Animals (Directive 86/609) and were approved by the local and national Ethical Committee (No. 2158/61-02-139/2-06 and No. 2158/61-07-14-119).

Tff3 gene, high salt diet, ion channels, artery, flow-induced dilation

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