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. 2020 Dec 15:11:597395.
doi: 10.3389/fphys.2020.597395. eCollection 2020.

The Functional Availability of Arterial Kv7 Channels Is Suppressed Considerably by Large-Conductance Calcium-Activated Potassium Channels in 2- to 3-Month Old but Not in 10- to 15-Day Old Rats

Dongyu Ma  1   2 , Dina Gaynullina  1   3 , Nadine Schmidt  1 , Mitko Mladenov  4   5 , Rudolf Schubert  1   6
Affiliations

The Functional Availability of Arterial Kv7 Channels Is Suppressed Considerably by Large-Conductance Calcium-Activated Potassium Channels in 2- to 3-Month Old but Not in 10- to 15-Day Old Rats

Dongyu Ma et al. Front Physiol. .

Abstract

Background: Voltage-gated potassium (Kv) channels, especially Kv7 channels, are major potassium channels identified in vascular smooth muscle cells with a great, albeit differential functional impact in various vessels. Vascular smooth muscle Kv7 channels always coexist with other K channels, in particular with BK channels. BK channels differ in the extent to which they influence vascular contractility. Whether this difference also causes the variability in the functional impact of Kv7 channels is unknown. Therefore, this study addressed the hypothesis that the functional impact of Kv7 channels depends on BK channels.

Experimental approach: Experiments were performed on young and adult rat gracilis and saphenous arteries using real-time PCR as well as pressure and wire myography.

Key results: Several subfamily members of Kv7 (KCNQ) and BK channels were expressed in saphenous and gracilis arteries: the highest expression was observed for BKα, BKβ1 and KCNQ4. Arterial contractility was assessed with methoxamine-induced contractions and pressure-induced myogenic responses. In vessels of adult rats, inhibition of Kv7 channels or BK channels by XE991 or IBTX, respectively enhanced arterial contractility to a similar degree, whereas activation of Kv7 channels or BK channels by retigabine or NS19504, respectively reduced arterial contractility to a similar degree. Further, IBTX increased both the contractile effect of XE991 and the anticontractile effect of retigabine, whereas NS19504 reduced the effect of retigabine and impaired the effect of XE991. In vessels of young rats, inhibition of Kv7 channels by XE991 enhanced arterial contractility much stronger than inhibition of BK channels by IBTX, whereas activation of Kv7 by retigabine reduced arterial contractility to a greater extent than activation of BK channels by NS19504. Further, IBTX increased the anticontractile effect of retigabine but not the contractile effect of XE991, whereas NS19504 reduced the effect of retigabine and impaired the effect of XE991.

Conclusion: Kv7 and BK channels are expressed in young and adult rat arteries and function as negative feedback modulators in the regulation of contractility of these arteries. Importantly, BK channels govern the extent of functional impact of Kv7 channels. This effect depends on the relationship between the functional activities of BK and Kv7 channels.

Keywords: BK channel; Kv7 channel; arteries; ion channels; ontogenesis; vascular smooth muscle.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Expression of KCNQ and BK channel genes. (A) Relative expression profile (related to Hmbs) of KCNQ and BK channel genes in Saphenous artery with endothelium (E+) and without endothelium (E–). (B) Relative expression profile of KCNQ and BK channel genes in gracilis artery with endothelium (E+) and without endothelium (E–). n = 8; **p < 0.01; ***p < 0.001.
FIGURE 2
FIGURE 2
Effect of XE991 and IBTX on methoxamine-induced contractions of the saphenous artery. (A) Normalized tension of saphenous arteries with different methoxamine concentrations in the absence of potassium channel active agents (Control), in the presence of IBTX (IBTX 10–7M), in the presence of XE991 (XE991 3*10–6M) and in the combined presence of XE991 and IBTX (XE991 + IBTX). (B) XE991 contractile effect in the absence (Control) and presence of IBTX (IBTX 10–7M). (C) IBTX contractile effect in the absence (Control) and presence of XE991 (XE991 3*10–6M). n = 12; *p < 0.05, ***p < 0.001.
FIGURE 3
FIGURE 3
Effect of retigabine and IBTX on methoxamine-induced contractions of the saphenous artery. (A1,A2) Normalized tension of saphenous arteries with different methoxamine concentrations in the absence of potassium channel active agents (Control), in the presence of IBTX (IBTX 10–7M), in the presence of retigabine (A1: Retigabine 3*10–6M; A2: Retigabine 10–5M) and in the combined presence of retigabine and IBTX (Retigabine + IBTX). (B1,B2) Retigabine anti-contractile effect in the absence of (Control) and presence of IBTX (IBTX 10–7M). (C1,C2) IBTX contractile effect in the absence of (Control) and presence of retigabine (C1: Retigabine 3*10–6M, C2: Retigabine 10–5M). n1 = 9, n2 = 9; *p < 0.05, **p < 0.01; ***p < 0.001.
FIGURE 4
FIGURE 4
Effect of retigabine and NS19504 on methoxamine-induced contractions of the saphenous artery. (A1,A2) Normalized tension of saphenous arteries at different methoxamine concentration in the absence of potassium channel active agents (Control), in the presence of retigabine (Retigabine 10–5M), in the presence of NS19504 (A1: NS19504 3*10–6M, A2: NS19504 6*10–6M) and in the combined presence of retigabine and NS19504 (Retigabine + NS19504). (B1,B2) Retigabine anti-contractile effect in the absence (Control) and presence of NS19504 (B1: NS19504 3*10–6M, B2: NS19504 6*10–6M). (C1,C2) NS19504 anti-contractile effect in the absence (Control) and presence of retigabine (Retigabine 10–5M). n1 = 11, n2 = 9; *p < 0.05, **p < 0.01; ***p < 0.001.
FIGURE 5
FIGURE 5
Effect of NS19504 and XE991 on methoxamine-induced contractions of the saphenous artery. (A) Normalized tension of saphenous arteries with different methoxamine concentrations in the absence of potassium channel active agents (Control), in the presence of XE991 (XE991 3*10–6M), in the presence of NS19504 (NS19504 6*10–6M) and in the combined presence of NS19504 and XE991 (NS19504 + XE991). (B) NS19504 anti-contractile effect in the absence (Control) and presence of XE991 (XE991 3*10–6M). (C) XE991 contractile effect in the absence (Control) and presence of NS19504 (NS19504 6*10–6M). n = 10; **p < 0.01; ***p < 0.001.
FIGURE 6
FIGURE 6
Expression of KCNQ4 and BK channel genes in the saphenous artery of young and adult rats. Normalized expression (related to Gapdh and normalized to the mean of the expression of vessels from adult rats) of KCNQ4 and BK channel genes in saphenous arteries from young (n = 8) and adult (n = 7) rats. **p < 0.01.
FIGURE 7
FIGURE 7
Effect of NS19504, IBTX, Retigabine and XE991 on methoxamine-induced contractions of the saphenous artery in adult and young rats. (A) Normalized tension of adult saphenous arteries with different methoxamine concentrations in the absence of BK channel active agents (Control), in the presence of IBTX (IBTX 10–7M) and in the presence of NS19504 (NS19504 6*10–6M). (B) Normalized tension of adult saphenous arteries at different methoxamine concentrations in the absence of Kv7 channel active agents (Control), in the presence of XE991 (XE991 3*10–6M), in the presence of retigabine (Retigabine 3*10–5M). (C) Normalized tension of young saphenous arteries with different methoxamine concentrations in the absence of BK channel active agents (Control), in the presence of IBTX (IBTX 10–7M) and in the presence of NS19504 (NS19504 6*10–6M). (D) Normalized tension of young saphenous arteries at different methoxamine concentrations in the absence of Kv7 channel active agents (Control), in the presence of XE991 (XE991 3*10–6M), in the presence of retigabine (Retigabine 3*10–5M).
FIGURE 8
FIGURE 8
Effect of XE991 and IBTX on methoxamine-induced contractions of the saphenous artery of young rats. (A) Normalized tension of saphenous arteries with different methoxamine concentrations in the absence of potassium channel active agents (Control), in the presence of IBTX (IBTX 10–7M), in the presence of XE991 (XE991 3*10–6M) and in the combined presence of XE991 and IBTX (XE991 + IBTX). (B) XE991 contractile effect in the absence (Control) and presence of IBTX (IBTX 10–7M). (C) IBTX contractile effect in the absence (Control) and presence of XE991 (XE991 3*10–6M). n = 11; *p < 0.05, **p < 0.01; ***p < 0.001.
FIGURE 9
FIGURE 9
Effect of retigabine and IBTX on methoxamine-induced contractions of the saphenous artery of young rats. (A) Normalized tension of saphenous arteries with different methoxamine concentrations in the absence of potassium channel active agents (Control), in the presence of IBTX (IBTX 10–7M), in the presence of retigabine (Retigabine 10–5M) and in the combined presence of retigabine and IBTX (Retigabine + IBTX). (B) Retigabine anti-contractile effect in the absence of (Control) and presence of IBTX (IBTX 10–7M). C) IBTX contractile effect in the absence of (Control) and presence of retigabine (Retigabine 10–5M). n = 11; *p < 0.05, **p < 0.01; ***p < 0.001.
FIGURE 10
FIGURE 10
Effect of retigabine and NS19504 on methoxamine-induced contractions of the saphenous artery of young rats. (A) Normalized tension of saphenous arteries at different methoxamine concentration in the absence of potassium channel active agents (Control), in the presence of retigabine (Retigabine 10–5M), in the presence of NS19504 (NS19504 6∗10–6M) and in the combined presence of retigabine and NS19504 (Retigabine + NS19504). (B) Retigabine anti-contractile effect in the absence (Control) and presence of NS19504 (NS19504 6∗10–6M). (C) NS19504 anti-contractile effect in the absence (Control) and presence of retigabine (Retigabine 10–5M). n = 16; ∗∗p < 0.01; ∗∗∗p < 0.001.
FIGURE 11
FIGURE 11
Effect of NS19504 and XE991 on methoxamine-induced contractions of the saphenous artery of young rats. (A) Normalized tension of saphenous arteries with different methoxamine concentrations in the absence of potassium channel active agents (Control), in the presence of XE991 (XE991 3*10–6M), in the presence of NS19504 (NS19504 6*10–6M) and in the combined presence of NS19504 and XE991 (NS19504 + XE991). (B) NS19504 anti-contractile effect in the absence (Control) and presence of XE991 (XE991 3*10–6M). (C) XE991 contractile effect in the absence (Control) and presence of NS19504 (NS19504 6*10–6M). n = 12; *p < 0.05, **p < 0.01; ***p < 0.001.
FIGURE 12
FIGURE 12
Effect of Retigabine, XE991, NS19504 and IBTX on methoxamine-induced contractions of the saphenous artery of adult rats. (A) Normalized tension of saphenous arteries at different methoxamine concentrations in the absence of Kv7 channel active agents (Control), in the presence of XE991 (XE991 3*10–6M), in the presence of retigabine (Retigabine 3*10–5M). (B) Normalized tension of saphenous arteries with different methoxamine concentrations in the presence of IBTX (IBTX 10–7M), in the combined presence of IBTX and XE991 (IBTX + XE991), and in the combined presence of IBTX and retigabine (IBTX + Retigabine). (C) Normalized tension of saphenous arteries with different methoxamine concentrations in the presence of NS19504 (NS19504 6*10–6M), in the combined presence of NS19504 and XE991 (NS19504 + XE991) and in the combined presence of NS19504 and retigabine (NS19504 + Retigabine). *p < 0.05, ***p < 0.001.
FIGURE 13
FIGURE 13
Effect of Retigabine, XE991, NS19504 and IBTX on methoxamine-induced contractions of the saphenous artery of young rats. (A) Normalized tension of saphenous arteries at different methoxamine concentrations in the absence of Kv7 channel active agents (Control), in the presence of XE991 (XE991 3*10–6M), in the presence of retigabine (Retigabine 3*10–5M). (B) Normalized tension of saphenous arteries with different methoxamine concentrations in the presence of IBTX (IBTX 10–7M), in the combined presence of IBTX and XE991 (IBTX + XE991), and in the combined presence of IBTX and retigabine (IBTX + Retigabine). (C) Normalized tension of saphenous arteries with different methoxamine concentrations in the presence of NS19504 (NS19504 6*10–6M), in the combined presence of NS19504 and XE991 (NS19504 + XE991) and in the combined presence of NS19504 and retigabine (NS19504 + Retigabine). ***p < 0.001.
FIGURE 14
FIGURE 14
Summary of the role of BK and KV7 channels in saphenous arteries of young and adult rats. In vessels from adult rats BK and Kv7 channels evoke a similar negative feedback regulation on vessel contraction whereby BK channels produce a considerable functional inhibition on Kv7 channels. In vessels from young rats BK and Kv7 channels evoke different negative feedback regulation on vessel contraction with Kv7 channels dominating. BK channels produce almost no functional inhibition on Kv7 channels.
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