M-currents (Kv7.2-7.3/KCNQ2-KCNQ3) Are Responsible for Dysfunctional Autonomic Control in Hypertensive Rats

Figures

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  Figure 1. M-currents are responsible for the vagal dysfunction and failing autonomic control of HR in SHR. By inhibiting Kv, 3,4-DAP will induce Ach release primarily from preganglionic parasympathetic neurons and norepinephrine from sympathetic nerve endings as indicated, and through that induce bradycardia followed by tachycardia.(Berg, 2015) M-currents (Kv7.2-7.3) hamper neuron excitability. In the parasympathetic branch, the M-channels may be located both in the preganglionic and postganglionic neurons, whereas a postganglionic localization seemed likely in the sympathetic branch. Drug names indicate site of main action. Arrows and blunted arrows indicate stimulatory and inhibitory actions, respectively.

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  Figure 2. The acute HR-, TPR-, and MBP-response to KV7-inhibitors and -openers. Preferred drug selectivity is indicated by symbol legends. The drugs were given alone or, in SHR, in combination as indicated. The immediate HR- and MBP-response was recorded at the initial TPR-peak/nadir-response. Significant changes in response to channel inhibitors/openers compared to that following the sham-injection of PBS in the control groups were detected as indicated (asterix below/above columns). Involvement of ganglion transmission, sympathetic nerve norepinephrine release and M2AchR activity in the response to Kv-drug was further analyzed in SHR by prior administration of hexamethonium, reserpine or methoctramine, respectively (* in bar). * above columns—P ≤ 0.0167 in WKY and 0.0056 in SHR. * in brackets—P ≤ 0.0167 for XE-991 (none detected) and 0.025 for retigabine.

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  Figure 3. The HR-response to 3,4-DAP after pre-treatment with the KV7.1-7.4-inhibitor XE-991 in WKY (A) and SHR (B–D), pre-treated as indicated by symbol legends. Significant responses (* within symbol) and group differences (* in brackets) at about 1 (recorded at the TPR-peak-response) and at 25 min were located as indicated. Comparisons were made between corresponding control and experimental groups, and between the SHR groups pre-treated with hexamethonium/reserpine/methoctramine alone and hexamethonium/reserpine/methoctramine+XE-991. *P < 0.025 after curve analyses.

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  Figure 4. The HR-response to 3,4-DAP after pre-treatment with Kv7-openers. Retigabine (KV7.2-7.5) and ICA-27243 (KV7.2-7.3) were administered alone or after reserpine, as indicated by symbol legends. Significant responses (* within symbol) and group differences (* in brackets) at about 1 (recorded at the TPR-peak-response) and at 25 min were located as indicated. Comparisons were made between corresponding control and experimental groups, and between groups pre-treated with retigabine/ICA-27243 alone and reserpine+retigabine/ICA-27243. *P < 0.025 after curve analyses.

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  Figure 5. The TPR-response to 3,4-DAP in WKY (A) and SHR (B–D) after pre-treatment with Kv7-opener or -inhibitor, alone or combined with hexamethonium, reserpine or methoctramine, as indicated by symbol legends. Significant responses (* within symbol) and group differences (* in brackets) at about 1 (at the TPR-peak-response) and at 25 min were located as indicated. Comparisons were made between corresponding control and experimental groups, and between groups pre-treated with corresponding channel opener/inhibitor alone and hexamethonium/reserpine/methoctramine+channel opener/inhibitor. *P < 0.025 after curve analyses.