TASK‐1 channel blockade by AVE1231 increases vasocontractile responses and BP in 1‐ to 2‐week‐old but not adult rats

Abstract

Background and Purpose: The vasomotor role of K2P potassium channels during early postnatal development has never been investigated. We tested the hypothesis that TASK-1 channel (K2P family member) contribution to arterial vascular tone and BP is higher in the early postnatal period than in adulthood. Experimental Approach: We studied 10-to 15-day-old ("young") and 2-to 3-monthold ("adult") male rats performing digital PCR (dPCR) (using endothelium-intact saphenous arteries), isometric myography, sharp microelectrode technique, quantitative PCR (qPCR) and Western blotting (using endothelium-denuded saphenous arteries), and arterial pressure measurements under urethane anaesthesia. Key Results: We found mRNA of Kcnk1-Kcnk7, Kcnk12, and Kcnk13 genes to be expressed in rat saphenous artery, and Kcnk3 (TASK-1) and Kcnk6 (TWIK-2) were most abundant in both age groups. The TASK-1 channel blocker AVE1231 (1 μmol•L −1) prominently depolarized arterial smooth muscle and increased basal tone level and contractile responses to methoxamine of arteries from young rats but had almost no effect in adult rats. The level of TASK-1 mRNA and protein expression was higher in arteries from young compared with adult rats. Importantly, intravenous administration of AVE1231 (4 mg•kg −1) had no effect on mean arterial pressure in adult rats but prominently raised it in young rats. Conclusion and Implications: We showed that TASK-1 channels are important for negative feedback regulation of vasocontraction in young but not adult rats. The influence of TASK-1 channels most likely contributes to low BP level at perinatal age.

Remodeling of Arterial Tone Regulation in Postnatal Development: Focus on Smooth Muscle Cell Potassium Channels

“…Finally, the anticontractile influence of the vascular endothelium decreases with age [ 22 , 23 ]. This structural and functional remodeling leads to a dramatic rise of systemic blood pressure, which almost doubles from the time of birth [ 18 , 23 , 24 , 25 ].…”

“…The ontogenetic aspect of TASK-1 channel function in systemic arteries has been studied very little. The only work devoted to this issue indicated a decrease in their vasomotor role in early postnatal ontogenesis [ 24 ].…”

“…Blockade of TASK-1 channels was shown to increase basal tone and contractile responses to methoxamine in the saphenous artery of young, but not adult, rats [ 24 ]. In arteries of adult rats, TASK-1 channel blockade did not lead to such a pronounced depolarization of the smooth muscle cells as was observed in young animals.…”

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

“…Thus, BK channels seem to be a good candidate for the above mentioned dominant potassium conductance able to affect the functional role of other K channels including Kv7 channels. Indeed, BK channels have been shown to be the dominant negative feedback regulator of vasocontraction in adult rat saphenous arteries, whereas K ATP -, Kv1-, Kv2-and TASK-1 channels, each one tested for itself, are not involved in this response and Kir2-and Kv7-channels play only a small role (Shvetsova et al, 2019(Shvetsova et al, , 2020. However, none of the latter studies explores the interaction of K channels.…”

“…Thus, the hypothesis was tested that the functional impact of Kv7 channels depends on BK channels. This interaction was studied initially for agonist-induced vasocontraction in rat saphenous arteries, where the role of different VSMC K channels has been described recently in detail (Shvetsova et al, 2019(Shvetsova et al, , 2020 and extended to the gracilis artery myogenic response, another important contractile stimulus. The gracilis artery was used because it possesses prominent myogenic reactivity (see data of the present manuscript), in contrast to the larger saphenous artery and belongs to the same vascular region as the saphenous artery.…”