The negative feedback regulation of vasocontraction by potassium channels varies during maturation depending on the channel type. A dominating contribution of K 7 channels to the regulation of basal tone and agonist-induced contraction was observed in arteries of 10- to 15-day-old animals.
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.
Rho-kinase contribution to contractile responses of mesenteric and especially sural arteries is augmented in adult PTU rats. Therefore, maternal thyroid deficiency may have long-term detrimental consequences for vasculature in adult offspring.
The mechanisms of vascular alterations resulting from early thyroid hormones deficiency are poorly understood. We tested the hypothesis that antenatal/early postnatal hypothyroidism would alter the activity of endothelial NO pathway and Rho-kinase pathway, which are specific for developing vasculature. Dams were treated with propylthiouracil (PTU, 7 ppm) in drinking water during gestation and 2 weeks after delivery, and their progeny had normal body weight but markedly reduced blood levels of thyroid hormones (ELISA). Small arteries from 2-week-old male pups were studied using wire myography, qPCR and Western blotting. Mesenteric arteries of PTU pups, compared to controls, demonstrated smaller maximum response to α-adrenergic agonist methoxamine and reduced mRNA contents of smooth muscle differentiation markers α-actin and SERCA2A. Inhibition of basal NO synthesis by l-NNA led to tonic contraction of mesenteric arteries and augmented their contractile responses to methoxamine; both l-NNA effects were impaired in PTU pups. PTU pups demonstrated lower blood level of NO metabolites compared to control group (Griess reaction). Rho-kinase inhibitor Y27632 strongly reduced mesenteric arteries responses to methoxamine in PTU pups, that was accompanied by elevated Rho-kinase content in their arteries in comparison to control ones. Unlike mesenteric, saphenous arteries of PTU pups, compared to controls, had no changes in α-actin and SERCA2A contents and in responses to l-NNA and Y27632. In conclusion, thyroid hormones deficiency suppresses the anticontractile effect of NO and potentiates the procontractile Rho-kinase effects in mesenteric arteries of 2-week-old pups. Such alterations disturb perinatal cardiovascular homeostasis and might lead to cardiovascular pathologies in adulthood.
Membrane transporters and their functional contribution in vasculature change during early postnatal development. Here we tested the hypothesis that the contribution of Cl− channels to arterial contraction declines during early postnatal development and this decline is associated with the trophic sympathetic influence. Endothelium‐denuded saphenous arteries from 1- to 2-week-old and 2- to 3-month-old male rats were used. Arterial contraction was assessed in the isometric myograph, in some experiments combined with measurements of membrane potential. mRNA and protein levels were determined by qPCR and Western blot. Sympathectomy was performed by treatment with guanethidine from the first postnatal day until 8–9-week age. Cl− substitution in the solution as well as Cl−-channel blockers (MONNA, DIDS) had larger suppressive effect on the methoxamine-induced arterial contraction and methoxamine-induced depolarization of smooth muscle cells in 1- to 2-week-old compared to 2- to 3-month-old rats. Vasculature of younger group demonstrated elevated expression levels of TMEM16A and bestrophin 3. Chronic sympathectomy increased Cl− contribution to arterial contraction in 2-month-old rats that was associated with an increased TMEM16A expression level. Our study demonstrates that contribution of Cl− channels to agonist-induced arterial contraction and depolarization decreases during postnatal development. This postnatal decline is associated with sympathetic nerves development.
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