ИСТИНА

Potassium channels are key regulators of arterial smooth muscle membrane potential. Consequently, they are important checkpoints for the control of arterial tone. There are five types of potassium channels in arterial smooth muscle: voltage-gated potassium channels (Kv1, Kv2 and Kv7 families), large-conductance Ca2+-activated potassium channels (BKCa), inward-rectifier potassium channels (Kir), ATP-sensitive potassium channels (KATP) and two-pore potassium channels (K2P). Importantly, widespread cardiovascular disorders, such as ischemia/reperfusion and hypertension are often associated with altered functions of potassium channels. Cardiovascular system undergoes crucial structural and functional alterations during maturation. However, the data related to the potassium channel functioning are rather controversial and were obtained on the arteries of cerebral and pulmonary circulation. Therefore, there is no information about the changes in potassium channel functioning during ontogenesis in arteries of peripheral circulation, which are extremely essential for the control of arterial pressure. Thus, the aim of my doctoral project is to test the hypothesis that the contribution of potassium channels to contraction in peripheral arteries changes during maturation. This will be achieved by pursuing the following research tasks: Task 1. To study the effects of potassium channels inhibitors on the contractility and membrane potential (MP) of endothelium-denuded arteries of 10-15-day old and adult rats under basal conditions and during agonist stimulation; Task 2. To compare mRNA expression levels of pore-forming and regulatory potassium channel subunits in endothelium-denuded arteries of 10-15-day old and adult rats. Methods. All experiments were performed on endothelium-denuded saphenous arteries isolated from hindlimb of young (10-15-day) and adult (2-3-month) male rats. Isometric force and MP were recorded using wire myography and the sharp microelectrode technique, respectively. The functional role of potassium channels was studied using their specific inhibitors. Potassium channel subunit expression was determined by qPCR. Current outcome. We demonstrated that the effects of K2P, Kv1, Kir and Kv7 channel blockers (AVE1231 1μM, DPO-1 1μM, BaCl2 30μM, XE991 3μM) on contraction were larger in arteries of young compared to adult animals. In contrast, the BKCa channel blocker iberiotoxin (0.1μM) had a stronger influence in adult animals. The effects of KATP and Kv2 channel blockers (glibenclamide 3μM, stromatoxin 0.1μM) were not pronounced in either adult or young animals. The larger influence of Kv7 and Kir channel blockade on arterial contraction in young rats was associated with more prominent smooth muscle depolarization. The developmental alterations in potassium channel function were generally consistent with their mRNA expression patterns in arterial smooth muscle. Conclusions and future directions. The contribution of potassium channels to the regulation of contractile responses of peripheral arteries during maturation varies depending on the channel type. A dominating contribution of Kir and especially Kv7 channels to the regulation of basal tone and contraction was observed in arteries of young animals. We suggest that high activity of several types of potassium channels in the circulatory system of young animals can serve as a mechanism keeping peripheral resistance low in the immature cardiovascular system, thereby reducing the risk of vessel injury/remodeling and associated hypertension. Thus, in future experiments we are going to study the effects of potassium channel blockers on blood pressure level in vivo in young rats.