This review summarizes the data on the functional significance of ubiquitous (NKCC1) and renal-specific (NKCC2) isoforms of electroneutral sodium, potassium and chloride cotransporters. These carriers contribute to the pathogenesis of hypertension via regulation of intracellular chloride concentration in vascular smooth muscle and neuronal cells and via sensing chloride concentration in the renal tubular fluid, respectively. Both NKCC1 and NKCC2 are inhibited by furosemide and other high-ceiling diuretics widely used for attenuation of extracellular fluid volume. However, the chronic usage of these compounds for the treatment of hypertension and other volume-expanded disorders may have diverse side-effects due to suppression of myogenic response in microcirculatory beds.

The hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) is about 6% and has not decreased in recent years. The leading cause of death of these patients is ischemia/reperfusion (I/R) cardiac injury. It is quite obvious that there is an urgent need to create new drugs for the treatment of STEMI based on knowledge about the pathogenesis of I/R cardiac injury, in particular, based on knowledge about the molecular mechanism of ferroptosis. In this study, it was demonstrated that ferroptosis is involved in the development of I/R cardiac injury, antitumor drug-induced cardiomyopathy, diabetic cardiomyopathy, septic cardiomyopathy, and inflammation. There is indirect evidence that ferroptosis participates in stress-induced cardiac injury. The activation of AMPK, PKC, ERK1/2, PI3K, and Akt prevents myocardial ferroptosis. The inhibition of HO-1 alleviates myocardial ferroptosis. The roles of GSK-3β and NOS in the regulation of ferroptosis require further study. The stimulation of Nrf2, STAT3 prevents ferroptosis. The activation of TLR4 and NF-κB promotes ferroptosis of cardiomyocytes. MiR-450b-5p and miR-210-3p can increase the tolerance of cardiomyocytes to hypoxia/reoxygenation through the inhibition of ferroptosis. Circ_0091761 RNA, miR-214-3p, miR-199a-5p, miR-208a/b, miR-375-3p, miR-26b-5p and miR-15a-5p can aggravate myocardial ferroptosis.

This study examines the relative impact of canonical hypoxia-inducible factor-1alpha- (HIF-1α and Na⁺_i/K⁺_i-mediated signaling on transcriptomic changes evoked by hypoxia and glucose deprivation. Incubation of RASMC in ischemic conditions resulted in ∼3-fold elevation of [Na⁺]_i and 2-fold reduction of [K⁺]_i. Using global gene expression profiling we found that Na⁺,K⁺-ATPase inhibition by ouabain or K⁺-free medium in rat aortic vascular smooth muscle cells (RASMC) led to the differential expression of dozens of genes whose altered expression was previously detected in cells subjected to hypoxia and ischemia/reperfusion. For further investigations, we selected Cyp1a1, Fos, Atf3, Klf10, Ptgs2, Nr4a1, Per2 and Hes1, i.e. genes possessing the highest increments of expression under sustained Na⁺,K⁺-ATPase inhibition and whose implication in the pathogenesis of hypoxia was proved in previous studies. In ouabain-treated RASMC, low-Na⁺, high-K⁺ medium abolished amplification of the [Na⁺]_i/[K⁺]_i ratio as well as the increased expression of all tested genes. In cells subjected to hypoxia and glucose deprivation, dissipation of the transmembrane gradient of Na⁺ and K⁺ completely eliminated increment of Fos, Atf3, Ptgs2 and Per2 mRNAs and sharply diminished augmentation expression of Klf10, Edn1, Nr4a1 and Hes1. In contrast to low-Na⁺, high-K⁺ medium, RASMC transfection with Hif-1a siRNA attenuated increments of Vegfa, Edn1, Klf10 and Nr4a1 mRNAs triggered by hypoxia but did not impact Fos, Atf3, Ptgs2 and Per2 expression. Thus, our investigation demonstrates, for the first time, that Na⁺_i/K⁺_i-mediated, Hif-1α- -independent excitation-transcription coupling contributes to transcriptomic changes evoked in RASMC by hypoxia and glucose deprivation.

Экспериментальная модель метаболического синдрома у крыс на основе высокожировой и высокоуглеводной диеты

This review summarizes the data on the functioning of carriers providing electroneutral symport of sodium, potassium, and chloride (Na+,K+,2Cl− cotransport), potassium and chloride (K+,Cl−...

Objectives: This study examined the dose-dependent actions of hydrogen sulfide donor sodium hydrosulphide (NaHS) on isometric contractions and ion transport in rat aorta smooth muscle cells (SMC). Methods: Isometric contraction was measured in ring aortas segments from male Wistar rats. Activity of Na⁺/K⁺-pump and Na⁺,K⁺,2Cl^-cotransport was measured in cultured endothelial and smooth muscle cells from the rat aorta as ouabain-sensitive and ouabain-resistant, bumetanide-sensitive components of the ⁸⁶Rb influx, respectively. Results: NaHS exhibited the bimodal action on contractions triggered by modest depolarization ([K⁺]_o=30 mM). At 10⁻⁴ M, NaHS augmented contractions of intact and endothelium-denuded strips by ~ 15% and 25%, respectively, whereas at concentration of 10⁻³ M it decreased contractile responses by more than two-fold. Contractions evoked by 10⁻⁴ M NaHS were completely abolished by bumetanide, a potent inhibitor of Na⁺,K⁺,2Cl^-cotransport, whereas the inhibition seen at 10⁻³ M NaHS was suppressed in the presence of K⁺ channel blocker TEA. In cultured SMC, 5×10⁻⁵ M NaHS increased Na⁺,K⁺,2Cl^- - cotransport without any effect on the activity of this carrier in endothelial cells. In depolarized SMC, ⁴⁵Ca influx was enhanced in the presence of 10⁻⁴ M NaHS and suppressed under elevation of [NaHS] up to 10⁻³ M. ⁴⁵Ca influx triggered by 10⁻⁴ M NaHS was abolished by bumetanide and L-type Ca²⁺ channel blocker nicardipine. Conclusions: Our results strongly suggest that contractions of rat aortic rings triggered by low doses of NaHS are mediated by activation of Na⁺,K⁺,2Cl^-cotransport and Ca²⁺ influx via L-type channels.