This article reviews the existing knowledge about the effects of physical exercise on nitric oxide (NO) production in the cardiopulmonary system. The authors review the sources of NO in the cardiopulmonary system; involvement of three forms of NO synthases (eNOS, nNOS, and iNOS) in exercise physiology; exercise-induced modulation of NO and/or NOS in physiological and pathophysiological conditions in human subjects and animal models in the absence and presence of pharmacological modulators; and significance of exercise-induced NO production in health and disease. The authors suggest that physical activity significantly improves functioning of the cardiovascular system through an increase in NO bioavailability, potentiation of antioxidant defense, and decrease in the expression of reactive oxygen species-forming enzymes. Regular physical exercises are considered a useful approach to treat cardiovascular diseases. Future studies should focus on detailed identification of (i) the exercise-mediated mechanisms of NO exchange; (ii) optimal exercise approaches to improve cardiovascular function in health and disease; and (iii) physical effort thresholds.

Here we review available data on nitric oxide (NO)-mediated signaling in skeletal muscle during physical exercise. Nitric oxide modulates skeletal myocyte function, hormone regulation, and local microcirculation. Nitric oxide underlies the therapeutic effects of physical activity whereas the pharmacological modulators of NO-mediated signaling are the promising therapeutic agents in different diseases. Nitric oxide production increases in skeletal muscle in response to physical activity. This molecule can alter energy supply in skeletal muscle through hormonal modulation. Mitochondria in skeletal muscle tissue are highly abundant and play a pivotal role in metabolism. Considering NO a plausible regulator of mitochondrial biogenesis that directly affects cellular respiration, we discuss the mechanisms of NO-induced mitochondrial biogenesis in the skeletal muscle cells. We also review available data on myokines, the molecules that are expressed and released by the muscle fibers and exert autocrine, paracrine and/or endocrine effects. The article suggests the presence of putative interplay between NO-mediated signaling and myokines in skeletal muscle. Data demonstrate an important role of NO in various diseases and suggest that physical training may improve health of patients with diabetes, chronic heart failure, and even degenerative muscle diseases. We conclude that NO-associated signaling represents a promising target for the treatment of various diseases and for the achievement of better athletic performance.

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.

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.

Extensive exercise increases the plasma content of IL-6, IL-8, IL-15, leukemia inhibitory factor (LIF), and several other cytokines via their augmented transcription in skeletal muscle cells. However, the relative impact of aerobic and resistant training interventions on cytokine production remains poorly defined. In this study, we compared effects of dynamic and static load on cytokine plasma content in elite strength- and endurance-trained athletes versus healthy untrained volunteers. The plasma cytokine content was measured before, immediately after, and 30 min post-exercise using enzyme-linked immunosorbent assay. Pedaling on a bicycle ergometer increased IL-6 and IL-8 content in the plasma of trained athletes by about 4- and 2-fold, respectively. In contrast to dynamic load, weightlifting had negligible impact on these parameters in strength exercise-trained athletes. Unlike IL-6 and IL-8, endurance exercise had no impact on IL-15 and LIF, whereas static load increases the content of these cytokines by ~50%. Two-fold increment of IL-8 content seen in athletes subjected to endurance exercise was absent in untrained individuals, whereas the ~50% increase in IL-15 triggered by static load in the plasma of weightlifting athletes was not registered in the control group. Thus, our results show the distinct impact of static and dynamic exercise on cytokine content in the plasma of trained athletes. They also demonstrate that both types of exercises differentially affect cytokine content in plasma of athletes and untrained persons.

Recent studies demonstrated that in addition to Na⁺,K⁺-ATPase inhibition cardiotonic steroids (CTSs) affect diverse intracellular signaling pathways. This study examines the relative impact of [Na⁺]_i/[K⁺]_i-mediated and -independent signaling in transcriptomic changes triggered by the endogenous CTSs ouabain and marinobufagenin (MBG) in human umbilical vein endothelial cells (HUVEC). We noted that prolongation of incubation increased the apparent affinity for ouabain estimated by the loss of [K⁺]_i and gain of [Na⁺]_i. Six hour exposure of HUVEC to 100 and 3,000 nM ouabain resulted in elevation of the [Na⁺]_i/[K⁺]_i ratio by ~15 and 80-fold and differential expression of 258 and 2185 transcripts, respectively. Neither [Na⁺]_i/[K⁺]_i ratio nor transcriptome were affected by 6-h incubation with 30 nM ouabain. The 96-h incubation with 3 nM ouabain or 30 nM MBG elevated the [Na⁺]_i/[K⁺]_i ratio by ~14 and 3-fold and led to differential expression of 880 and 484 transcripts, respectively. These parameters were not changed after 96-h incubation with 1 nM ouabain or 10 nM MBG. Thus, our results demonstrate that elevation of the [Na⁺]_i/[K⁺]_i ratio is an obligatory step for transcriptomic changes evoked by CTS in HUVEC. The molecular origin of upstream [Na⁺]_i/[K⁺]_i sensors involved in transcription regulation should be identified in forthcoming studies.