Fluid replacement modulates oxidative stress- but not nitric oxide-mediated cutaneous vasodilation and sweating during prolonged exercise in the heat

The roles of nitric oxide synthase (NOS), reactive oxygen species (ROS), and angiotensin II type 1 receptor (AT₁R) activation in regulating cutaneous vasodilation and sweating during prolonged (≥60 min) exercise are currently unclear. Moreover, it remains to be determined whether fluid replacement (FR) modulates the above thermoeffector responses. To investigate, 11 young men completed 90 min of continuous moderate intensity (46% Vo_2peak) cycling performed at a fixed rate of metabolic heat production of 600 W (No FR condition). On a separate day, participants completed a second session of the same protocol while receiving FR to offset sweat losses (FR condition). Cutaneous vascular conductance (CVC) and local sweat rate (LSR) were measured at four intradermal microdialysis forearm sites perfused with: 1) lactated Ringer (Control); 2) 10 mM N^G-nitro-l-arginine methyl ester (l-NAME, NOS inhibition); 3) 10 mM ascorbate (nonselective antioxidant); or 4) 4.34 nM losartan (AT₁R inhibition). Relative to Control (71% CVC_max at both time points), CVC with ascorbate (80% and 83% CVC_max) was elevated at 60 and 90 min of exercise during FR (both P < 0.02) but not at any time during No FR (all P > 0.31). In both conditions, CVC was reduced at end exercise with l-NAME (60% CVC_max; both P < 0.02) but was not different relative to Control at the losartan site (76% CVC_max; both P > 0.19). LSR did not differ between sites in either condition (all P > 0.10). We conclude that NOS regulates cutaneous vasodilation, but not sweating, irrespective of FR, and that ROS influence cutaneous vasodilation during prolonged exercise with FR.

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The plateau in the NIRS-derived [HHb] signal near the end of a ramp incremental test does not indicate the upper limit of O2 extraction in the vastus lateralis

This study aimed to examine, at the level of the active muscles, whether the plateau in oxygen (O₂) extraction normally observed near the end of a ramp incremental (RI) exercise test to exhaustion is caused by the achievement of an upper limit in O₂ extraction. Eleven healthy men (27.3 ± 3.0 yr, 81.6 ± 8.1 kg, 183.9 ± 6.3 cm) performed a RI cycling test to exhaustion. O₂ extraction of the vastus lateralis (VL) was measured continuously throughout the test using the near-infrared spectroscopy (NIRS)-derived deoxygenated hemoglobin [HHb] signal. A leg blood flow occlusion was performed at rest (LBF_OCC1) and immediately after the RI test (LBF_OCC2). The [HHb] values during the resting occlusion (108.1 ± 21.7%; LBF_OCC1) and the peak values during exercise (100 ± 0%; [HHb]_plateau) were significantly greater than those observed at baseline (0.84 ± 10.6% at baseline 1 and 0 ± 0% at baseline 2) (P < 0.05). No significant difference was found between LBF_OCC1 and [HHb]_plateau (P > 0.05) or between the baseline measurements (P > 0.05). [HHb] values at LBF_OCC2 (130.5 ± 19.7%) were significantly greater than all other time points (P < 0.05). These results support the existence of an O₂ extraction reserve in the VL muscle at the end of a RI cycling test and suggest that the observed plateau in the [HHb] signal toward the end of a RI test is not representative of an upper limit in O₂ extraction.

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Comparative NMR and NIRS analysis of oxygen-dependent metabolism in exercising finger flexor muscles

Muscle contraction requires the physiology to adapt rapidly to meet the surge in energy demand. To investigate the shift in metabolic control, especially between oxygen and metabolism, researchers often depend on near-infrared spectroscopy (NIRS) to measure noninvasively the tissue O₂. Because NIRS detects the overlapping myoglobin (Mb) and hemoglobin (Hb) signals in muscle, interpreting the data as an index of cellular or vascular O₂ requires deconvoluting the relative contribution. Currently, many in the NIRS field ascribe the signal to Hb. In contrast, ¹H NMR has only detected the Mb signal in contracting muscle, and comparative NIRS and NMR experiments indicate a predominant Mb contribution. The present study has examined the question of the NIRS signal origin by measuring simultaneously the ¹H NMR, ³¹P NMR, and NIRS signals in finger flexor muscles during the transition from rest to contraction, recovery, ischemia, and reperfusion. The experiment results confirm a predominant Mb contribution to the NIRS signal from muscle. Given the NMR and NIRS corroborated changes in the intracellular O₂, the analysis shows that at the onset of muscle contraction, O₂ declines immediately and reaches new steady states as contraction intensity rises. Moreover, lactate formation increases even under quite aerobic condition.

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A new paradigm of sodium regulation in inflammation and hypertension

Dysregulation of sodium (Na⁺) balance is a major cause of hypertensive cardiovascular disease. The current dogma is that interstitial Na⁺ readily equilibrates with plasma and that renal excretion and reabsorption is sufficient to regulate extracellular fluid volume and control blood pressure. These ideas have been recently challenged by the discovery that Na⁺ accumulates in tissues without commensurate volume retention and activates immune cells, leading to hypertension and autoimmune disease. However, objections have been raised to this new paradigm, with some investigators concerned about where and how salt is stored in tissues. Further concerns also include how Na⁺ is mobilized from tissue stores and how it interacts with various organ systems to cause hypertension and end-organ damage. This review assesses these two paradigms of Na⁺ regulation in the context of inflammation-mediated hypertension and cardiovascular disease pathogenesis. Also highlighted are future perspectives and important gaps in our understanding of how Na⁺ is linked to inflammation and hypertension. Understanding mechanisms of salt and body fluid regulation is the sine qua non of research efforts to identify therapeutic targets for hypertension and cardiovascular disease.

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Immune regulation of systemic hypertension, pulmonary arterial hypertension, and preeclampsia: shared disease mechanisms and translational opportunities

Systemic hypertension, preeclampsia, and pulmonary arterial hypertension (PAH) are diseases of high blood pressure in the systemic or pulmonary circulation. Beyond the well-defined contribution of more traditional pathophysiological mechanisms, such as changes in the renin–angiotensin–aldosterone system, to the development of these hypertensive disorders, there is substantial clinical evidence supporting an important role for inflammation and immunity in the pathogenesis of each of these three conditions. Over the last decade, work in small animal models, bearing targeted deficiencies in specific cytokines or immune cell subsets, has begun to clarify the immune-mediated mechanisms that drive changes in vascular structure and tone in hypertensive disease. By summarizing the clinical and experimental evidence supporting a contribution of the immune system to systemic hypertension, preeclampsia, and PAH, the current review highlights the cellular and molecular pathways that are common to all three hypertensive disorders. These mechanisms are centered on an imbalance in CD4⁺ helper T cell populations, defined by excessive Th17 responses and impaired T_reg activity, as well as the excessive activation or impairment of additional immune cell types, including macrophages, dendritic cells, CD8⁺ T cells, B cells, and natural killer cells. The identification of common immune mechanisms in systemic hypertension, preeclampsia, and PAH raises the possibility of new therapeutic strategies that target the immune component of hypertension across multiple disorders.

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Small functional If current in sinoatrial pacemaker cells of the brown trout (Salmo trutta fario) heart despite strong expression of HCN channel transcripts

Funny current (I_f), formed by hyperpolarization-activated cyclic nucleotide-gated channels (HCN channels), is supposed to be crucial for the membrane clock regulating the cardiac pacemaker mechanism. We examined the presence and activity of HCN channels in the brown trout (Salmo trutta fario) sinoatrial (SA) pacemaker cells and their putative role in heart rate (f_H) regulation. Six HCN transcripts (HCN1, HCN2a, HCN2ba, HCN2bb, HCN3, and HCN4) were expressed in the brown trout heart. The total HCN transcript abundance was 4.0 and 4.9 times higher in SA pacemaker tissue than in atrium and ventricle, respectively. In the SA pacemaker, HCN3 and HCN4 were the main isoforms representing 35.8 ± 2.7 and 25.0 ± 1.5%, respectively, of the total HCN transcripts. Only a small I_f with a mean current density of –1.2 ± 0.37 pA/pF at –140 mV was found in 4 pacemaker cells out of 16 spontaneously beating cells examined, despite the optimization of recording conditions for I_f activity. I_f was not found in any of the 24 atrial myocytes and 21 ventricular myocytes examined. HCN4 coexpressed with the MinK-related peptide 1 (MiRP1) β-subunit in CHO cells generated large I_f currents. In contrast, HCN3 (+MiRP1) failed to produce I_f in the same expression system. Cs⁺ (2 mM), which blocked 84 ± 12% of the native I_f, reversibly reduced f_H 19.2 ± 3.6% of the excised multicellular pacemaker tissue from 53 ± 5 to 44 ± 5 beats/min (P < 0.05). However, this effect was probably due to the reduction of I_Kr, which was also inhibited (63.5 ± 4.6%) by Cs⁺. These results strongly suggest that f_H regulation in the brown trout heart is largely independent on I_f.

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Correction to: Telomere length of gallbladder epithelium is shortened in patients with congenital biliary dilatation: measurement by quantitative fluorescence in situ hybridization

Abstract

In the original publication of this article, Fig. 5 was published with incorrect color of the approximate lines of CBD and Control.

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