Pflugers Archiv : European journal of physiology最新文献

Bradykinin (BK) may increase renal sodium excretion by decreasing tubular ENaC activity. Afferent renal nerve activity (ARNA) putatively controls renal sympathetic nerve activity (RSNA) involved in renal sodium handling. We recently found tonic sympatho-inhibition due to intrarenal ARNA stimulation by the TRPV1 agonist capsaicin (CAP). Since BK is known to augment TRPV1 effects, we hypothesized that intrarenally applied BK also tonically inhibits RSNA. Four groups of rats (n = 8; BK, CAP, HOE + BK, NaCl-control) were equipped with arterial and venous catheters for blood pressure (BP) and heart rate (HR) recordings and drug application; bipolar electrodes for RSNA and ARNA recordings, renal arterial catheter for intrarenal administration (IRA) of bradykinin (BK: 10^-5 M, 20 µl and 10^-4 M; 2.5, 5, 10 µl), capsaicin (CAP 3.3, 6.6, 10 and 33*10^-7 M, 10 µl). The B2-receptor antagonist HOE-140 (10^-4 M, 40 µl) was administered intravenously (IV) just before IRA BK (HOE + BK), finally the NK₁-receptor blocker RP67580 (10^-2 M, 15 µl; IV) was applied in all groups at the end of the experiment. IRA BK and CAP momentarily increased ARNA. IRA CAP, IRA BK, and IRA HOE + BK, decreased RSNA from 4.2 ± 0.8 to 1.3 ± 0.2 µV*sec (BK, P < 0.01), 3.6 ± 0.5 to 0.9 ± 0.2 µV*sec (CAP, P < 0.01) and 3.2 ± 0.3 to 0.8 ± 0.1 µV*sec (HOE-BK, P < 0.01). Suppressed RSNA (BK, CAP, HOE + BK) was unmasked by IV RP67580: 1.6 ± 0.5 to 8.6 ± 2.9 µV*sec (BK, P < 0.01); 1.0 ± 0.2 to 6.1 ± 1.5 µV*sec (CAP, P < 0.01); 0.8 ± 0.2 to 4.5 ± 0.8 µV*sec (HOE-BK, P < 0.05). IRA BK was associated with momentary increases of RSNA, abolished by HOE-140. Intrarenal stimulation of renal afferent nerves by BK induced tonic renal sympathodepression likely augmenting sodium and water excretion.

Rhinorrhoea associated with viral upper respiratory tract infections or reactions to aeroallergens affects all human beings and has been associated with loss of quality of life. Pulmonary fluid accumulation in acute lung injury is a leading cause of hospital admission and death from lower respiratory tract infection and sepsis. In this review, the evidence is presented supporting the hypothesis that both rhinorrhoea and inflammation-related pulmonary fluid accumulation are primarily due to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR). Novel concepts of the mechanisms involved are introduced. Upper airway as well as alveolar surface liquid volumes have been shown to be dependent on the function of the CFTR. Its function is regulated directly by cytokines and through increased hydrostatic tissue pressure secondary to vasodilatation in allergic inflammation and infection. Regulation of upper airway fluid secretion manifested in allergic inflammation and viral infections can be explained by CFTR activation through vasodilatation mediated by bradykinin and histamine, and CFTR upregulation by interleukin-4. Alveolar fluid accumulation is related to inactivation of CFTR through microRNA derived from genomic cytokine effects including interleukin-1, interleukin-8, transforming growth factor, and tumour necrosis factor. The role of concomitant sodium-potassium ATPase inhibition is explained. Therapeutic interventions including already known CFTR inhibitors for excessive fluid secretion in the upper respiratory tract and remedies for inflammation-induced fluid accumulation in the lower respiratory tract due to CFTR dysfunction using anti-inflammatory and CFTR activating agents are introduced.

The beneficial effects of regular exercise may be mediated through its regulatory influence on circadian rhythm. Here, we investigated how regular exercise training affects spontaneous locomotor activity (SLA) and body temperature (T-body) rhythms and its influence on temporal changes in brain dopaminergic and serotonergic activity, corticosterone levels, and muscle Per1 and Bmal1 gene expression. The aerobic exercise schedule consisted of five days of training in the light phase (Zeitgeber time = ZT4 to ZT6, with light on at 7:00 h) followed by a two-day recovery period. After 8 weeks, brain, blood, and muscle samples were collected from adult male rats. Dopamine (DA) and serotonin (5-HT) and their respective metabolites, DOPAC and 5-HIAA, were measured in microdissections of the caudate putamen (CP), preoptic area (POA), and the paraventricular nucleus of the hypothalamus (PVN). Exercise increased the SLA at the end of the night, delayed the acrophase, and increased the mesor of the SLA rhythm. No alterations were found in the T-body rhythm and corticosterone blood levels, although hyperthermia was observed after exercise sessions. Exercise increased muscle Per1 expression at ZT0, leading to a non-rhythmic profile in exercised animals. There were no changes in the CP dopaminergic and serotonergic activity, but there was a decrease in POA at ZT6 and an increase in PVN serotonergic activity at ZT0, resulting in a non-rhythmic profile in exercised animals. Thus, regular physical exercise during the light phase with alterations in SLA promotes adjustments in the daily oscillation in monoaminergic activity in areas directly involved in regulating daily T-body and SLA.

Pericytes in microvasculature of the bladder suburothelium develop spontaneous Ca²⁺ transients that propagate within the pericyte network. Here, the expression of ANO1 Ca²⁺-activated Cl^- channels that serve as smooth muscle pacemaker channels was investigated in mural cells of the mouse bladder microvasculature. The involvement of ANO1 in the generation of propagating spontaneous Ca²⁺ transients or vasocontractions was also examined. Fluorescence immunohistochemistry was utilised to visualise ANO1 expression in different microvascular segments. Intercellular Ca²⁺ dynamics in pericytes of capillaries or pre-capillary arterioles (PCAs) were visualised using NG2-GCaMP6 mice, while Ca²⁺ signals in venular pericytes were detected using Cal-520 fluorescence. Spontaneous or electrical field stimulation (EFS)-induced vascular diameter changes were measured using a video-tracking system. ANO1 expression was greatest in capillary pericytes, followed by pericytes in PCAs or post-capillary venules, while arteriolar smooth muscle cells (SMCs) or venular pericytes exhibited lower ANO1 immunoreactivity. In capillaries where pericytes developed nifedipine-resistant propagating spontaneous Ca²⁺ transients, Ani9 (3 µM), the specific ANO1 inhibitor, disrupted the intercellular synchrony of Ca²⁺ transients. In venules, Ani9 disrupted the synchrony of spontaneous Ca²⁺ transients amongst venular pericytes and prevented the generation of spontaneous phasic constrictions (SPCs). Ani9 also diminished EFS-evoked, α-adrenergic venular constrictions. In contrast, Ani9 failed to attenuate EFS-induced, predominantly α-adrenergic constrictions in arterioles where SPCs were absent. Thus, ANO1 appears to play a fundamental role in the generation of propagating spontaneous Ca²⁺ transients in capillary, PCA and venular pericytes. Lack of spontaneous Ca²⁺ transients/SPCs in arterioles may be partly attributable to the low ANO1 expression in arteriolar SMCs.

Single-nucleotide polymorphisms in mitochondrial DNA (mtDNA) encoded genes of respiratory chain complexes are known to be associated with severe diseases and life-threatening syndromes. In the assembly of the ATP synthase, the enzyme that in the final steps of oxidative phosphorylation generates ATP from ADP and inorganic phosphate, two subunits (ATP6 and ATP8) are mtDNA-encoded. In our study, we investigated the impact of a single-nucleotide polymorphism in MT-ATP8 with respect to memory function in a preclinical model. Here, we have employed two conplastic mouse strains. The mouse strain C57BL/6 J-mt^AKR/J served as a control with wild-type sequence in MT-ATP8, while C57BL/6 J-mt^FVB/NJ exhibited an m.7778G > T transversion. Using two age groups (3 months and 24 months), levels of reactive oxygen species (ROS), spatial learning in the Morris-Water-Maze, and long-term potentiation were assessed. Immunohistologically, the expressions of NeuN and GFAP were quantified. Additionally, the lifespan of both strains was registered. In comparison to young C57BL/6 J-mt^FVB/NJ mice, aged animals had higher ROS levels in the hippocampus. A decreased NeuN/GFAP level was found in C57BL/6 J-mt^FVB/NJ mice as well as in old animals of the control strain. Aged animals performed worse in the swimming trials, but no significant differences between both strains were detected. The long-term potentiation recordings revealed reduced synaptic plasticity in young C57BL/6 J-mt^FVB/NJ mice. Interestingly, C57BL/6 J-mt^FVB/NJ mice presented an extended lifespan compared to animals of the control strain. Together, our data suggest a minor impact of a single-nucleotide polymorphism in MT-ATP8 on spatial learning and oxidative stress depending on the neuronal tissue. In line with the concept of mitohormesis, our findings may be linked to the longevity of mice harbouring single-nucleotide polymorphisms.

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by systemic oxidative stress and inflammation that extends beyond the pulmonary vasculature to the musculoskeletal system. Combined exercise training (ET), incorporating aerobic and resistance components, is a promising non-pharmacological intervention, but its effects on musculoskeletal oxidative stress and inflammation remain unclear. To evaluate the effects of combined ET on musculoskeletal oxidative stress and inflammation, muscle wasting, and survival in a monocrotaline (MCT)-induced PAH. Male Wistar rats were assigned to MCT-treated sedentary (MCT-SED) or ET (MCT-ET) groups (n = 12/group), or saline-treated sedentary (SAL-SED) or ET (SAL-ET) controls (n = 8/group). PAH was induced via MCT injection (MCT, 40 mg/kg). The ET consisted of moderate-intensity interval aerobic (3x/week) and resistance (2x/week) training for four weeks. Muscle mass, oxidative stress and inflammation markers (IL-6, IL-10, TNF-α) were assessed in gastrocnemius and diaphragm muscles. PAH increased oxidative damage, reduced antioxidant defences, and elevated inflammatory markers in both muscles, contributing to muscle loss. Combined ET enhanced gastrocnemius antioxidant capacity (FRAP, SOD), reduced pro-oxidants (hydrogen peroxide, nitrite), and attenuated oxidative damage (TBARS, carbonyls) in both muscles. Combined ET decreased pro-inflammatory markers (IL-6, TNF-α), prevented diaphragm atrophy, and improved survival (MCT-SED vs. MCT-ET, p = 0.03; hazard ratio, 4.3; 95% CI, 1.2-15.1). Combined interval ET improved redox balance and inflammatory profiles in both peripheral and respiratory muscles. These adaptations were linked to reduced diaphragm muscle wasting and enhanced survival in MCT-induced PAH. Our findings support combined ET as a non-pharmacological strategy for managing systemic complications of PAH.