Experimental Physiology最新文献

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that plays an important role in aldehyde detoxification. A large percentage (30-50%) of the East Asian population carry a single point mutation in the ALDH2 gene (ALDH2*2 variant) that causes a severe reduction or lack of ALDH2 enzyme activity, and leads to disrupted cellular homeostasis due to the accumulation of toxic reactive aldehydes. The ALDH2*2 variant has been associated with several degenerative diseases, with evidence suggesting a link to cardiovascular disease, potentially mediated by endothelial dysfunction. This, however, remains to be confirmed. We aimed to investigate whether the ALDH2*2 variant is associated with impaired endothelial function in young, healthy East Asians. Twenty-two participants were genotyped and divided into non-carriers (ALDH2*1/*1; n = 12; 7 females and 5 males; age = 23 ± 3 years; height = 167.4 ± 8.7 cm; body mass = 60.1 ± 9.0 kg) and carriers (ALDH2*1/*2 and ALDH2*2/*2; n = 10; 8 females and 2 males; age = 24 ± 5 years; height = 162.6 ± 10.1 cm; body mass = 62.1 ± 9.7 kg) of the ALDH2*2 allele. Endothelial function was assessed via flow-mediated dilation (FMD) following current guidelines. Carriers displayed lower FMD, either absolute or relative, which was not statistically significant but approached significance (unpaired t-test) (FMD%: non-carriers = 10.2 ± 1.9% vs. carriers = 8.1% ± 3.1%, P = 0.079, effect size: Cohen's d = 0.82; FMD_abs: non-carriers = 0.32 ± 0.06 mm vs. carriers = 0.26 ± 0.09 mm, P = 0.082, effect size: Cohen's d = 0.78). In conclusion, our data seem to suggest that the ALDH2*2 variant impairs endothelial function even in young and healthy individuals without the presence of other stressor agents. Future studies with larger sample size are necessary to confirm our findings.

The endothelium plays a pivotal role in regulating cerebrovascular blood flow, and its dysfunction increases the risk of cerebrovascular disease. Endothelial shear stress, a primary mechanical stimulus for endothelial nitric oxide production, is a key modulator of vascular adaptation. In recent years, transient hypercapnia-induced flow-mediated dilation of the internal carotid artery (ICA-FMD) has emerged as a valuable in vivo approach for assessing cerebrovascular endothelial function in humans. This review first synthesizes methodological advances in ICA-FMD assessment, emphasizing the importance of transient carbon dioxide (CO₂) inhalation, normalizing ICA-FMD to the shear stress, and consideration of unique ICA haemodynamics. Second, it consolidates mechanistic insights and conditions for improving ICA-FMD, elucidating effective and ineffective strategies. Intermittent hypoxia-induced increases in shear stress improve ICA dilatory response, underscoring the pivotal role of shear rate. Although ICA blood flow during exercise has been extensively studied, data on shear rate during exercise are limited. Moderate-intensity leg cycling that avoids hyperventilation and elevates end-tidal CO₂ partial pressure increases ICA shear rate and augments post-exercise ICA-FMD, whereas higher-intensity exercise or small-muscle exercise fails to produce similar benefits. These observations suggest that a threshold shear stimulus may be required for post-exercise improvements in ICA-FMD. Future research should establish standardized methodologies, define the shear stimulus threshold, elucidate the time course of vascular adaptations, and extend investigations to populations at elevated cerebrovascular risk. Translating these mechanistic insights into clinical strategies has the potential to optimize cerebrovascular endothelial function and thereby contribute to the prevention of cerebrovascular diseases.

Synaptic input to the motoneuron pool is altered during fatiguing muscle contractions. In humans, the corticospinal tract is often studied, with equivocal findings regarding its role in the reduction of force. To date, the involvement of the reticulospinal tract during states of fatigue has not been explored. Fourteen participants (28 ± 6 years, nine males) visited the laboratory twice, first for a familiarisation, then for an experimental trial. Participants completed a 5-min sustained elbow flexor contraction at an intensity eliciting 40% of the EMG recorded during a maximal isometric voluntary contraction (MVC). Before, during and after the contraction, transcranial magnetic stimulation and electrical cervicomedullary stimulation were used to elicit motor evoked potentials (MEPs) and cervicomedullary evoked potentials during the silent period (SP-CMEPs), respectively, with CMEPs also being evoked in combination with a startling acoustic sound (CMEPcon). Electrical stimulation of the brachial plexus was used to evoke maximal compound action potentials of the elbow flexors (M_max). The 5-min contraction induced a 53% loss of force (P < 0.001), with no change in background EMG (∼4% M_max, P = 0.293). Neither MEP amplitude (P = 0.246) nor CMEPcon ratio (P = 0.489) was altered during the contraction, whereas CMEP and SP-CMEP amplitudes were reduced by ∼20% and 50%, respectively (P < 0.001) and remained depressed post-task. The results suggest that neither corticospinal nor reticulospinal tract excitability was altered during a 5-min constant-EMG task at 40% maximal EMG. Instead, the aetiology of the neural contribution to fatigability appeared to be primarily related to the loss of motoneuron excitability.

This study investigated the acute effects of two isoenergetic high-intensity interval exercise (HIIE) sessions, running (HIIE-RUN) and cycling (HIIE-BIKE), on post-exercise oxygen consumption ( ${\dot{V}}_{O_2}$ ), carbon dioxide production ( ${\dot{V}}_{C{O}_2}$ ), substrate oxidation and 24-h energy intake (EI) in men with overweight or obesity. Twelve fasted men (44.4 ± 14.5 years; body mass index: 28.3 ± 1.9 kg m^-2) completed both HIIE sessions. ${\dot{V}}_{O_2}$ and ${\dot{V}}_{C{O}_2}$ were measured before, during and after exercise, while substrate oxidation was calculated before and after exercise. The rate of perceived exertion was recorded during each exercise. Appetite was assessed throughout each session using a visual analogue scale (VAS) and EI was recorded via a 24-h dietary questionnaire. Both exercise modalities resulted in similar energy expenditure (EE), but HIIE-BIKE elicited a significantly higher respiratory exchange ratio (P = 0.002). No significant effect of exercise modality or time × modality interaction was observed for ${\dot{V}}_{O_2}$ and EE during the post-exercise period. Fat oxidation was significantly increased during recovery compared with the pre-exercise levels (P < 0.001), but did not differ between modalities. Appetite and 24-h EI were unaffected by the exercise modality. In men with overweight or obesity, isoenergetic HIIE-RUN and HIIE-BIKE seem to induce comparable post-exercise ${\dot{V}}_{O_2}$ , EE and substrate oxidation during the 2-h recovery period. Both modalities similarly promoted fat oxidation without specific dietary compensation observed.

Chronic visceral pain is a key symptom of irritable bowel syndrome. Modulation of voltage-gated calcium and potassium channels by G protein-coupled receptors plays a key role in dampening nociceptive transmission. Both baclofen and the analgesic peptide α-conotoxin Vc1.1 activate GABA_B receptors (GABA_BR), resulting in inhibition of Ca_V2.2 and Ca_V2.3 calcium channels to reduce colonic nociception. Recent studies have also shown that GABA_BR activation potentiates G-protein-coupled inwardly rectifying potassium (GIRK)-1/2 channels in mammalian sensory afferent neurons. In this study, we investigated the expression of these ion channel targets in rodent and human dorsal root ganglion (DRG) neurons, including those innervating the colon. We examined how Ca_V2.2 and GIRK channel antagonists, as well as a GIRK channel activator, influence the passive and active electrical properties of adult mouse DRG neurons. We also assessed the effects of α-conotoxin Vc1.1 on neuronal excitability in the presence of the selective Ca_V2.2 antagonist ω-conotoxin CVIE and the GIRK channel activator ML297. We further evaluated the impact of the GIRK channel antagonist tertiapin-Q on excitability in mouse colonic DRGs and afferents and explored the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Our findings demonstrate that both Ca_V2.2 inhibition and GIRK channel potentiation reduce excitability in mouse DRGs, likely mediating the antinociceptive effects of Vc1.1 and baclofen observed in vivo. However, GIRK channel potentiation appears to play only a limited role in modulating excitability in colon-innervating DRGs and colonic afferents. These findings suggest that neurons innervating different body regions use distinct mechanisms to regulate excitability and nociceptive signalling.