Exogenous glucose oxidation (CHOexo) is suppressed during endurance exercise performed in hot conditions, although the underlying mechanisms and effects of heat acclimation are unknown. The present study investigated whether heat acclimation alleviates the heat‐induced suppression of CHOexo and the underlying physiological mechanisms. Seventeen endurance‐trained adults (10 males and seven females) completed 90 min cycling trials at 45% W max with glucose ingestion (90 g·h −1 ) under temperate [20°C; 20% relative humidity (RH); COOL] and hot (40°C; 20% RH; HOT) conditions, and again in the heat (40°C; 20% RH; POST) following a heat acclimation protocol (9 days of isothermic exercise‐heat acclimation across a 10 day period). Dual stable isotope tracers ([U 13 C 6 ] glucose ingestion, [6,6‐ 2 H 2 ]glucose‐infusion), indirect calorimetry and muscle biopsies were used to assess CHOexo, glucose kinetics and muscle glycogen utilisation during exercise. CHOexo (mean [95% confidence limits]) was reduced by ∼27% in HOT compared to COOL (0.37 [0.31, 0.43] g·min −1 vs . 0.51 [0.45, 0.57] g·min −1 ; P < 0.001) and, despite clear thermoregulatory adaptation following heat acclimation, remained suppressed in POST (0.38 [0.31, 0.44] g·min −1 ; P < 0.01 vs . COOL). Rates of plasma glucose appearance, disappearance and exogenous glucose appearance were unaffected by environmental condition or heat acclimation. Glucose metabolic clearance rates and plasma glucose oxidation were reduced in HOT and POST compared to COOL ( P < 0.05). A decreased capacity for plasma glucose disposal and utilisation rather than limitations in splanchnic glucose appearance underpin the reduced exogenous glucose oxidation observed during exercise in the heat, and this is not alleviated by heat acclimation. image Key points Exogenous glucose oxidation is suppressed during endurance‐exercise performed in hot conditions, although the underlying mechanisms and effects of heat acclimation are unknown. A decreased capacity for plasma glucose disposal and utilisation rather than limitations in splanchnic glucose appearance appear to underpin the reduced exogenous glucose oxidation observed during exercise in the heat. Heat acclimation does not alleviate the reduction in exogenous glucose oxidation that occurs when exercising in hot conditions.
Abstract Sympathetic stimulation produces beneficial changes in cardiac function through β‐adrenergic receptor (βAR) production of cAMP and subsequent alteration of electrical and mechanical activity. Long‐term activation of cAMP production also contributes to cardiac remodelling and detrimental changes associated with heart failure. However, sympathetic responses are mediated by the endogenous neurotransmitter norepinephrine (NE), which is also a potent α 1 ‐adrenergic receptor (α 1 AR) agonist, and α 1 AR activation can produce significant effects on the heart as well. What is less clear is how α 1 ‐ and β‐adrenergic responses interact with one another. Previous studies have demonstrated that α 1 AR activation can inhibit β‐adrenergic regulation of the electrical and mechanical activity of cardiac myocytes, although the signalling mechanisms involved were not previously known. In the present study, we used fluorescence resonance energy transfer (FRET)–based biosensors in adult rat ventricular myocytes to demonstrate that this cross‐talk effect involves the inhibition of cAMP production by intracellular α 1A ‐adrenergic receptors (α 1A ARs) acting on βARs found on the plasma membrane. Furthermore, we established that this inside‐out signalling mechanism involves a mitogen‐activated protein kinase (MAPK) pathway that uncouples βARs from downstream signalling in a G protein‐coupled receptor kinase (GRK)/arrestin‐dependent manner. These results reveal a novel, non‐canonical signalling mechanism contributing to α 1 AR responses in the heart, and that this effect limits βAR production of cAMP by NE. This mechanism may contribute to the cardioprotective effect previously ascribed to α 1A AR activation. These findings also clearly demonstrate the importance of considering the contributions of α 1 and βARs together when studying the influence of the sympathetic nervous system on the heart. image Key points Acute sympathetic stimulation produces beneficial changes in cardiac function through the release of norepinephrine (NE), activation of β‐adrenergic receptors (βARs) and subsequent production of cAMP. However, long‐term sympathetic stimulation of the same signalling pathway contributes to the development of heart failure and cardiac arrhythmias. NE also activates α 1 ‐adrenergic receptors (α 1 ARs), which have been linked to a cardioprotective effect involving a mechanism not well defined. The present study demonstrates that the activation of intracellular α 1A ‐adrenergic receptors (α 1A ARs) reduces cAMP production by βARs found on the cell surface. This ‘inside‐out’ signalling mechanism acts through a mitogen‐activated protein kinase (MAPK) pathway to enhance β‐arrestin‐mediated uncoupling of βARs from downstream signalling. By limiting excessive cAMP production, α 1A AR signalling may help protect the heart during prolonged sympathetic stimulation, highlighting the importance of considering the effects of α 1 ‐ and βAR signalling together when studying sympathetic responses in the heart.
Abstract Hypertension, the leading modifiable risk factor for global mortality, is driven in >50% of cases by neurogenic mechanisms linked to heightened sympathetic nerve activity (SNA). A hallmark of neurogenic hypertension is the exacerbation of respiratory‐modulated SNA (RespSNA) and resulting blood pressure Traube–Hering (TH) waves, which emerges during the prehypertensive period and contributes to disease development. Carotid bodies (CBs), the peripheral chemoreceptors involved in the hypoxic response, are hyperactive in hypertensive patients and animal models. Their chronic intermittent stimulation, as seen in obstructive sleep apnoea, promotes hypertension characterised by exacerbated RespSNA and TH waves. Yet, their causal role in initiating these changes remains unclear. Here, we investigated whether acute intermittent CB stimulations could directly enhance RespSNA, TH waves and blood pressure from a physiological baseline, using the in situ working heart–brainstem preparation in rats. Four brief CB stimulations with sodium cyanide, mimicking acute intermittent hypoxia, were sufficient to induce a prolonged (>20 min) increase in both inspiratory and late expiratory RespSNA bursts, TH waves and perfusion pressure, with these effects being prevented by carotid sinus denervation. These changes were accompanied by a reconfiguration of central respiratory and cardiovascular control, including elevated respiratory heart rate variability and enhanced respiratory drive targeting upper airway and abdominal muscles. Our findings demonstrate that acute intermittent CB activation triggers sustained RespSNA and elevation of TH waves, supporting its potential role in development of hypertension. Our data also suggest that CBs play a key role in initiating this respiratory–cardiovascular plasticity and that central mechanisms might contribute to its long‐term maintenance. image Key points Carotid body (CB) overactivity is implicated in sympathetic excitation and development of hypertension, but its direct role in initiating respiratory–cardiovascular dysfunction remains unresolved. We tested whether brief, repeated CB stimulations could trigger lasting changes in breathing and blood pressure control from a physiological baseline. In rats, only four stimulations induced a persistent increase in respiratory‐modulated sympathetic activity, elevating blood pressure fluctuations (Traube–Hering waves) and mean blood pressure. These effects, prevented by carotid sinus denervation, were linked to enhanced respiratory–cardiovascular coupling and altered upper airway and abdominal motor control. Our findings reveal that short‐term CB activation can induce long‐term facilitation of respiratory–cardiovascular coupling, relevant to both physiological adaptations and hypertension pathogenesis.
Abstract During exercise in the heat, skin vasodilatation occurs as heat loss response. Increased respiratory muscle work by inspiratory loading during high‐intensity exercise causes vasoconstriction in active skeletal muscles without altering arterial blood pressure. We hypothesized that, during high‐intensity exercise in the heat, inspiratory loading would induce skin vasoconstriction and thus reduce skin blood flow to maintain the pressor response associated with high‐intensity exercise. Fifteen healthy young men cycled in the heat (35°C, 50% relative humidity), consisting of 14 min at 50% peak oxygen uptake () followed by 3 min at 90% . A 1 min inspiratory loading was applied 10 min into exercise at 50% and 1 min into exercise at 90% . The protocol without inspiratory loading was performed on a separate day as the control. Upper back skin blood flow was measured using a laser‐Doppler flowmeter. Arterial blood pressure was measured using finger photoplethysmography, and skin vascular conductance was calculated as skin blood flow/mean arterial pressure. Skin blood flow decreased, whereas mean arterial pressure increased gradually during exercise at 90% , and these responses were greater and smaller, in the inspiratory load than control ( P < 0.003). Skin vascular conductance did not differ between conditions at 90% . At 50% , the inspiratory loading slightly reduced mean arterial pressure but did not modulate skin blood flow or skin vascular conductance. We show that increased respiratory muscle work augments the reduction in skin blood flow, whereas it attenuates the pressor response during high‐intensity exercise in the heat, without modulating skin vasoconstriction. image Key points Skin vasodilatation plays a pivotal role in heat loss during exercise in the heat. Breathing, and thus respiratory muscle work, can be augmented by hyperthermia, ageing and lung or cardiovascular disease. However, whether increased respiratory muscle work influences skin vasodilatation during exercise in the heat remains unknown. Inspiratory loading, which increased the work of breathing, was applied during exercise at 50% and at 90% in the heat. We showed that an inspiratory load reduced skin blood flow and attenuated the increase in mean arterial pressure during exercise at 90% without influencing skin vascular conductance. However, these effects associated with inspiratory loading were not clearly observed during exercise at 50% . Our findings suggest that increased inspiratory muscle work may reduce heat loss associated with increases in skin blood flow and blunted pressor response during high‐intensity exercise in the heat.
Sickle cell disease (SCD) is characterized by recurrent, debilitating pain. Opioid analgesics are routinely used in its management, but limited efficacy and pervasive side effects prompt many patients with SCD to seek alternatives, including cannabis. Prior work has shown that 2 major cannabis constituents, 09-tetrahydro-cannabinol (0 9-THC) and cannabidiol (CBD), exert antinociceptive effects in HbSS-BERKmice, a model of SCD. The present study investigated the pharmacological interaction between these 2 agents and characterized the effects associated with repeated coadministration. Fixed-ratio isobolographic analyses demonstrated that 0 9-THC and CBD produced dose-dependent antinociception following acute coadministration. Fixed-ratio isobolographic analyses showed that the experimentally determined median effective dose of the mixture was lower than the theoretical additive dose, but the difference was not statistically significant, supporting an additive antinociceptive interaction. Repeated coadministration maintained antinociceptive efficacy over 14 days and reduced SCD-evoked anxiety-like behavior in one cohort but did not improve recognition-memory deficits. Liquid chromatography-tandem mass spectrometry analyses revealed that repeated coadministration increased plasma CBD concentrations, produced a modest increase in 0 9-THC exposure, and markedly elevated circulating levels of the endocannabinoid 2-arachidonoyl-sn-glycerol. Molecular analyses of spinal cord tissue showed that HbSS-BERK mice exhibited increased oxidative stress (malondialdehyde, MDA) and proinflammatory signaling (interleukin [IL]-13 mRNA), with no change in antiinflammatory signaling (IL-10 mRNA). Following 14 days of treatment, CBD reduced MDA and IL-13 transcription, whereas 0 9-THC reduced MDA and increased IL-10. Notably, the combination treatment simultaneously reduced oxidative stress, suppressed IL-13, and enhanced IL-10. Together, these findings demonstrate an additive antinociceptive interaction between 0 9-THC and CBD and sustained efficacy during repeated administration in SCD mice. Significance Statement: Chronic pain in sickle cell disease remains difficult to treat, and many patients use cannabis despite limited understanding of how its constituents interact to produce analgesia. This study demonstrates that the 2 major phytocannabinoids in cannabis, 09-tetrahydrocannabinol and cannabidiol, produce additive antinociceptive effects in a humanized mouse model of sickle cell disease, and their combined efficacy is maintained during repeated administration without detectable tolerance. (c) 2026 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
