Sulfonylureas Compromise Microvascular Flow in Mouse Skeletal Muscle
Notice bibliographique
Résumé
Sulfonylureas are among the most prescribed oral anti-hyperglycaemics, particularly in low- and middle-income countries. Sulfonylureas are insulin secretagogues through blocking ATP-sensitive potassium channels (K ATP ) in β-cells of the pancreas. Despite wide usage, sulfonylureas are associated with increased cardiovascular disease morbidity and all-cause mortality, with ill-defined mechanisms. We tested the hypothesis that glyburide could block K ATP channels in the microvasculature, thereby disrupting tissue oxygen demand-supply balance. We further investigated the contribution of other potassium channels to capillary-to-arteriole signalling. Experiments were conducted using an in-vivo anesthetized mouse skeletal muscle preparation (extensor digitorum longus, EDL); exteriorized and situated at in-situ length, overtop an oxygen-permeable membrane covering a gas chamber, and bathed in PlasmaLyte. C57BL/6 mice were employed (n=6-8). Brightfield images were captured at two wavelengths: oxygen-dependent and oxygen-independent, enabling the simultaneous determination of capillary hemodynamics and RBC oxygen content. Low oxygen challenges were achieved by dropping oxygen levels in the gas chamber from 7% to 2% for 3 minutes. Challenges were conducted before (control) and after drugs were added to bathing solution. Parameters were obtained before the challenge (baseline), during the challenge (2 regions) and after the challenge (recovery). Statistical significance was determined using a paired Student’s t-test. Target channels localization was investigated using immunofluorescence in formalin-fixed EDL. Oxygen challenges augmented EDL surface capillary hematocrit and RBC velocity and supply rate, while reducing RBC oxygen saturation. Incubation of the EDL with 10 μM glyburide decreased the baseline RBC supply rate (p<0.05 vs control) and blunted the magnitude of capillary responses to the oxygen challenge (p<0.05 vs control). Immunofluorescence confirmed the localization of K ATP channels in EDL capillaries. Normal capillary responses were obtained when small and intermediate conductance or inward rectifier potassium channels were neutralized. This implies minimal or no contribution of these channels in oxygen signaling in the microvasculature. This data begins to elucidate the acute and direct effects of systemic K ATP blockers on capillary-to-arteriole conducted signaling, which is likely key to optimal tissue oxygen regulation. Further experiments are warranted to confirm this conclusion. This work was supported by the Natural Science and Engineering Research Council of Canada (NSERC, RGPIN/04659-2017), an Ontario Graduate Scholarship (M.A.E) and a CIHR doctoral award (M.A.E). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».