New Anti-contractile Effect Of Skeletal Muscle Is Lost In Hypertension

Since the discovery of the anti-contractile effect of perivascular adipose tissue (PVAT), it has been established that it has a crucial role in vascular function and diseases, including hypertension. However, PVAT has a minimal role in arteries surrounded by skeletal muscles (SM) compared to other vessels. During physical exercise, SM releases several factors ("myokines") that can modulate blood flow, but it is unclear if SM directly controls vascular tone in physiological conditions. The type of SM, glycolytic or oxidative, may also affect vascular dynamics. We hypothesized that SM exhibits an anti-contractile effect crucial for vascular function, which is lost in hypertension. Femoral (FA) and carotid (CA) arteries, adjacent to glycolytic and oxidative SM, respectively, from male and female SHR and Wistar (W) (12-weeks old) rats were mounted in a wire myograph in the absence (-SM) or presence (+SM) of attached or de-attached SM. Concentration-response curves (1nM-100μM) to serotonin (5-HT), phenylephrine (Phe), and thromboxane A2 analog (U46619) were performed. The presence of SM reduced contraction in FA from male (AUC 5-HT: -SM: 442±1 vs. +SM 339±2; p>0.05) and female W rats (AUC: 5-HT: -SM 258.7 ± 18.5 vs. +SM 277±21; p>0.05). Similarly, SM-induced anti-contractile effects were observed in Phe and U46619 curves and in de-attached SM. The anti-contractile effect was absent in W rats CA (AUC: 5-HT: Male: -SM 270±19 vs. +SM 257 ± 25; Female: -SM 250±35 vs. +SM 258±32). Lactate dehydrogenase inhibitor (GSK2837808A, 10nM) abolished the SM anti-contractile effect. In SHR, this anti-contractile effect in FA was not observed (AUC: 5-HT: -SM 103±27 vs. +SM 94±25). FA from SHR showed hypo-contractility to 5-HT (32%) and increased smoothelin expression, an atrophy marker, when measured by Western blot (AU: FA: W: 22861±4504 vs. SHR: 6065±1026; p>0.05). Tests of plantarflexion were performed in vivo to assess SM function. SHR showed a reduction in tetanic contraction (27%), isometric twitch force (27%), and fatigue (22%). These data reveal a new anti-contractile effect of glycolytic SM mediated by lactate and lost in hypertension. Therefore, paracrine and endocrine factors from SM represent a new frontier of vascular physiology research.