Altered distribution of adrenergic constrictor responses contributes to skeletal muscle perfusion abnormalities in metabolic syndrome.

PURPOSE: Although studies suggest elevated adrenergic activity paralleling metabolic syndrome in OZRs, the moderate hypertension and modest impact on organ perfusion question the multi-scale validity of these data. METHODS: To understand how adrenergic function contributes to vascular reactivity in OZR, we utilized a multi-scale approach to investigate pressure responses, skeletal muscle blood flow, and vascular reactivity following adrenergic challenge. RESULTS: For OZR, adrenergic challenge resulted in increased pressor responses vs LZRs, mediated via α1 receptors, with minimal contribution by either ROS or NO bioavailability. In situ gastrocnemius muscle of OZR exhibited blunted functional hyperemia, partially restored with α1 inhibition, although improved muscle performance and VO2 required combined treatment with TEMPOL. Within OZR in situ cremaster muscle, proximal arterioles exhibited a more heterogeneous constriction to adrenergic challenge, biased toward hyperresponsiveness, vs LZR. This increasingly heterogeneous pattern was mirrored in ex vivo arterioles, mediated via α1 receptors, with roles for ROS and NO bioavailability evident in hyperresponsive vessels only. CONCLUSIONS: These results support the central role of the α1 adrenoreceptor for augmented pressor responses and elevations in vascular resistance, but identify an increased heterogeneity of constrictor reactivity in OZR that is presently of unclear purpose.

Insidious incrementalism: The silent failure of the microcirculation with increasing peripheral vascular disease risk.

This review summarizes material presented in "Adaptive Outcomes of Microvascular Networks to Obesity and Type II Diabetes/Insulin Resistance" on July 30, 2016, at the Joint Meeting of the American Physiological Society and the Physiological Society, in Dublin, Ireland. We discuss the poor predictive power of traditional markers of vascular dysfunction for functional outcomes of muscle fatigue-resistance and active hyperemia within the setting of elevated peripheral vascular disease risk. Using the obese Zucker rat model of the metabolic syndrome, we describe how blood flow distribution at arteriolar bifurcations (γ) is altered with PVD risk reflecting increased spatial heterogeneity of distribution within networks. The ability of the microvasculature to compensate for increased heterogeneity is attenuated in OZR, creating a condition wherein the inability to match perfusion to local demand is entrenched and made more difficult to overcome. This appears to be an incremental process, as multiple models of increased PVD risk manifest incremental shifts to the spatial and temporal behavior of γ. These data suggest that γ, a superior predictor of functional outcomes for skeletal muscle, may represent a broadly applicable concept that can inform us about system behavior, with health and increased disease/disease risk, and with imposition of therapeutic regimens.

Impact of increased intramuscular perfusion heterogeneity on skeletal muscle microvascular hematocrit in the metabolic syndrome.

OBJECTIVE: To determine HMV and PS in skeletal muscle of OZR and evaluate the impact of increased microvascular perfusion heterogeneity on mass transport/exchange. METHODS: The in situ gastrocnemius muscle from OZR and LZR was examined under control conditions and following pretreatment with TEMPOL (antioxidant)/SQ-29548 (PGH2 /TxA2 receptor antagonist), phentolamine (adrenergic antagonist), or all agents combined. A spike input of a labeled blood tracer cocktail was injected into the perfusing artery. Tracer washout was analyzed using models for HMV and PS. HT was determined in in situ cremaster muscle of OZR and LZR using videomicroscopy. RESULTS: HMV was decreased in OZR versus LZR. While TEMPOL/SQ-29548 or phentolamine had minor effects, treatment with all three agents improved HMV in OZR. HT was not different between strains, although variability was increased in OZR, and normalized following treatment with all three agents. PS was reduced in OZR and was not impacted by intervention. CONCLUSIONS: Increased microvascular perfusion heterogeneity in OZR reduces HMV in muscle vascular networks and increases its variability, potentially contributing to premature muscle fatigue. While targeted interventions can ameliorate this, the reduced microvascular surface area is not acutely reversible.

Differential impact of dilator stimuli on increased myogenic activation of cerebral and skeletal muscle resistance arterioles in obese zucker rats.

OBJECTIVE: To use the OZR model of the metabolic syndrome to determine the impact of dilator stimuli on MA of GA and MCA. We tested the hypothesis that increased oxidant stress and TxA2 exacerbate MA, and prevent its blunting with dilator stimuli, in OZR. METHODS: GA/MCA from OZR and LZR was pressurized ex vivo. MA was determined under control conditions and following challenge with acetylcholine, hypoxia, and adenosine. Responses were also evaluated after pre-treatment with TEMPOL (antioxidant) and SQ-29548 (PGH2 /TxA2 receptor antagonist). RESULTS: MA was increased (and dilator responses decreased) in GA/MCA from OZR, dependent on the endothelium and ROS. In GA, the impact of ROS on MA and dilator effects was largely via TxA2 , while in MCA, this appeared was more dependent on NO bioavailability. Intrinsic responses of GA/MCA to carbacyclin, U46619, and NO donors were similar between strains. CONCLUSIONS: A developing ROS-based endothelial dysfunction in MCA and GA of OZR contributes to an enhanced MA of these vessels. Although treatment of GA/MCA with TEMPOL attenuates MA in OZR, the mechanistic contributors to altered MA, distal to ROS, differ between the two resistance vessels.