sq-29548 and Metabolic-Syndrome

To determine HMV and PS in skeletal muscle of OZR and evaluate the impact of increased microvascular perfusion heterogeneity on mass transport/exchange.. 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.. 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.. 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.

Topics: Animals; Antioxidants; Bridged Bicyclo Compounds, Heterocyclic; Cyclic N-Oxides; Fatty Acids, Unsaturated; Hematocrit; Hydrazines; Metabolic Syndrome; Microcirculation; Muscle, Skeletal; Rats; Receptors, Thromboxane A2, Prostaglandin H2; Spin Labels

A key clinical outcome for peripheral vascular disease (PVD) in patients is a progressive decay in skeletal muscle performance and its ability to resist fatigue with elevated metabolic demand. We have demonstrated that PVD in obese Zucker rats (OZR) is partially due to increased perfusion distribution heterogeneity at successive microvascular bifurcations within skeletal muscle. As this increased heterogeneity (γ) is longitudinally present in the network, its cumulative impact is a more heterogeneous distribution of perfusion between terminal arterioles than normal, causing greater regional tissue ischemia. To minimize this negative outcome, a likely compensatory mechanism against an increased γ should be an increased temporal switching at arteriolar bifurcations to minimize downstream perfusion deficits. Using in situ cremaster muscle, we determined that temporal activity (the cumulative sum of absolute differences between successive values of γ, taken every 20 s) was lower in OZR than in control animals, and this difference was present in both proximal (1A-2A) and distal (3A-4A) arteriolar bifurcations. Although adrenoreceptor blockade (phentolamine) improved temporal activity in 1A-2A arteriolar bifurcations in OZR, this was without impact in the distal microcirculation, where only interventions against oxidant stress (Tempol) and thromboxane A(2) activity (SQ-29548) were effective. Analysis of the attractor for γ indicated that it was not only elevated in OZR but also exhibited severe reductions in range, suggesting that the ability of the microcirculation to respond to any challenge is highly restricted and may represent the major contributor to the manifestation of poor muscle performance at this age in OZR.

Topics: Adrenergic alpha-Antagonists; Animals; Antioxidants; Arterioles; Bridged Bicyclo Compounds, Heterocyclic; Cyclic N-Oxides; Disease Models, Animal; Fatty Acids, Unsaturated; Humans; Hydrazines; Male; Metabolic Syndrome; Microvessels; Muscle, Skeletal; Obesity; Oxidative Stress; Peripheral Vascular Diseases; Phentolamine; Rats; Rats, Zucker; Spin Labels

The metabolic syndrome is associated with elevated peripheral vascular disease risk, characterized by mismatched blood flow delivery/distribution and local metabolism. The obese Zucker rat (OZR) model of the metabolic syndrome exhibits myriad vascular impairments, although their integrated impact on functional hyperaemia remains unclear. In this study, arterial pressor responses and skeletal muscle perfusion were assessed in lean Zucker rats (LZRs) and OZRs during adrenergic stimulation (phenylephrine), challenge with thromboxane (U46619) and endothelium-dependent dilatation (methacholine). The OZRs were hypertensive compared with the LZRs, but this was abolished by adrenoreceptor blockade (phentolamine); pressor responses to U46619 were similar between strains and were abolished by blockade with the prostaglandin H(2)/thromboxane A(2) receptor antagonist, SQ-29548. Depressor reactivity to methacholine was impaired in OZRs, but was improved by antioxidant treatment (TEMPOL). Across levels of metabolic demand, blood flow to in situ gastrocnemius muscle was restrained by adrenergic constriction in OZRs, although this diminished with increased demand. Oxygen extraction, reduced in OZRs compared with LZRs across levels of metabolic demand, was improved by TEMPOL or SQ-29548; treatment with phentolamine did not impact extraction, and neither TEMPOL nor SQ-29548 improved muscle blood flow in OZRs. While oxygen uptake and muscle performance were consistently reduced in OZRs versus LZRs, treatment with all three agents improved outcomes, while treatment with individual agents was less effective. These results suggest that contributions of vascular dysfunction to perfusion, oxygen uptake and muscle performance are spatially distinct, with adrenergic constriction impacting proximal resistance and endothelial dysfunction impacting distal microvessel-tissue exchange. Further, these data suggest that increasing skeletal muscle blood flow in OZRs is not sufficient to improve performance, unless distal perfusion inhomogeneities are rectified.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antioxidants; Arteries; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hyperemia; Hypertension; In Vitro Techniques; Male; Metabolic Syndrome; Methacholine Chloride; Muscle Fatigue; Muscle, Skeletal; Obesity; Oxygen; Perfusion; Peripheral Vascular Diseases; Phenylephrine; Rats; Rats, Zucker; Vasoconstriction

These studies tested the hypothesis that in obese Zucker rats (OZRs), a model of metabolic syndrome, the impaired functional vasodilation is due to increased thromboxane receptor (TP)-mediated vasoconstriction and/or decreased prostacyclin-induced vasodilation. Spinotrapezius arcade arterioles from 12-wk-old lean (LZR) and OZR were chosen for microcirculatory observation. Arteriolar diameter (5 LZR and 6 OZR) was measured after 2 min of muscle stimulation in the absence or presence of 1 microM SQ-29548 (TP antagonist). Additionally, arteriolar diameter (6 for each group) was measured after application of iloprost (prostacyclin analog; 0.28, 2.8, and 28 microM), arachidonic acid (10 microM), and sodium nitroprusside (0.1, 1, and 10 microM) in the absence or presence of 1 microM SQ-29548. A 10 microM concentration of adenosine was used to induce a maximal dilation. Basal diameters were not different between LZRs and OZRs. Functional hyperemia and arachidonic acid-mediated vasodilations were significantly attenuated in OZR compared with LZR, and treatment with 1 microM SQ-29548 significantly enhanced the dilations in OZRs, although it had no effect in LZRs. Vasodilatory responses to iloprost and sodium nitroprusside (1 and 10 microM) were significantly reduced in OZR. Adenosine-mediated vasodilation was not different between groups. These results suggest that the impaired functional dilation in the OZR is due to an increased TP-mediated vasoconstriction and a decreased PGI2-induced vasodilation.

Topics: Animals; Arachidonic Acid; Arterioles; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Hydrazines; Iloprost; Metabolic Syndrome; Muscle, Skeletal; Nitroprusside; Obesity; Rats; Rats, Zucker; Vasodilation; Vasodilator Agents