Integration of skeletal muscle resistance arteriolar reactivity for perfusion responses in the metabolic syndrome

Abstract

Previous study suggests that with evolution of the metabolic syndrome, patterns of arteriolar reactivity are profoundly altered and may constrain functional hyperemia. This study investigated interactions between parameters of vascular reactivity at two levels of resistance arterioles in obese Zucker rats (OZR), translating these observations into perfusion regulation for in situ skeletal muscle. Dilation of isolated and in situ resistance arterioles from OZR to acetylcholine, arachidonic acid (AA), and hypoxia (isolated arterioles only) were blunted vs. lean Zucker rats (LZR), although dilation to adenosine was intact. Increased adrenergic tone (phenylephrine) or intralumenal pressure (ILP) impaired dilation in both strains (OZR>LZR). Treatment of OZR arterioles with Tempol (superoxide dismutase mimetic) or SQ-29548 (prostaglandin H2/thromboxane A2 receptor antagonist) improved dilator reactivity under control conditions and with increased ILP, but had minimal effect with increased adrenergic tone. Arteriolar dilation to adenosine was well maintained in both strains under all conditions. For in situ cremasteric arterioles, muscle contraction-induced elevations in metabolic demand elicited arteriolar dilations and hyperemic responses that were blunted in OZR vs. LZR, although distal parallel arterioles were characterized by heterogeneous dilator and perfusion responses. alpha-Adrenoreceptor blockade improved outcomes at rest but had minimal effect with elevated metabolic demand. Treatment with Tempol or SQ-29548 had minimal impact at rest, but lessened distal arteriolar perfusion heterogeneity with increased metabolic demand. In blood-perfused gastrocnemius of OZR, perfusion was constrained primarily by adrenergic tone, while myogenic activation and endothelium-dependent dilation did not appear to contribute significantly to ischemia. These results of this novel, integrated approach suggest that adrenergic tone and metabolic dilation are robust determinants of bulk perfusion to skeletal muscle of OZR, while endothelial dysfunction may more strongly regulate perfusion distribution homogeneity via the impact of oxidant stress and AA metabolism.

Fig. 1.

Schematic of in situ cremasteric arteriolar preparation used for assessing parent and daughter arteriolar mechanical and hemodynamic/perfusion responses to pharmacological challenge and muscle contraction. Open arrows represent determination of parent or daughter arteriolar diameter in response to a specific challenge; filled arrows represent parent or daughter arteriolar erythrocyte velocity in response to a specific challenge. RBC, red blood cell. These data are utilized to determine both arteriolar flow volume and perfusion heterogeneity at bifurcations. Please see text for details.

Fig. 2.

A: dilator sensitivity of arterioles from lean Zucker rats (LZR; upper surfaces) and obese Zucker rats (OZR; lower surfaces) to acetylcholine with increasing adrenergic and myogenic tone. Sensitivity is defined as the slope coefficient describing arteriolar dilation to increasing concentrations of acetylcholine at a specific level of phenylephrine concentration and intralumenal pressure. C: effects of Tempol (superoxide dismutase mimetic) treatment on arteriolar sensitivity to acetylcholine under the identical, imposed conditions. All data presented in A and B have been replicated and grey scaled in C and D for effective comparison and clear interpretation of the data following Tempol treatment: B and D are identical to that in A and C but have been rotated 180 degrees to facilitate visual presentation and interpretation of the data; n = 28–36 LZR or OZR for each surface. Please see text for details.

Fig. 3.

A: dilator sensitivity of arterioles from LZR (upper surfaces) and OZR (lower surfaces) to arachidonic acid with increasing adrenergic and myogenic tone. Sensitivity is defined as the slope coefficient describing arteriolar dilation to increasing concentrations of arachidonic acid at a specific level of phenylephrine concentration and intralumenal pressure. C and E: effects of Tempol and SQ-29548 (PGH₂/TxA₂ receptor antagonist) treatment, respectively, on arteriolar sensitivity to arachidonic acid under the identical, imposed conditions. All data presented in A and B have been replicated and grey scaled in subsequent panels for effective comparison and clear interpretation of the data following Tempol or SQ-29548 treatment: B, D, and F are identical to that in A, C, and E but have been rotated 180 degrees to facilitate visual presentation and interpretation of the data; n = 28–36 LZR or OZR for each surface. Please see text for details.

Fig. 4.

A: dilator sensitivity of arterioles from LZR (upper surfaces) and OZR (lower surfaces) to hypoxia with increasing adrenergic and myogenic tone. Sensitivity is defined as the slope coefficient describing arteriolar dilation to reduced oxygen tension at a specific level of phenylephrine concentration and intralumenal pressure. C and E: effects of Tempol and SQ-29548 treatment, respectively, on arteriolar sensitivity to hypoxia under the identical, imposed conditions. All data presented in A and B have been replicated and grey scaled in subsequent panels for effective comparison and clear interpretation of the data following Tempol or SQ-29548 treatment: B, D, and F are identical to that in A, C, and E, but have been rotated 180 degrees to facilitate visual presentation and interpretation of the data; n = 28–36 (LZR or OZR) for each surface. Please see text for details.

Fig. 5.

A: dilator sensitivity of arterioles from LZR (upper surfaces) and OZR (lower surfaces) to adenosine with increasing adrenergic and myogenic tone. Sensitivity is defined as the slope coefficient describing arteriolar dilation to increasing concentrations of adenosine at a specific level of phenylephrine concentration and intralumenal pressure. B is identical to that in A, but has been rotated 180 degrees to facilitate visual presentation and interpretation of the data; n = 28–36 animals (LZR or OZR) for each surface. Please see text for details.

Fig. 6.

Dilator responses of in situ cremaster muscle parent arterioles from OZR and LZR in response to increasing concentrations of acetylcholine (A), arachidonic acid (B), and adenosine (C). Data (means ± SE) are presented for arteriolar responses under control conditions, and following treatment of cremaster muscles of OZR with the antioxidant Tempol, the PGH₂/TxA₂ receptor antagonist SQ-29548, the α₁/α₂ adrenoreceptor blocker phentolamine, or all three agents; n = 6 LZR and 18 OZR; *P < 0.05 vs. untreated LZR; †P < 0.05 vs. untreated OZR. Please see text for details.

Fig. 7.

Data describing the responses of in situ cremaster muscle parent arterioles under rest conditions and in response to increasing metabolic demand (muscle contraction). Data (means ± SE) are presented for arteriolar diameter (A), erythrocyte velocity (B) and perfusion (C) under control conditions, and following treatment of cremaster muscle of OZR with the antioxidant Tempol, the PGH₂/TxA₂ receptor antagonist SQ-29548, the α₁/α₂ adrenoreceptor blocker phentolamine, or all three agents; n = 6 LZR and 18 OZR. *P < 0.05 vs. untreated LZR; †P < 0.05 vs. untreated OZR. Please see text for details.

Fig. 8.

Data describing the responses of in situ cremaster muscle daughter arterioles under rest conditions and in response to increasing metabolic demand (muscle contraction). Data (means ± SE) are presented as the heterogeneity between daughter arteriolar diameter (A), erythrocyte velocity (B) and perfusion (C) under control conditions, and following treatment of cremaster muscles of OZR with the antioxidant Tempol, the PGH₂/TxA₂ receptor antagonist SQ-29548, the α₁/α₂ adrenoreceptor blocker phentolamine, or all three agents; n = 6 LZR and 18 OZR; *P < 0.05 vs. untreated LZR; †P < 0.05 vs. untreated OZR. Please see text for details.

Fig. 9.

Blood flow to in situ gastrocnemius muscle of LZR and OZR at rest (A) and in response to 1- (B) and 3-Hz (C) contraction. Data (means ± SE) are presented for responses under control conditions and following treatment of the animal with intravenous infusion of Tempol, SQ-29548, and/or phentolamine; n = 5 LZR and 16 OZR; *P < 0.05 vs. untreated LZR; †P < 0.05 vs. untreated OZR.