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J Appl Physiol 97: 764-772, 2004. First published April 9, 2004; doi:10.1152/japplphysiol.01216.2003
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HIGHLIGHTED TOPICS
Skeletal and Cardiac Muscle Blood Flow

Enhanced arteriolar {alpha}-adrenergic constriction impairs dilator responses and skeletal muscle perfusion in obese Zucker rats

Jefferson C. Frisbee

Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Submitted 13 November 2003 ; accepted in final form 31 March 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The present study tested the hypothesis that enhanced vascular {alpha}-adrenergic constriction in obese Zucker rats (OZR) impairs arteriolar dilation and perfusion of skeletal muscle at rest and with increased metabolic demand. In lean Zucker rats (LZR) and OZR, isolated gracilis arterioles were viewed via television microscopy, and the contralateral cremaster muscle or gastrocnemius muscle was prepared for study in situ. Gracilis and cremasteric arterioles were challenged with dilator stimuli under control conditions and after blockade of {alpha}-adrenoreceptors with prazosin, phentolamine, or yohimbine. Gastrocnemius muscles performed isometric twitch contractions of increasing frequency, and perfusion was continuously monitored. In OZR, dilator responses of arterioles to hypoxia (gracilis), wall shear rate (cremaster), acetylcholine, and iloprost (both) were impaired vs. LZR. Treatment with prazosin and phentolamine (and in cremasteric arterioles only, yohimbine) improved arteriolar reactivity to these stimuli in OZR, although responses remained impaired vs. LZR. Gastrocnemius muscle blood flow was reduced at rest in OZR; this was corrected with intravenous infusion of phentolamine or prazosin. At all contraction frequencies, blood flow was reduced in OZR vs. LZR; this was improved by infusion of phentolamine or prazosin at low-moderate metabolic demand only (1 and 3 Hz). At 5 Hz, adrenoreceptor blockade did not alter blood flow in OZR from levels in untreated rats. These results suggest that enhanced {alpha}-adrenergic constriction of arterioles of OZR contributes to impaired dilator responses and reduced muscle blood flow at rest and with mild-moderate (although not with large) elevations in metabolic demand.

skeletal muscle blood flow regulation; skeletal muscle perfusion; regulation of vascular tone; models of metabolic syndrome X; obesity

DIABETES MELLITUS IMPACTS 16 million Americans and, while contributing to the death of 180,000 Americans annually, is a potent risk factor for development of peripheral vascular disease, a debilitating condition impacting 60 million Americans (1, 2). When included with development of additional complicating factors, including obesity, hypertension, and dyslipidemia, a multipathology state develops, frequently referred to as the metabolic syndrome X (32). The obese Zucker rat (OZR) provides an excellent model for examining the impact of development of the metabolic syndrome X on the peripheral microcirculation, because, owing to a deficient leptin receptor gene causing chronic hyperphagia (5, 6, 21), OZR develop Type 2 diabetes, hypertriglyceridemia, and moderate hypertension (5, 6, 31).

Evolution of the metabolic syndrome X in OZR is associated with impairments to skeletal muscle arteriolar reactivity, including impaired dilator responses to hypoxia (12) and elevated wall shear rate (18), an increased constrictor reactivity of individual arterioles in response to elevated intraluminal pressure (16) and challenge with the {alpha}-adrenergic agonist norepinephrine (42). In our laboratory’s previous study, we determined that this enhanced {alpha}-adrenergic vasoconstriction had the potential to impair skeletal muscle blood flow, because pharmacological blockade of {alpha}-adrenoreceptors increased the diameter of in vivo arterioles of OZR while having no effect in control lean Zucker rats (LZR; Ref. 42). When integrated with results from a recent study demonstrating increased sympathetic nervous activity in OZR relative to those in LZR (7), our laboratory’s prior observation of an increased {alpha}-adrenergic tone of vessels themselves may have significant implications for the regulation of vascular diameter and the control of skeletal muscle perfusion.

Previous investigators have demonstrated that adrenergic constriction of skeletal muscle arterioles can impair reactivity to dilator stimuli (3, 14, 34, 35) and that an increased arteriolar adrenergic tone has the potential to negatively impact blood flow to downstream microvessel networks and perfusion of tissue (3, 23, 36, 47). The purpose of the present study was to test the hypothesis that enhanced {alpha}-adrenergic constriction of skeletal muscle arterioles in OZR impairs both dilator reactivity of these vessels and perfusion of skeletal muscle.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Animals.   Fifteen-week-old male LZR (Harlan; n = 30) and OZR (Harlan; n = 30) fed standard chow and tap water ad libitum were used for all experiments. Data describing the baseline characteristics of LZR and OZR in the present study are presented in Table 1. At 15 wk of age, OZR were significantly heavier than age-matched LZR controls and also demonstrated hyperglycemia, hyperinsulinemia, elevated plasma triglyceride levels, and hypertension. Rats were housed in an American Association for Accreditation of Laboratory Animal Care-accredited animal care facility at the Medical College of Wisconsin, and all protocols received prior Institutional Animal Care and Use Committee approval. Rats were anesthetized with injections of pentobarbital sodium (50 mg/kg ip) and received tracheal intubation to facilitate maintenance of a patent airway. In all rats, a carotid artery and an external jugular vein were cannulated for determination of arterial pressure and for intravenous infusion of additional substances as necessary (e.g., anesthetic, heparin, etc.).


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  		Table 1. Baseline characteristics of 15-wk-old lean and obese Zucker rats used in the present study

 
Investigation of isolated skeletal muscle resistance arterioles.   In anesthetized rats, the intramuscular continuation of the right gracilis artery was identified, its in vivo diameter was determined by use of an eyepiece micrometer, and the vessel was surgically removed. In LZR, arteriolar diameter estimated by this method was 107 ± 4 µm, whereas in OZR the value was reduced to 97 ± 3 µm. Arterioles were placed in a heated chamber (37°C) that allowed the vessel lumen and exterior to be perfused and superfused, respectively, with physiological salt solution (PSS; equilibrated with 21% O2-5% CO2-74% N2) from separate reservoirs. Vessels were cannulated at both ends and were secured to inflow and outflow pipettes connected to a reservoir perfusion system allowing intraluminal pressure and luminal gas concentration to be controlled. Vessel diameter was measured using television microscopy and an on-screen video micrometer. Arterioles were extended to their in situ length and were equilibrated at ~80% of the animal's mean arterial pressure (83 ± 5 mmHg for LZR, 102 ± 6 mmHg for OZR). We have previously demonstrated that this difference in equilibration pressure, although important for approximating the in vivo condition, does not significantly impair dilator reactivity in OZR (12). Active tone for vessels in the present study, calculated as ({Delta}D/Dmax)·100, where {Delta}D is the diameter increase from rest in response to Ca2+-free PSS, and Dmax is the maximum diameter measured at the equilibration pressure in Ca2+-free PSS, averaged 36 ± 3% in LZR and 31 ± 3% in OZR.

After an equilibration period, arteriolar constriction was assessed in response to increasing concentrations of phenylephrine (10–11 to 10–6 M) or clonidine (10–11 to 10–6 M) to establish baseline reactivity to {alpha}1- and {alpha}2-adrenoreceptor agonists, respectively. Before subsequent evaluation of arteriolar reactivity, the in vivo diameter of vessels was restored through addition of low levels of norepinephrine to the vessel chamber. This process required ~3 x 10–10 M norepinephrine in vessels from OZR. Although vessels from LZR usually regained their in vivo diameter without treatment with norepinephrine (n = 17), some vessels required a maximum norepinephrine concentration of ~1 x 10–10 M (n = 5). Subsequently, arteriolar reactivity in LZR and OZR was assessed in response to 1) hypoxia [{Delta}PO2 from ~140 to ~35 Torr (5% CO2-95% N2)], 2) acetylcholine (10–9 to 10–6 M; Sigma), 3) iloprost (10–15 g/ml to 10–9 g/ml; Berlex), and 4) forskolin (10–13 to 10–7 M; Sigma). Afterward, norepinephrine was washed out, and vessels were treated with either prazosin (10–8 M, {alpha}1-adrenoreceptor agonist; Sigma; n = 7 for LZR and OZR), phentolamine ({alpha}1/{alpha}2-adrenoreceptor antagonist; 10–5 M; Sigma; n = 8 for LZR and OZR), or yohimbine ({alpha}2-receptor antagonist; 10–5 M; Sigma; n = 7 for LZR and OZR). Effectiveness of these pharmacological blockades was determined by abolishment of vasoconstrictor responses to phenylephrine (10–7 M; for prazosin or phentolamine) or clonidine (10–7 M; for yohimbine or phentolamine). In preliminary experiments, treatment of vessels from LZR with yohimbine (10–5 M) did not significantly alter arteriolar constrictor responses to phenylephrine (10–8 M), as vessels retained 91 ± 5% of their constrictor response under control conditions. Each isolated vessel was treated with only one adrenoreceptor antagonist. Before a reevaluation of arteriolar reactivity, norepinephrine was returned to the vessel bath at its original concentration to reestablish in vivo arteriolar diameter.

Investigation of in situ skeletal muscle distal arterioles.   In half of the rats in the present study (n = 15 for LZR and OZR), the left cremaster muscle was prepared for television microscopy (30). After completion of the muscle preparation, the tissue was superfused with PSS, equilibrated with a gas mixture containing 5% CO2-95% N2, and maintained at 35°C as it flowed over the muscle. The ionic composition of the PSS was as follows (in mM): 119.0 NaCl, 4.7 KCl, 1.6 CaCl2, 1.18 NaH2PO4, 1.17 MgSO4, and 24.0 NaHCO3. Arteriolar diameter was determined with an on-screen video micrometer, and center-line erythrocyte velocity (mm/s) within arterioles was measured with an optical Doppler velocimeter (Microcirculation Research Institute, Texas A&M University, College Station, TX). After an initial postsurgical equilibration period of 30 min, a third-order arteriole (~20 µm diameter) was selected for investigation in a clearly visible region of the muscle. Arterioles chosen for study had walls that were clearly visible, a brisk flow velocity, and active tone, as indicated by the occurrence of significant dilation in response to topical application of 10–3 M adenosine. All arterioles that were studied were located in a region of the muscle that was away from any incision. Active tone for cremasteric arterioles, calculated as described above (with the inclusion of 10–3 M adenosine in Ca2+-free PSS), averaged 47 ± 4% in LZR and 43 ± 4% in OZR.

After an equilibration period, the reactivity of distal arterioles of LZR and OZR was assessed in response to increasing concentrations of phenylephrine or clonidine, as described above, to establish baseline reactivity to the {alpha}1- and {alpha}2-adrenoreceptor agonists, respectively. Subsequently, arteriolar reactivity was assessed in arterioles from both strains in response to 1) elevated wall shear rate, 2) acetylcholine (10–9 to 10–6 M; Sigma), 3) iloprost (10–15 to 10–9 g/ml; Berlex), and 4) forskolin (10–13 to 10–7 M; Sigma). After initial assessment of arteriolar reactivity, cremaster muscles were treated with prazosin (n = 5), phentolamine (n = 5), or yohimbine (n = 5), as described above. Each cremaster muscle was treated with only one adrenoreceptor antagonist. Effectiveness of these pharmacological blockades was determined by abolishment of vasoconstrictor responses to phenylephrine or clonidine, as described above. After treatment with either adrenoreceptor antagonist, the assessment of cremasteric arteriolar reactivity to the four dilator stimuli was repeated.

The method used for parallel arteriolar occlusion followed those described previously (26). Briefly, blood flow in one daughter branch (3rd-order arteriole) from a parent arteriole (2nd-order arteriole) was impeded by lowering a microoccluder onto the perfused daughter branch at a site located ~500–2,000 µm from the point of observation. Physical occlusion of this arteriole, henceforth referred to as "parallel occlusion," increases blood flow and wall shear rate in a parallel (nonoccluded) daughter branch from the parent vessel, leading to a shear-induced dilation of the nonoccluded daughter arteriole. The microoccluder used in these studies was a glass micropipette with a blunt, rounded end (diameter ~50 µm) to prevent vessel damage during occlusion.

Investigation of in situ blood perfused skeletal muscle.   In the remaining half of LZR and OZR (n = 15 for each), the left gastrocnemius muscle was isolated in situ (13, 15, 33). Briefly, the left leg received a medial incision from the calcaneus to the femoral triangle, and all muscles, vessels, and connective tissue overlaying gastrocnemius muscle were removed, thus exposing the gastrocnemius muscle, its vascular supply, and the sciatic nerve. The nerve was double ligated and sectioned proximally, leaving a ~1-in. length of the nerve to facilitate stimulation of muscle contraction. Branches from the femoral/popliteal artery that did not perfuse the gastrocnemius muscle were ligated or cauterized, depending on size and location. The distal stump of the sciatic nerve was inserted into a stimulating electrode and tied in place. Finally, a microcirculation flow probe (Transonic) was placed around the femoral artery, immediately distal to its origin from the iliac artery, to measure blood flow to the gastrocnemius muscle. The entire preparation was covered in PSS-soaked gauze and plastic film to minimize evaporative water loss and was placed under a heat lamp to maintain temperature at 37°C. At this time, heparin (1,500 IU/kg) was infused via the jugular vein to prevent blood coagulation.

On completion of the surgical preparation, the gastrocnemius muscle was stimulated (via the sciatic nerve) to perform bouts of isometric twitch contractions (1, 3, or 5 Hz, 0.4-ms duration, 5 V) lasting for 3 min followed by 15 min of self-perfused recovery time, with arterial pressure and femoral artery blood flow continuously monitored. After performance of the contraction regimen under control conditions, rats were treated with either prazosin (1 mg/kg iv; n = 5), phentolamine (5 mg/kg iv; n = 5), or yohimbine (5 mg/kg iv; n = 5), and the contraction regimen was repeated. Each animal was treated with only one adrenoreceptor antagonist.

Data and statistical analyses.   For experiments evaluating arteriolar reactivity in response to elevated wall shear rate, blood flow through the daughter vessel was calculated from erythrocyte velocity and vessel radius (4):

where F represents the volume of blood flow (nl/s), V represents centerline erythrocyte velocity (mm/s), and r represents vessel radius (µm). Wall shear rate was calculated as

where WSR represents wall shear rate (s–1), VM represents mean flow velocity in the daughter vessel (calculated by dividing the optical Doppler measurement of centerline velocity by 1.6 to correct for the parabolic flow pattern in the vessel), and D represents vessel diameter (26).

Arteriolar constrictor responses after challenge with phenylephrine or clonidine were fit with a three-parameter logistic equation

where y represents the change in arteriolar diameter, min and max represent the lower and upper bounds, respectively, of the change in arteriolar diameter with increasing agonist concentration, x is the logarithm of the agonist concentration, and logED50 represents the logarithm of the agonist concentration (x) at which the response (y) is halfway between the lower and upper bounds. Statistically significant differences in upper bound or in logED50 values employed Student's t-test.

Arteriolar reactivity data to all dilator stimuli except for hypoxia were fit with regression equations (linear [y = {alpha}0 + {beta}x] or semilogarithmic [y = {alpha}0 + {beta}log x], as appropriate; ordinary least squares, r2 > 0.86). In both cases, y represents arteriolar diameter in response to a linear or logarithmic change, as appropriate, in the independent variable x; {alpha}0 represents an intercept term, and {beta} represents the rate of change in arteriolar diameter with a change in the independent variable x. Statistically significant differences between slope coefficients and arteriolar reactivity to hypoxia were determined by ANOVA. Student-Newman-Keuls test post hoc was employed as appropriate.

Muscle perfusion experiments.   Muscle perfusion data were normalized to gastrocnemius muscle mass, which did not differ between LZR (2.37 ± 0.09 g) and OZR (2.27 ± 0.12 g). Vascular resistance within gastrocnemius muscle was calculated as the quotient of mean arterial pressure and muscle blood flow. Differences in muscle blood flow and vascular resistance during the final minute of contraction were determined using ANOVA, with Student-Newman-Keuls test post hoc.

In all cases, P < 0.05 was taken to reflect statistical significance. All data are presented as means ± SE.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The diameter of skeletal muscle arterioles from LZR and OZR under the conditions of the present study are presented in Table 2. These data indicate that in vivo diameter of gracilis muscle resistance arterioles was significantly reduced in OZR vs. LZR and that this difference was lost after mounting of the vessels in the chamber.


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  		Table 2. Diameter of gracilis muscle resistance arterioles and cremaster muscle distal arterioles from LZR and OZR under the conditions of the present study

 
Figure 1 presents the constrictor responses of skeletal muscle resistance (gracilis) and distal (cremaster) arterioles in response to challenge with {alpha}-adrenoreceptor agonists. In gracilis arterioles, application of increasing concentrations of the {alpha}1-agonist phenylephrine resulted in a significantly stronger constriction of arterioles from OZR vs. LZR (Fig. 1A). In contrast, challenge with the {alpha}2-agonist clonidine resulted in a similar degree of vasoconstriction in vessels from both LZR and OZR (Fig. 1B). However, between LZR and OZR, the sensitivity of gracilis arterioles in response to either phenylephrine (Fig. 1A) or clonidine (Fig. 1B) was similar, as the logED50 describing these concentration-response curves was not altered. In cremasteric arterioles, the degree of vasoconstriction in response to both phenylephrine (Fig. 1C) and clonidine (Fig. 1C) was increased in vessels of OZR vs. LZR across the range of agonist concentration. However, the sensitivity of cremasteric arterioles of OZR to phenylephrine was increased vs. LZR, as evidenced by a significant difference in the logED50 describing these data (Fig. 1C). A similar trend was determined with regard to the reactivity of cremasteric arterioles of OZR in response to clonidine, although the difference in logED50 vs. that in LZR failed to reach significance (P = 0.057).



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  		Fig. 1. Constriction of isolated gracilis muscle resistance arterioles and in situ cremaster muscle distal arterioles from lean (LZR) and obese Zucker rats (OZR) in response to increasing concentrations of phenylephrine ({alpha}1-adrenoreceptor agonist; A and C, respectively) and clonidine ({alpha}2-adrenoreceptor agonist; B and D, respectively). Data are presented as means ± SE. For gracilis muscle arterioles, n = 27 for LZR and n = 26 for OZR; for cremasteric arterioles, n = 15 for both LZR and OZR. *P < 0.05 vs. logarithm of the agonist concentration at which the response is halfway between the lower and upper bounds (logED50) determined in LZR for that agonist. {dagger}P < 0.05 vs. maximum arteriolar constriction determined in LZR for that agonist.

 
Data describing the responses of norepinephrine-preconstricted resistance arterioles from OZR and LZR after challenge with vasodilator stimuli are summarized in Fig. 2. With hypoxia, arteriolar dilation in OZR was reduced vs. responses in LZR (Fig. 2A). This impaired response was improved after treatment of vessels with prazosin or phentolamine, although hypoxic dilation remained significantly less than that in LZR. Treatment of the vessel with yohimbine had no impact on hypoxic dilation of resistance arterioles of OZR. Fig. 2, B and C present the dilation of resistance arterioles of LZR and OZR in response to challenge with acetylcholine and iloprost, respectively. In OZR, arteriolar dilation to acetylcholine or iloprost was abrogated compared with response in vessels of LZR. In both cases, treatment with prazosin or phentolamine improved dilator responses in vessels from OZR, although not to levels determined in LZR. Furthermore, in both cases, treatment of vessels with yohimbine did not have a significant effect on dilator responses of resistance arterioles from OZR after challenge with acetylcholine or iloprost. Fig. 2D presents the dilator responses of resistance arterioles to forskolin. The responses of resistance arterioles to increasing concentration of forskolin were not different between the two animal strains; as such, treatment with the adrenoreceptor antagonists had no impact on dilator responses to forskolin in OZR. Treatment of vessels from LZR with prazosin, phentolamine, or yohimbine had no significant effect on dilator responses to these four stimuli (data not shown).



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  		Fig. 2. Dilation of isolated gracilis muscle resistance arterioles, preconstricted with norepinephrine to their in vivo diameter, from LZR and OZR in response to reduced oxygen tension (A), or increasing concentrations of acetylcholine (B), iloprost (C) and forskolin (D). Data (means ± SE) are presented under control conditions and after treatment of vessels with prazosin (n = 7 for LZR and OZR), phentolamine (n = 8 for LZR; n = 7 for OZR) or yohimbine (n = 7 for LZR and OZR). To more closely approximate in vivo conditions, isolated arterioles from OZR were pretreated with ~3 x 10–10 M norepinephrine. Vessels from LZR usually attained in vivo diameter (n = 17), although some vessels required pretreatment with a maximum norepinephrine concentration of ~1 x 10–10 M (n = 5). *P < 0.05 vs. either response (hypoxia) or {beta} (slope) coefficient (agonists) determined in LZR. {dagger}P < 0.05 vs. either response (hypoxia) or {beta} (slope) coefficient (agonists) determined in OZR.

 
The responses of in situ cremasteric distal arterioles in OZR and LZR are presented in Fig. 3. With elevated wall shear rate (Fig. 3A), or treatment with either acetylcholine (Fig. 3B) or iloprost (Fig. 3C), arterioles of OZR exhibited an impaired dilation vs. responses in LZR. In each case, this response was improved significantly after treatment of cremaster muscle of OZR with either of the adrenoreceptor antagonists, although responses remained significantly impaired vs. those in LZR. Dilator responses to forskolin (Fig. 3D) were not impaired in cremasteric arterioles of OZR vs. LZR; subsequent treatment with the adrenoreceptor antagonists was without effect. Similar to data from resistance arterioles, treatment of distal arterioles from LZR with these receptor blockers had no significant effect on dilator reactivity to these four stimuli (data not shown).



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  		Fig. 3. Dilation of in situ cremasteric distal arterioles from LZR and OZR in response to elevated wall shear rate (A) and increasing concentrations of acetylcholine (B), iloprost (C), and forskolin (D). Data (means ± SE) are presented under control conditions and after treatment of the cremaster muscle with prazosin (n = 5 for LZR and OZR), phentolamine (n = 5 for LZR and OZR), or yohimbine (n = 5 for LZR and OZR). *P < 0.05 vs. {beta} (slope) coefficient determined in LZR. {dagger}P < 0.05 vs. {beta} (slope) coefficient determined in OZR.

 
As presented in Table 1, OZR demonstrated a moderate elevation in mean arterial pressure vs. LZR, 128 ± 5 vs. 104 ± 6 mmHg, respectively. After infusion of phentolamine (5 mg/kg iv) or prazosin (1 mg/kg iv), arterial pressure in OZR fell to 109 ± 6 and 111 ± 5 mmHg, respectively, whereas arterial pressure in LZR was not altered (102 ± 7 and 104 ± 8 mmHg, respectively). Infusion of yohimbine (5 mg/kg iv) caused a consistent, although not significant, fall in arterial pressure in OZR (to 118 ± 6 mmHg) and had no effects on pressure in LZR (107 ± 6 mmHg).

Figure 4 presents resting blood flow to (Fig. 4A), and vascular resistance within (Fig. 4B), gastrocnemius muscle of LZR and OZR under control conditions and after treatment of rats with prazosin, phentolamine, or yohimbine. Under control conditions, blood flow to the gastrocnemius muscle of OZR was significantly lower than that in LZR, reflected in an increased vascular resistance. After treatment of OZR with prazosin or phentolamine, blood flow to the gastrocnemius muscle was increased, and vascular resistance was reduced, such that these values were not different from those in LZR. Directionally similar alterations in resting blood flow and vascular resistance were determined in OZR after treatment of the rat with yohimbine, although these changes were not as large as those determined after phentolamine treatment. Infusion of either adrenoreceptor antagonist did not significantly alter blood flow to, or vascular resistance within, the gastrocnemius muscle of LZR (data not shown).



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  		Fig. 4. Gastrocnemius muscle blood flow (A) and vascular resistance (B) in LZR and OZR under resting conditions. Data (means ± SE) are presented under control conditions and after intravenous infusion of prazosin (n = 5 for LZR and OZR), phentolamine (n = 5 for LZR and OZR), or yohimbine (n = 5 for LZR and OZR) into anesthetized rats. *P < 0.05 vs. LZR. {dagger}P < 0.05 vs. OZR.

 
Data describing the perfusion of in situ gastrocnemius muscle of LZR and OZR in response to incremental elevations in metabolic demand, imposed via increasing twitch contraction frequency, are presented in Fig. 5. With increasing contraction frequency, muscle blood flow in both rat strains increased with metabolic demand, although hyperemic responses were attenuated in OZR (Fig. 5A). Treatment of OZR with prazosin or phentolamine improved this impaired hyperemic response in OZR at the lowest contraction frequency (1 Hz) and during 3-Hz contractions. However, this improvement in the hyperemic response in OZR after treatment with these antagonists was diminished with increased metabolic demand and was fully absent at the highest contraction frequency (5 Hz). A directionally similar pattern in improving hyperemic responses in OZR was observed after infusion of yohimbine, although these restorative effects were less pronounced. Alterations in vascular resistance reflected these perfusion data, as resistance was elevated in OZR at each level of twitch contraction frequency, and this elevated resistance was lowered by treatment with prazosin and phentolamine and, to a lesser extent yohimbine, at the lower twitch contraction frequencies (Fig. 5B). However, at the highest twitch contraction frequencies, a residual elevation in resistance was present in OZR, which was not impacted by adrenoreceptor blockade.



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  		Fig. 5. Gastrocnemius muscle blood flow (A) and vascular resistance (B) in LZR and OZR in response to elevated metabolic demand, imposed via increased isometric twitch contraction frequency. Data (means ± SE) are presented after 3 min of muscle contraction under control conditions and after intravenous infusion of prazosin (n = 5 for LZR and OZR), phentolamine (n = 5 for LZR and OZR), or yohimbine (n = 5 for LZR and OZR) into anesthetized rats. *P < 0.05 vs. LZR at that twitch contraction frequency. {dagger}P < 0.05 vs. OZR at that twitch contraction frequency.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Previous studies using the OZR model of the metabolic syndrome X have indicated that dilator responses of skeletal muscle arterioles to numerous stimuli are strongly impaired (12, 18, 28), whereas constrictor responses to adrenoreceptor activation are significantly enhanced (42). Given an additional recent study suggesting an increased activity within the sympathetic nervous system of OZR vs. LZR (7), the purpose of the present study was to determine whether this enhanced {alpha}-adrenergic tone impairs skeletal muscle arteriolar dilation and perfusion of in situ skeletal muscle.

The results of the present study suggest that an increased adrenergic constriction of skeletal muscle arterioles, and possibly an increased activity within the adrenergic system, contributes to an impaired microvessel dilation to the endothelium-dependent stimuli of acetylcholine, elevated wall shear rate, and hypoxia, as well as its predominant mediator, prostacyclin (11, 17). In contrast, dilator responses to forskolin, an adenylyl cyclase activator, resulted in a vasorelaxation that was capable of overcoming the competing influence of adrenergic activity. In OZR, the vasorelaxation in response to challenge with forskolin was ~65% of the maximum possible dilation of the vessel (Table 2), compared with 25–30% of the maximal response elicited by hypoxia, acetylcholine, or iloprost. However, the improvement in dilator responses of skeletal muscle arterioles after adrenoreceptor blockade was only partial, as a significant impairment in the reactivity of these arterioles of OZR remained vs. responses in LZR. On the basis of our previous efforts, this residual impairment may be due to elevated vascular oxidative stress reducing bioavailability of vasodilator signaling molecules (12, 18).

Impairments in arteriolar reactivity were also suggested from experiments using in situ blood-perfused skeletal muscle. Under resting conditions, perfusion of gastrocnemius muscle of OZR was reduced vs. LZR, and this relative ischemia was minimized after adrenoreceptor blockade, suggesting that increased adrenergic constriction of skeletal muscle microvessels reduces blood flow in OZR under conditions of low metabolic demand. With mild increases in metabolic demand (1 Hz, and to a lesser extent 3 Hz, twitch contraction), this increased arteriolar {alpha}-adrenergic tone also contributes to reducing skeletal muscle perfusion, as intravenous infusion of adrenoreceptor antagonists improved blood flow to levels that were similar to those in LZR. However, with further elevations in metabolic demand, the restorative effect of adrenoreceptor blockade was diminished, such that at 5-Hz twitch contraction there was no effect on blood flow or vascular resistance after infusion of prazosin, phentolamine, or yohimbine. In light of our recent studies (13, 15), and that by Lash et al. (29), the persistent reduction in blood flow under high metabolic demand suggests that structural alterations to the skeletal muscle microcirculation of OZR (structural narrowing of individual vessels and/or rarefaction of the microvascular network) may ultimately impair skeletal muscle perfusion through a maintained increase in vascular resistance (20) beyond that which can be rectified through acute pharmacological means.

Faber and colleagues (9, 34, 35) have demonstrated a longitudinal heterogeneity regarding adrenergic control of vascular tone in rat skeletal muscle, where regulation of larger resistance arteries and arterioles occurs primarily via the {alpha}1-adrenoreceptor, with a lesser contribution from the {alpha}2 subtype, whereas distal arterioles demonstrated the contrasting relationship. The results of the present study support this previous work, because, in gracilis muscle arterioles of OZR, blockade of {alpha}2-adrenoreceptors (yohimbine) had minimal impact on vascular reactivity to dilator stimuli, although combined blockade of {alpha}1- and {alpha}2-adrenoreceptors (phentolamine) or blockade of {alpha}1-adrenoreceptors (prazosin) improved dilator responses to hypoxia, acetylcholine, and iloprost. In contrast, treatment of cremasteric distal arterioles of OZR with prazosin, phentolamine, or yohimbine had very similar consequences in terms of improving microvessel dilator responses to wall shear rate, acetylcholine, and iloprost. Taken together, these results suggest that the increased skeletal muscle arteriolar constriction to adrenergic activation may be predominantly mediated via {alpha}1-adrenoreceptors in resistance arterioles, with an additional contribution of {alpha}2-adrenoreceptors in distal arterioles. Although these results are in keeping with the previous studies cited above (9, 34, 35), they also suggest that this relationship is not altered by development of metabolic syndrome X.

Previous work in rat skeletal muscle (3, 43, 44) and in human subjects (8, 24, 39) has demonstrated that adrenergic vasoconstriction of skeletal muscle arterioles, although playing a vital role in regulating arteriolar diameter and muscle blood flow, can be overridden by increased metabolic demand. The present results support this previous work and also suggest that the relationship of metabolic dilator influences overriding {alpha}-adrenergic tone could be altered in OZR, such that a greater metabolic demand is required to override basal {alpha}-adrenergic vasoconstriction. Furthermore, previous studies in human subjects suggested that metabolism-induced abrogation of sympathetic tone may be dependent on muscle contraction intensity (46), whereas results from rat skeletal muscle (3) imply that this process is progressive, as low-moderate increases in metabolic demand inhibit {alpha}2-based components of adrenergic tone and greater intensity is required for inhibition of both {alpha}2- and {alpha}1-based components of adrenergic tone. The present results suggest that these characteristics of metabolism-based inhibition of adrenergic tone are qualitatively consistent in the OZR model of the metabolic syndrome X, where vascular adrenergic tone is elevated. Under conditions in which {alpha}-adrenoreceptor blockade improved skeletal muscle perfusion (i.e., at rest and during mild-moderate elevations in metabolic demand), infusion of prazosin or phentolamine into OZR was more effective at increasing blood flow than was infusion of yohimbine. In speculation, this effect may have represented the pharmacological inhibition of the enhanced vascular adrenergic sensitivity less susceptible to metabolic suppression ({alpha}1-adrenoreceptors) combined with metabolic inhibition of {alpha}2-adrenoreceptor component of adrenergic tone.

An increase in the activity of the sympathetic nervous system with development of the individual pathologies comprising the metabolic syndrome X in both humans and in animal models has reported repeatedly (10, 19, 22, 25, 27, 37, 40, 45), and this has commonly been associated with the development of hypertension. However, the ensuing development of hypertension with obesity is not certain, and many obese individuals display minimal elevations in mean arterial pressure despite an increased sympathetic neural activity. Despite this variability in the development of hypertension in obese individuals, previous studies have suggested that obesity-induced increases in sympathetic nerve activity can lead to elevated vascular resistance in skeletal muscle and a decreased blood flow (38). The results of the present study are consistent with those from previous efforts and also provide evidence that this adrenergic-based elevation in vascular resistance exerts its effects primarily under resting conditions or during modest elevations in metabolic demand.

Both in the present study and in our laboratory's previous efforts (13, 15, 41), we have consistently demonstrated that skeletal muscle resistance arterioles of OZR remodel, resulting in a reduced passive diameter, incremental distensibility, and a left-shifted circumferential stress vs. strain relation. However, we have found minimal evidence that this microvessel remodeling results in a generalized enhancement of constrictor reactivity, as vasoconstrictor responses after challenge with endothelin-1 (42), angiotensin II (42), and elevated oxygen tension (unpublished results) were not different from those in vessels of LZR. These results suggest that the increased constriction of skeletal muscle arterioles in response to adrenergic activation may represent alterations to specific signaling pathways.

There are limitations to the present study. In response to systemic {alpha}-adrenoreceptor blockade, OZR demonstrated a decreased mean arterial pressure, consistent with our laboratory's previous observations (13, 42). This fall in pressure could result in autoregulatory dilation of skeletal muscle resistance vessels, which would be directionally identical to a direct effect of adrenergic blockade. Determining the extent to which the decreased vascular resistance after adrenoreceptor blockade represents autoregulatory dilation, alleviation of increased adrenergic tone, or a combination of both processes is not possible in the present study. Additionally, the present study examines the skeletal muscle microcirculation by using arterioles from three distinct muscles: isolated resistance arterioles from gracilis muscle, in situ cremaster muscle arterioles, and the in situ perfused gastrocnemius muscle. As such, the results must be viewed from a more integrated perspective of skeletal muscle blood flow regulation and may not be adequate for explaining the control of perfusion to any single skeletal muscle.

In conclusion, the presence of an increased skeletal muscle arteriolar constriction to adrenergic activation inherent to the OZR model of the metabolic syndrome X contributes to an impaired arteriolar reactivity to an array of dilator stimuli, a reduction in blood flow to resting skeletal muscle, and a blunted active hyperemia for skeletal muscle with low-moderate elevations in metabolic demand. However, with greater elevations in metabolic demand, the impact of elevated adrenergic activity on skeletal muscle perfusion is diminished, and altered physical structure of the microcirculation may play a dominant role in limiting blood flow in OZR.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This work was supported by an American Heart Association Scientist Development Grant 0330194N and National Heart, Lung, and Blood Institute Grants HL-65289 and HL-29587.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The author expresses thanks to Camille Torres, Lisa Henderson, Anne Ansley, and Brian Corson for expert technical assistance in performing the biochemical assays used in the present study.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. C. Frisbee, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: jfrisbee{at}mcw.edu).


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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