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Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is an integral mediator of vascular control during muscle contractions. However, it is not known whether neuronal NOS (nNOS)-derived NO regulates tissue hyperaemia in healthy subjects, particularly during exercise. We tested the hypothesis that selective nNOS inhibition would reduce blood flow and vascular conductance (VC) in rat hindlimb locomotor muscle(s), kidneys and splanchnic organs at rest and during dynamic treadmill exercise (20 m min−1, 10% grade). Nineteen male Sprague–Dawley rats (555 ± 23 g) were assigned to either rest (n= 9) or exercise (n= 10) groups. Blood flow and VC were determined via radiolabelled microspheres before and after the intra-arterial administration of the selective nNOS inhibitor S-methyl-l-thiocitrulline (SMTC, 2.1 ± 0.1 μmol kg−1). Total hindlimb muscle blood flow (control: 20 ± 2 ml min−1 100g−1, SMTC: 12 ± 2 ml min−1 100g−1, P 0.05) between control and SMTC conditions. SMTC reduced (P < 0.05) blood flow and VC at rest and during exercise in the kidneys, adrenals and liver. These results enhance our understanding of the role of NO-mediated circulatory control by demonstrating that nNOS does not appear to subserve an obligatory role in the exercising muscle hyperaemic response in the rat.

The time course of muscle V ˙ O 2 recovery from contractions (i.e., muscle V ˙ O 2 off-kinetics), measured directly at the site of O2 exchange, i.e., in the microcirculation, is unknown. Whereas biochemical models based upon creatine kinase flux rates predict slower V ˙ O 2 off- than on-transients [Kushmerick, M.J., 1998. Comp. Biochem. Physiol. B: Biochem. Mol. Biol.] whole muscle V ˙ O 2 data [Krustrup, et al. J. Physiol.] suggest on–off symmetry. Purpose We tested the hypothesis that the slowed recovery blood flow (Qm) kinetics profile in the spinotrapezius muscle [Ferreira et al., 2006. J. Physiol.] was associated with a slowed muscle V ˙ O 2 recovery compared with that seen at the onset of contractions (time constant, τ ∼ 23 s, Behnke et al., 2002. Resp. Physiol.), i.e., on–off asymmetry. Methods Measurements of capillary red blood cell flux and microvascular pressure of O2 ( P O 2 mv ) were combined to resolve the temporal profile of muscle V ˙ O 2 across the moderate intensity contractions-to-rest transition. Results Muscle V ˙ O 2 decreased from an end-contracting value of 7.7 ± 0.2 ml/100 g/min to 1.7 ± 0.1 ml/100 g/min at the end of the 3 min recovery period, which was not different from pre-stimulation V ˙ O 2 . Contrary to our hypothesis, muscle V ˙ O 2 in recovery began to decrease immediately (i.e., time delay P O 2 during the recovery from contractions. Conclusions The slowed Qm kinetics in recovery serves to elevate the Qm / V ˙ O 2 ratio and thus microvascular P O 2 . Whether this Qm response is obligatory to the rapid muscle V ˙ O 2 kinetics and hence speeds the repletion of high-energy phosphates by maximizing conductive and diffusive O2 flux is an important question that awaits resolution.

Alterations of skeletal muscle redox state via antioxidant supplementation have the potential to impact contractile function and vascular smooth muscle tone. The effects of antioxidants on the regulation of muscle O(2) delivery-O(2) utilization (Q(O(2)m/V(O(2)m)) matching (which sets the microvascular partial pressure of O(2); P(O(2)mv)) in young healthy muscle are not known. Therefore, the purpose of this study was to test the effects of acute antioxidant supplementation on rat spinotrapezius muscle force production, blood flow, V(O(2)m) and P(O(2)mv) (phosphorescence quenching). Anaesthetized male Fischer 344 x Brown Norway rats (6-8 months old) had their right spinotrapezius muscles either exposed for measurement of blood flow and (n = 13) or exteriorized for measurement of muscle force production (n = 6). Electrically stimulated 1 Hz twitch contractions (approximately 7-9 V) were elicited for 180 s, and measurements were made before and after acute intra-arterial antioxidant supplementation (76 mg kg(-1) ascorbic acid, 52 mg kg(-1) tempol) dissolved in saline and infused over 30 min. The principal effects of antioxidants were a approximately 25% decrease (P < 0.05) in contracting spinotrapezius muscle force production concurrent with reductions in muscle blood flow and V(O(2)m) at rest and during contractions (P < 0.05 for both). Antioxidant supplementation reduced the resting baseline P(O(2)mv) (before, 29.9 +/- 1.2 mmHg; after, 25.6 +/- 1.3 mmHg; P < 0.05), and this magnitude of depression was sustained throughout the rest-to-exercise transition (steady-state value before, 16.4 +/- 0.7 mmHg; after, 13.6 +/- 0.9 mmHg; P < 0.05). In addition, the time constant of the P(O(2)mv) decrease was reduced after antioxidant supplementation (before, 23.4 +/- 4.3 s; after, 15.6 +/- 2.7 s; P < 0.05). These results demonstrate that antioxidant supplementation significantly impacts the control of (Q(O(2)m/V(O(2)m)) in young rats at rest and during contractions.

Advancing age alters the structural and functional determinants of convective and diffusive muscle oxygen (O(2)) flux. However, capillary red blood cell (RBC) hemodynamics have not been investigated during contractions in muscles of old animals. Therefore, we tested the hypothesis that aging induces significant capillary hemodynamic alterations during electrically-induced contractions in the spinotrapezius muscle of old Fischer 344 x Brown Norway rats when compared to younger counterparts. The spinotrapezius muscle was observed via intravital microscopy under both resting and contracting conditions in 8 old (O: 26-30 months) and 5 young (Y: 6-8 months) animals. Capillary RBC flux (F(RBC)), velocity (V(RBC)), hematocrit (H(CAP)), and lineal F(RBC) (F(RBC) x capillary lineal density) were determined in all visible capillaries and fields at rest and during the steady-state of muscle contractions. At rest F(RBC) and V(RBC) were elevated in O compared to Y rats, while there was no difference in H(CAP) or lineal F(RBC) between groups. During the contracting steady-state, Delta F(RBC) (Y: 28.8+/-7.7, O: -2.9+/-1.4 cells/s), Delta V(RBC) (Y: 253+/-68, O: -4+/-15 microm/s), Delta H(CAP) (Y: 0.02+/-0.02, O: -0.03+/-0.01), and the Delta lineal F(RBC) (Y: 892+/-255, O: -24+/-30 cells/s/mm) were all lower (P0.05) in O compared to Y rats. These results indicate that despite maintained total perfusive and diffusive O(2) transport at rest, advancing age results in significant impairments in capillary hemodynamics during electrically-induced contractions. These alterations likely contribute to the mechanisms responsible for the reduced exercise capacity commonly found in elderly populations.

Aged rats exhibit a decreased muscle microvascular O2 partial pressure (PmvO2) at rest and during contractions compared with young rats. Age-related reductions in nitric oxide bioavailability due, in part, to elevated reactive O2 species, constrain muscle blood flow (Q̇m). Antioxidants may restore nitric oxide bioavailability, Q̇m, and ameliorate the reduced PmvO2. We tested the hypothesis that antioxidants would elevate Q̇m and, therefore, PmvO2 in aged rats. Spinotrapezius muscle PmvO2 and Q̇m were measured, and oxygen consumption (V̇mO2) was estimated in anesthetized male Fisher 344 × Brown Norway hybrid rats at rest and during 1-Hz contractions, before and after antioxidant intravenous infusion (76 mg/kg vitamin C and 52 mg/kg tempol). Before infusion, contractions evoked a biphasic PmvO2 that fell from 30.6 ± 0.9 Torr to a nadir of 16.8 ± 1.2 Torr with an “undershoot” of 2.8 ± 0.7 Torr below the subsequent steady-state (19.7 ± 1.2 Torr). The principal effect of antioxidants was to elevate baseline PmvO2 from 30.6 ± 0.9 to 35.7 ± 0.8 Torr ( P < 0.05) and reduce or abolish the undershoot ( P < 0.05). Antioxidants reduced Q̇m and V̇mO2 during contractions ( P < 0.05), while decreasing force production 16.5% ( P < 0.05) and elevating the force production-to-V̇mO2 ratio (0.92 ± 0.03 to 1.06 ± 0.6, P < 0.05). Thus antioxidants increased PmvO2 by altering the balance between muscle O2 delivery and V̇mO2 at rest and during contractions. It is likely that this effect arose from antioxidants reducing myocyte redox below the level optimal for contractile performance and directly (decreased tension) or indirectly (altered balance of vasoactive mediators) influencing O2 delivery and V̇mO2.

Whether the speed of recovery of microvascular O2 pressures () differs within muscles composed primarily of type II fibres with contrasting oxidative capacity has not been determined. We tested the hypothesis that, following contractions, the recovery of would be slower in the white (WG; low oxidative capacity) versus the mixed gastrocnemius (MG; comparatively high oxidative capacity). Radiolabelled microsphere and phosphorescence quenching techniques were used to measure muscle blood flow (, hence O2 delivery, ) and during contractions (1 Hz twitch) at low (LO, 2.5 V) and high intensities (HI, 4.5 V) in rat (n= 15) MG and WG muscle and during subsequent recovery. Following the LO protocol, end-contraction was lower in WG (11.6 ± 0.5 mmHg) than in MG (16.2 ± 0.6 mmHg; P 0.05) were not different. In contrast, end-contraction baseline was not different following the HI protocol (MG 10.3 ± 0.6 mmHg and WG 9.2 ± 0.6 mmHg; P > 0.05) but, in agreement with our hypothesis, /dt was slower (MG 0.07 ± 0.01 mmHg s−1 and WG 0.03 ± 0.003 mmHg s−1; P < 0.05) and MRT longer (WG 180.8 ± 4.5 s and MG 115.4 ± 6.7 s; P < 0.05) in WG versus MG following the HI protocol. These data suggest that following high-intensity, though submaximal, muscle contractions, recovers much faster in the more oxidative mixed gastrocnemius than in the less oxidative white gastrocnemius.

We tested the hypothesis that the biochemical properties of cardiac beta-adrenergic receptors (βAR), as determined by standard in vitro methods, limit physiological responsiveness of dogs to PAR stimulation during peak exercise. Accordingly, we measured oxygen consumption, left ventricular dP/dt at 40 mmHg developed pressure, heart rate, and cardiac output during maximal dynamic exercise in 13 adult mongrel dogs. These studies were followed by biochemical analysis of PAR in membrane homogenates of left ventricle from the same animals using saturation binding and agonist competition curves for [125I] cyanopindolol. There was a substantial range in both biochemical and physiological variables within this population of normal dogs. However, there were no significant correlations between biochemical descriptors of cardiac PAR and any physiological variables measured during exercise. These results suggest that receptor-effector coupling and maximal cardiac performance during intense sympathetic stimulation of peak exercise are limited by factors other than the biochemical properties of cardiac PAR.

Vascular hyperpolarization mediated, in part, by the ATP-sensitive K(+) (KATP) channel contributes to exercise-induced increases in skeletal muscle O2 delivery. We hypothesized that KATP channel inhibition via glibenclamide (GLI) would speed the fall of microvascular O2 driving pressure (PO2mv; set by the O2 delivery-O2 utilization ratio), during muscle contractions. Spinotrapezius muscle PO2mv (phosphorescence quenching) was measured in 12 adult Sprague Dawley rats during 180s of 1-Hz twitch contractions (∼ 6 V) under control and GLI (5mg/kg) conditions. The total mean PO2mv response time was greater with GLI (i.e., slowed; control: 42.0 ± 14.2, GLI: 79.5 ± 14.7s, p0.05). A clear undershoot of the contracting steady-state PO2mv was evident with GLI (15.6 ± 5.3%, p0.05) but not control (2.3 ± 1.6%, p0.05). This indicates that KATP channel inhibition does not speed PO2mv kinetics per se during small muscle mass contraction. However, it does induce a transient mismatch of O2 delivery-O2 utilization, lowers PO2mv, and delays attainment of the contracting steady-state.

Chronic heart failure (CHF) reduces nitric oxide (NO) bioavailability and impairs skeletal muscle vascular control during exercise. Reduction of NO2− to NO may impact exercise-induced hyperemia, particularly in muscles with pathologically reduced O2 delivery. We tested the hypothesis that NO2− infusion would increase exercising skeletal muscle blood flow (BF) and vascular conductance (VC) in CHF rats with a preferential effect in muscles composed primarily of type IIb + IId/x fibers. CHF (coronary artery ligation) was induced in adult male Sprague-Dawley rats. After a >21-day recovery, mean arterial pressure (MAP; carotid artery catheter) and skeletal muscle BF (radiolabeled microspheres) were measured during treadmill exercise (20 m/min, 5% incline) with and without NO2− infusion. The myocardial infarct size (35 ± 3%) indicated moderate CHF. NO2− infusion increased total hindlimb skeletal muscle VC (CHF: 0.85 ± 0.09 ml·min−1·100 g−1·mmHg−1 and CHF + NO2−: 0.93 ± 0.09 ml·min−1·100 g−1·mmHg−1, P < 0.05) without changing MAP (CHF: 123 ± 4 mmHg and CHF + NO2−: 120 ± 4 mmHg, P = 0.17). Total hindlimb skeletal muscle BF was not significantly different (CHF: 102 ± 7 and CHF + NO2−: 109 ± 7 ml·min−1·100 g−1 ml·min−1·100 g−1, P > 0.05). BF increased in 6 (∼21%) and VC in 8 (∼29%) of the 28 individual muscles and muscle parts. Muscles and muscle portions exhibiting greater BF and VC after NO2− infusion comprised ≥63% type IIb + IId/x muscle fibers. These data demonstrate that NO2− infusion can augment skeletal muscle vascular control during exercise in CHF rats. Given the targeted effects shown herein, a NO2−-based therapy may provide an attractive “needs-based” approach for treatment of the vascular dysfunction in CHF.

The ATP-sensitive K+ (KATP) channel is a class of inward rectifier K+ channels that contributes to systemic basal vasomotor tone. In rats blockade of KATP channels via glibenclamide (GLI) promotes ...

The systematic increase in V˙O2 uptake and O2 extraction with increasing work rates conceals a substantial heterogeneity of O2 delivery (Q˙O2)-to- V˙O2 matching across and within muscles and other organs. We hypothesize that whether increased/decreased Q˙O2/V˙O2 heterogeneity can be judged as "good" or "bad," for example, after exercise training or in aged individuals or with disease (heart failure, diabetes) depends on the resultant effects on O2 transport and contractile performance.

Microcirculatory red blood cell (RBC) hemodynamics are impaired within skeletal muscle of Type I diabetic rats (Kindig CA, Sexton WL, Fedde MR, and Poole DC. Respir Physiol 111: 163–175, 1998). Whether muscle microcirculatory dysfunction occurs in Type II diabetes, the more prevalent form of the disease, is unknown. We hypothesized that Type II diabetes would reduce the proportion of capillaries supporting continuous RBC flow and RBC hemodynamics within the spinotrapezius muscle of the Goto-Kakizaki Type II diabetic rat (GK). With the use of intravital microscopy, muscle capillary diameter ( dc), capillary lineal density, capillary tube hematocrit (Hctcap), RBC flux ( FRBC), and velocity ( VRBC) were measured in healthy male Wistar (control: n = 5, blood glucose, 105 ± 5 mg/dl) and male GK ( n = 7, blood glucose, 263 ± 34 mg/dl) rats under resting conditions. Mean arterial pressure did not differ between groups ( P > 0.05). Sarcomere length was set to a physiological length (∼2.7 μm) to ensure that muscle stretching did not alter capillary hemodynamics; dcwas not different between control and GK rats ( P > 0.05), but the percentage of RBC-perfused capillaries (control: 93 ± 3; GK: 66 ± 5 %), Hctcap, VRBC, FRBC, and O2delivery per unit of muscle were all decreased in GK rats ( P < 0.05). This study indicates that Type II diabetes reduces both convective O2delivery and diffusive O2transport properties within muscle microcirculation. If these microcirculatory deficits are present during exercise, it may provide a basis for the reduced O2exchange characteristic of Type II diabetic patients.

Splenic nerve denervation abrogates enhanced splenic cytokine gene expression responses to acute heating, demonstrating that hyperthermia-induced activation of splenic sympathetic nerve discharge (SND) increases splenic cytokine gene expression. Hypothermia alters SND responses; however, the role of the sympathetic nervous system in mediating splenic cytokine gene expression responses to hypothermia is not known. The purpose of the present study was to determine the effect of hypothermia on the relationship between the sympathetic nervous system and splenic cytokine gene expression in anesthetized F344 rats. Gene expression analysis was performed using a microarray containing 112 genes, representing inflammatory cytokines, chemokines, cytokine/chemokine receptors and housekeeping genes. A subset of differentially expressed genes was verified by real-time RT-PCR analysis. Splenic SND was decreased significantly during cooling (core temperature decreased from 38 to 30 degrees C) in splenic-intact rats but remained unchanged in sham-cooled splenic-intact rats (core temperature maintained at 38 degrees C). Hypothermia upregulated the transcripts of several genes, including, chemokine ligands CCL2, CXCL2, CXCL10, and CCL20, and interleukins IL-1alpha, IL-1beta, and IL-6. Gene expression responses to hypothermia were similar for the majority of cytokine genes in splenic-intact and splenic-denervated rats. These results suggest that hypothermia-enhanced splenic cytokine gene expression is independent of splenic SND.

AIM To test the hypothesis that diminished vascular nitric oxide availability might explain the inability of individuals with chronic heart failure (CHF) to maintain the microvascular PO(2)'s (PO(2mv) proportional, variant O(2) delivery-to-uptake ratio) seen in healthy animals. METHODS We superfused sodium nitroprusside (SNP; 300 microm), Krebs-Henseleit (control, CON) and L-nitro arginine methyl ester (L-NAME; 1.5 mM) onto the spinotrapezius muscle and measured PO(2mv) by phosphorescence quenching in female Sprague-Dawley rats (n = 26) at rest and during twitch contractions (1 Hz). Seven rats served as controls (Sham) while CHF was induced by myocardial infarction. CHF rats were grouped as moderate (MOD; n = 15) and severe CHF (SEV; n = 4) according to morphological data and baseline PO(2mv). RESULTS In contrast to Sham and MOD, L-NAME did not affect the PO(2mv) response (dynamics and steady-state) of SEV when compared with CON. SNP restored the PO(2mv) profile of SEV to that seen in Sham animals during CON. Specifically, the effect of L-NAME expressed as Delta(L-NAME - CON) were: Baseline PO(2mv) [in mmHg, DeltaSham = -7.0 +/- 1.6 (P < 0.05); DeltaSEV =-1.2 +/- 2.1], end-contractions PO(2mv) [in mmHg, DeltaSham = -5.0 +/- 1.0 (P < 0.05); DeltaSEV = -2.5 +/- 0.5] and time constant of PO(2mv) decrease [in s, DeltaSham = -6.5 +/- 3.0 (P < 0.05); DeltaSEV = -3.2 +/- 1.8]. CONCLUSION These data provide the first direct evidence that the pathological profiles of PO(2mv) associated with severe CHF can be explained, in part, by a diminished vascular NO availability.

In skeletal muscle capillaries, red blood cell (RBC) flux (F RBC), velocity (V RBC) and haematocrit (HctCAP) are key determinants of microvascular O2 exchange. However, the mechanisms leading to the changes in F RBC, V RBC and HctCAP during muscle contractions and recovery thereafter are not fully understood. To address this issue we used intravital microscopy to investigate the temporal profile of the rat spinotrapezius muscle (n = 5) capillary haemodynamics during recovery from 3 min of twitch muscle contractions (1 Hz, 4‐6 V). Specifically, we hypothesized that (1) during early recovery F RBC and V RBC would decrease rapidly and F RBC would display a biphasic response (consistent with a muscle pump effect on capillary haemodynamics), and (2) there would be a dynamic relationship between changes (Δ )i nV RBC and HctCAP. The values at rest (R) and end-recovery (ER) were significantly lower (P 0.05). Based on the early decrease in F RBC (within 5 s), overall dynamic profile of F RBC and the ∼20 s ‘delay’ to the decrease in V RBC we conclude that the muscle pump does not appear to contribute substantially to the steady-state capillary haemodynamics in the contracting rat spinotrapezius muscle. Moreover, our findings suggest that alterations in V RBC do not obligate proportional changes in HctCAP within individual capillaries following muscle contractions.

Purpose: Organ transplant patients treated with cyclosporine-A (CsA) often exhibit weight loss and muscle weakness. The cellular target of CsA, calcineurin, has been implicated in maintenance of muscle fiber size and in expression of the type I skeletal muscle phenotype. We hypothesized that CsA treatment would cause fiber atrophy, as well as increase type IIa myosin heavy chain (MHC) content and oxidative enzyme activities in the soleus muscle. Methods: Rats were treated with CsA for 21 d (20 mg·kg-1·d-1; N = 16) and compared with control rats given olive oil vehicle (Veh; N = 16). Soleus muscles were excised bilaterally. MHC content was determined by gel electrophoresis, oxidative enzyme activities by spectrophotometric methods, and fiber type and size by histochemistry. Results: Lymphocyte count was depressed in CsA rats (P < 0.05), indicating treatment efficacy. Type IIa MHC content was increased in the soleus muscle with CsA (Veh, 10.4 ± 1.7%; CsA, 15.1 ± 2.0; P < 0.05) at the expense of type I MHC. Soleus muscle oxidative enzyme activities were also increased with CsA treatment (P < 0.05). Soleus muscle atrophy occurred, reflected by a 22% decrease in fiber cross-sectional area (Veh, 3255 ± 105 µm2; CsA, 2533 ± 125; P < 0.05). Conclusion: These findings indicate that CsA treatment is associated with changes in skeletal muscle fiber size and phenotype. The former may underlie clinical symptoms of transplant patients treated with CsA.

Healthy aging acts to redistribute blood flow (Q) and thus O2 delivery (QO2 ) among and within the exercising muscles such that QO2 to highly oxidative muscle fibers may be compromised. Within the microcirculation of old muscles capillary hemodynamics are altered and the matching of QO2 to oxidative requirements (VO2) is impaired such that at exercise onset the microvascular O2 pressure falls below that seen in their younger counterparts. This is important because the microvascular O2 pressure denotes the sole driving force for blood-myocyte O2 transfer and any compromise may slow VO2 kinetics and reduce exercise tolerance. This review considers the microcirculatory evidence for a reduced perfusive (QO2 ) and diffusive O2 flux within aged muscle and highlights the pressing need for intravital microscopy studies of the muscle microcirculation during exercise.

Neuronal activity has been shown to be attenuated in cardiorespiratory and locomotor centers of the brain in response to a single bout of exercise in trained (TR) vs. untrained (UN) animals, but the mechanisms remain obscure. Based on this finding, dendritic branching patterns of seven brain areas associated with cardiorespiratory and locomotor activity were examined in TR and UN animals. Twenty-eight male Sprague-Dawley rats were kept in individual cages and divided into TR and UN. TR were provided with a running wheel and exercised spontaneously. After 85 or 120 days, exercise training indexes were obtained, including maximal oxygen consumption, percent body fat, resting heart rate, and heart weight-to-body weight ratios. The brain was removed and processed according to a modified Golgi-Cox procedure. Impregnated neurons from seven brain areas were examined in coronal sections: the periaqueductal gray, posterior hypothalamic area, nucleus of the tractus solitarius, rostral ventrolateral medulla, cuneiform nucleus, nucleus cuneatus, and cerebral cortex. Neurons were traced using a camera lucida technique and analyzed using the Sholl analysis of dendritic branching. t-tests were conducted to compare the mean number of intersections per neuron by grouping inner rings and outer rings and also comparing the total number of intersections per animal. There were significant differences between groups in the posterior hypothalamic area, periaqueductal gray, cuneiform nucleus, and nucleus of the tractus solitarius in the inner rings, outer rings, and the total number of intersections per animal. Our results show that dendritic fields of neurons in important cardiorespiratory and locomotor centers of the brain are attenuated in TR animals.

We tested the hypothesis that central angiotensin II (ANG II) administration would activate splenic sympathetic nerve discharge (SND), which in turn would alter splenic cytokine gene expression. Experiments were completed in sinoaortic nerve-lesioned, urethane-chloralose-anesthetized, splenic nerve-intact (splenic-intact) and splenic nerve-lesioned (splenic-denervated) Sprague-Dawley rats. Splenic cytokine gene expression was determined using gene-array and real-time RT-PCR analyses. Splenic SND was significantly increased after intracerebroventricular administration of ANG II (150 ng/kg, 10 μl), but not artificial cerebrospinal fluid (aCSF). Splenic mRNA expression of IL-1β, IL-6, IL-2, and IL-16 genes was increased in ANG II-treated splenic-intact rats compared with aCSF-treated splenic-intact rats. Splenic IL-1β, IL-2, and IL-6 gene expression responses to ANG II were significantly reduced in splenic-denervated compared with splenic-intact rats. Splenic gene expression responses did not differ significantly in ANG II-treated splenic-denervated and aCSF-treated splenic-intact rats. Splenic blood flow responses to intracerebroventricular ANG II administration did not differ between splenic-intact and splenic-denervated rats. These results provide experimental support for the hypothesis that ANG II modulates the immune system through activation of splenic SND, suggesting a novel relation between ANG II, efferent sympathetic nerve outflow, and splenic cytokine gene expression.

A single bout of eccentric exercise results in muscle damage, but it is not known whether this is correlated with microcirculatory dysfunction. We tested the following hypotheses in the spinotrapezius muscle of rats either 1 (DH-1; n = 6) or 3 (DH-3; n = 6) days after a downhill run to exhaustion (90–120 min; −14° grade): 1) in resting muscle, capillary hemodynamics would be impaired, and 2) at the onset of subsequent acute concentric contractions, the decrease of microvascular O2 pressure (P mvo2), which reflects the dynamic balance between O2 delivery and O2 utilization, would be accelerated compared with control (Con, n = 6) rats. In contrast to Con muscles, intravital microscopy observations revealed the presence of sarcomere disruptions in DH-1 and DH-3 and increased capillary diameter in DH-3 (Con: 5.2 ± 0.1; DH-1: 5.1 ± 0.1; DH-3: 5.6 ± 0.1 μm; both P < 0.05 vs. DH-3). At rest, there was a significant reduction in the percentage of capillaries that sustained continuous red blood cell (RBC) flux in both DH running groups (Con: 90.0 ± 2.1; DH-1: 66.4 ± 5.2; DH-3: 72.9 ± 4.1%, both P < 0.05 vs. Con). Capillary tube hematocrit was elevated in DH-1 but reduced in DH-3 (Con: 22 ± 2; DH-1: 28 ± 1; DH-3: 16 ± 1%; all P < 0.05). Although capillary RBC flux did not differ between groups ( P > 0.05), RBC velocity was lower in DH-1 compared with Con (Con: 324 ± 43; DH-1: 212 ± 30; DH-3: 266 ± 45 μm/s; P < 0.05 DH-1 vs. Con). Baseline P mvO2 before contractions was not different between groups ( P > 0.05), but the time constant of the exponential fall to contracting P mvO2 values was accelerated in the DH running groups (Con: 14.7 ± 1.4; DH-1: 8.9 ± 1.4; DH-3: 8.7 ± 1.4 s, both P < 0.05 vs. Con). These findings are consistent with the presence of substantial microvascular dysfunction after downhill eccentric running, which slows the exercise hyperemic response at the onset of contractions and reduces the P mvO2 available to drive blood-muscle O2 delivery.

Chronic heart failure (CHF) is manifested principally in the elderly population. Therefore, to understand the causes of exercise intolerance in CHF patients, it is imperative to resolve the effects of aging on muscle blood flow (BF) in CHF. To address this issue, we determined the muscle BF response to submaximal treadmill exercise (20 m/min, 5% grade) in young (YCHF: 6–8 mo, 412 ± 11 g, n = 11) and old (OCHF: 27–29 mo, 494 ± 10 g, n = 8) Fischer 344 × Brown Norway rats with similar degrees of myocardial infarction-induced left ventricular (LV) dysfunction [resting LV end-diastolic pressure: YCHF= 24 ± 2, OCHF= 22 ± 2 mmHg; derivative of LV pressure over time: YCHF= 5,168 ± 285; OCHF= 5,050 ± 165 mmHg/s; lung weight normalized to body weight: YCHF= 9.14 ± 0.72; OCHF= 8.21 ± 0.29 mg/g (all P > 0.05)]. The exercising heart rate response was blunted in OCHFcompared with YCHFrats (YCHF= 454 ± 8, OCHF= 395 ± 9 beats/min; P < 0.05). BF (radiolabeled microspheres) to the total hindlimb musculature and to each of the 28 individual muscles examined was similar between YCHFand OCHFrats under resting conditions. During exercise, BF to five of the hindlimb muscles that normally possess a majority of slow-twitch oxidative and fast-twitch oxidative glycolytic muscle fibers increased significantly less (−25 to −42%) for OCHFcompared with YCHFrats. In contrast, BF to 14 of the hindlimb muscles that normally possess a majority of fast-twitch glycolytic muscle fibers was increased (+22 to +337%) for OCHFvs. YCHFrats, which contributed to a greater mass-specific total hindlimb BF response in OCHFrats (YCHF= 78 ± 5, OCHF= 100 ± 11 ml·min−1·100 g−1; P < 0.05) and coincided with greater reductions in BF to the kidneys and splanchnic organs during exercise in OCHFvs. YCHF. In conclusion, there appears to be a profound age-related redistribution of BF from the highly oxidative to the highly glycolytic muscles of the hindlimb during exercise in OCHFcompared with YCHFrats. This phenomenon is qualitatively similar to that reported previously for healthy young and old rats.

Aging alters skeletal muscle vascular geometry and control such that the dynamics of muscular blood flow (Q) and O2 delivery (Q(O2)) may be impaired across the rest-exercise transition. If, at the onset of muscle contractions, Q dynamics are slowed disproportionately to those of muscle O2 uptake (V(O2), microvascular PO2 (PO2m) would be reduced and blood-tissue O2 transfer compromised. This investigation determined the effects of aging on PO2m (a direct reflection of the Q(O2)-to-V(O2) ratio), at rest and across the rest-contractions transition in the spinotrapezius of young (approximately 6 months, n = 9) and old (>24 months, n = 10) male Fisher 344/Brown Norway hybrid rats. Phosphorescence quenching techniques were used to quantify PO2m, and test the hypothesis that, across the rest-contractions (twitch, 1 Hz; 4-6 V, 240 s) transition, aging would transiently reduce the Q(O2)-to-V(O2) ratio causing a biphasic profile in which PO2m fell below steady-state contracting values. Old rats had a lower pre-contraction baseline PO2m than young (27.1+/-1.9 versus 33.8+/-1.6 mmHg, P

In response to an elevated metabolic rate ((.-)V(O(2)), increased microvascular blood-muscle O(2) flux is the product of both augmented O(2) delivery ((.-)Q(O(2)), and fractional O(2) extraction. Whole body and exercising limb measurements demonstrate that (.-)Q(O(2) and fractional O(2) extraction increase as linear and hyperbolic functions, respectively, of (.-)V(O(2). Given the presence of disparate vascular control mechanisms among different muscle fibre types, we tested the hypothesis that, in response to muscle contractions, (.-)Q(O(2) would be lower and fractional O(2) extraction (as assessed via microvascular O(2) pressure, P(mvO(2))) higher in fast- versus slow-twitch muscles. Radiolabelled microsphere and phosphorescence quenching techniques were used to measure (.-)Q(O(2) and P(mvO(2)), respectively at rest and across the transition to 1 Hz twitch contractions at low (Lo, 2.5 V) and high intensities (Hi, 4.5 V) in rat (n = 20) soleus (Sol, slow-twitch, type I), mixed gastrocnemius (MG, fast-twitch, type IIa) and white gastrocnemius (WG, fast-twitch, type IIb) muscle. At rest and for Lo and Hi (steady-state values) transitions, P(mvO(2)) was lower (all P < 0.05) in MG (mmHg: rest, 22.5 +/- 1.0; Lo, 15.3 +/- 1.3; Hi, 10.2 +/- 1.6) and WG (mmHg: rest, 19.0 +/- 1.3; Lo, 12.2 +/- 1.1; Hi, 9.9 +/- 1.1) than in Sol (rest, 33.1 +/- 3.2 mmHg; Lo, 19.0 +/- 2.3 mmHg; Hi, 18.7 +/- 1.8 mmHg), despite lower (.-)V(O(2) and (.-)Q(O(2) in MG and WG under each set of conditions. These data suggest that during submaximal metabolic rates, the relationship between (.-)Q(O(2) and O(2) extraction is dependent on fibre type (at least in the muscles studied herein), such that muscles comprised of fast-twitch fibres display a greater fractional O(2) extraction (i.e. lower P(mvO(2))) than their slow-twitch counterparts. These results also indicate that the greater sustained P(mvO(2)) in Sol may be important for ensuring high blood-myocyte O(2) flux and therefore a greater oxidative contribution to energetic requirements.

Whole body hyperthermia (WBH) has been used in experimental settings as an adjunct to radiochemotherapy for the treatment of various malignant diseases. The therapeutic effect of WBH has been hypothesized to involve activation of the immune system, although the effect of hyperthermia-induced activation of sympathetic nerve discharge (SND) on splenic immune function is not known. We tested the hypothesis that heating-induced splenic sympathoexcitation would alter splenic cytokine gene expression as determined using gene array and real-time RT-PCR analyses. Experiments were performed in splenic-intact and splenic-denervated anesthetized Sprague-Dawley rats (n=32). Splenic SND was increased during heating (internal temperature increased from 38 degrees to 41 degrees C) in splenic-intact rats but remained unchanged in nonheated splenic-intact rats. Splenic interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and growth-regulated oncogene 1 (GRO 1) mRNA expression was higher in heated than in nonheated splenic-intact rats. Splenic IL-1beta, IL-6, and GRO 1 mRNA expression was reduced in heated splenic-denervated compared with heated splenic-intact rats, but did not differ between heated splenic-denervated and nonheated splenic-intact rats. These results support the hypothesis that hyperthermia-induced activation of splenic SND enhances splenic cytokine gene expression.

Chronic heart failure (CHF) impairs muscle O2 delivery (QO2) and, at a given O2 uptake (VO2), lowers microvascular O2 pressures (PmvO2: determined by the QO2-to-VO2 ratio), which may impair recovery of high-energy phosphates following exercise. Because CHF preferentially decreases QO2 to slow-twitch muscles, we hypothesized that recovery PmvO2 kinetics would be slowed to a greater extent in soleus (SOL: ∼84% type I fibres) than in peroneal (PER: ∼14% type I) muscles of CHF rats. PmvO2 dynamics were determined in SOL and PER muscles of control (CON: n= 6; left ventricular end-diastolic pressure, LVEDP: ∼3 mmHg), moderate CHF (MOD: n= 7; LVEDP: ∼11 mmHg) and severe CHF (SEV: n= 4; LVEDP: ∼25 mmHg) following cessation of electrical stimulation (180 s; 1 Hz). In PER, neither the recovery PmvO2 values nor the mean response time (MRT; a weighted average of the time to 63% of the overall response) were altered by CHF (CON: 66.8 ± 8.0, MOD: 72.4 ± 11.8, SEV: 69.1 ± 9.5 s). In marked contrast, SOL PmvO2, at recovery onset, was reduced significantly in the SEV group (∼6 Torr) and PmvO2 MRT was slowed with increased severity of CHF (CON: 45.1 ± 5.3, MOD: 63.2 ± 9.4, SEV: 82.6 ± 12.3 s; P < 0.05 CON vs. MOD and SEV). These data indicate that CHF slows PmvO2 recovery following contractions and lowers capillary O2 driving pressure in slow-twitch SOL, but not in fast-twitch PER muscle. These results may explain, in part, the slowed recovery kinetics (phosphocreatine and VO2) and pronounced fatigue following muscular work in CHF patients.

Renal and splanchnic sympathetic nerve discharge (SND) responses to heating are significantly reduced in senescent compared with young Fischer-344 (F344) rats (Kenney MJ and Fels RJ. Am J Physiol Regul Integr Comp Physiol 283: R513-R520, 2002). However, the functional significance of this finding is not known. We tested the hypothesis that blood flow distribution profiles to heating are altered in senescent (24 mo old) compared with mature (12 mo old) and young (3 mo old) F344 rats. Visceral organ, skeletal muscle, and tail blood flows were determined with the radionuclide-tagged microsphere technique before (control, 38 degrees C) and during heating that increased body temperature to 41 degrees C in anesthetized F344 rats. Vascular conductance in the kidney, stomach, large intestine, pancreas, spleen, and tail was significantly reduced during control before heating in senescent compared with young F344 rats. Heating significantly decreased kidney, stomach, small and large intestine, and pancreas vascular conductance in young and mature but not senescent F344 rats. Vascular conductance at 41 degrees C in the kidney and small intestine was significantly lower and in the stomach tended to be lower in young compared with senescent rats. Splenic conductance increased during heating in young and senescent rats but was highest in young rats. Tail conductance during heating was significantly increased in young rats but remained unchanged in mature and senescent rats. These results demonstrate a marked attenuation in heating-induced vascular conductance changes in senescent rats, suggesting an important functional consequence for the attenuated SND responses to heating in aged rats.

The speed with which muscle energetic status recovers after exercise is dependent on oxidative capacity and vascular O2pressures. Because vascular control differs between muscles composed of fast- vs. slow-twitch fibers, we explored the possibility that microvascular O2pressure (PmvO2; proportional to the O2delivery-to-O2uptake ratio) would differ during recovery in fast-twitch peroneal (Per: 86% type II) compared with slow-twitch soleus (Sol: 84% type I). Specifically, we hypothesized that, in Per, PmvO2would be reduced immediately after contractions and would recover more slowly during the off-transient from contractions compared with Sol. The Per and Sol muscles of six female Sprague-Dawley rats (weight = ∼220 g) were studied after the cessation of electrical stimulation (120 s; 1 Hz) to compare the recovery profiles of PmvO2. As hypothesized, PmvO2was lower throughout recovery in Per compared with Sol (end contraction: 13.4 ± 2.2 vs. 20.2 ± 0.9 Torr; end recovery: 24.0 ± 2.4 vs. 27.4 ± 1.2 Torr, Per vs. Sol; P ≤ 0.05). In addition, the mean response time for recovery was significantly faster for Sol compared with Per (45.1 ± 5.3 vs. 66.3 ± 8.1 s, Sol vs. Per; P < 0.05). Despite these findings, PmvO2rose progressively in both muscles and at no time fell below end-exercise values. These data indicate that, during the recovery from contractions (which is prolonged in Per), capillary O2driving pressure (i.e., PmvO2) is reduced in fast-compared with slow-twitch muscle. In conclusion, the results of the present investigation may partially explain the slowed recovery kinetics (phosphocreatine and O2uptake) found previously in 1) fast- vs. slow-twitch muscle and 2) various patient populations, such as those with congestive heart failure and diabetes mellitus.

In rat spinotrapezius muscle, chronic heart failure (CHF) speeds microvascular O2 pressure ( p O2; index of O2 delivery-to-O2 uptake) dynamics across the rest–contractions transition [Cardiovasc. Res. 56 (2002) 479]. Due to the mosaic nature of this muscle, the effect of CHF on microvascular p O2 dynamics in different fiber types remains unclear. Objective: Based upon derangements of endothelial function and blood flow responses, we hypothesized that CHF would speed microvascular p O2 dynamics (reduced O2 delivery-to-O2 uptake ratio) in type I muscle (soleus, ∼84% type I), but not in type II muscle (peroneal, ∼86% type II [J. Appl. Physiol. 80 (1996) 261]). Methods: Using phosphorescence quenching, microvascular p O2 was measured at rest and across the rest–contractions transition (1 Hz) in soleus and peroneal of non-infarcted control (control; n = 7), and Sprague–Dawley rats with moderate (moderate; elevated left ventricular end-diastolic pressure (LVEDP) 10±2 mm Hg; n = 10) and severe (severe; LVEDP 28±4 mm Hg; n = 5) CHF. Results: The microvascular p O2 mean response time (time delay+time constant) was progressively speeded with increasing severity of CHF in soleus (control, 38.7±2.0; moderate, 29.1±1.5; severe, 22.5±3.9 s; P ≤0.05), but not in peroneal (control=moderate=severe). Conclusion: As type I fibers are recruited predominately for moderate intensity exercise, the more rapid lowering of soleus microvascular p O2 in CHF would reduce the blood-muscle O2 driving gradient, exacerbate phosphocreatine and glycogen breakdown, and provide a mechanism for slowed O2 uptake kinetics and premature fatigue in CHF.

Maximal aerobic capacity and the ability to sustain submaximal exercise (Ex) declines with advancing age. Whether altered muscle blood flow (BF) plays a mechanistic role in these effects remains to be resolved. The present investigation determined the effects of aging on the hemodynamic and regional BF response to submaximal Ex in rats. Heart rate (HR), mean arterial pressure (MAP), and BF to different organs (kidneys, splanchnic organs, and 28 hindlimb muscles) were determined at rest and during submaximal treadmill Ex (20 m/min, 5% grade) with radiolabeled microspheres in young (Y; 6-8 mo old, 339 ± 8 g, n = 9) and old (O; 27-29 mo old, 504 ± 18 g, n = 7) Fischer 344 × Brown Norway rats. Results demonstrated that HR, MAP, and BF to the pancreas, small and large intestine, and total hindlimb musculature were similar between Y and O rats at rest. BF to the kidneys, spleen, and stomach were 33, 60, and 43% lower, respectively, in O compared with Y rats. BF to the total hindlimb musculature increased ( P < 0.05) during Ex and was similar for both Y and O rats (Y: 16 ± 3 to 124 ± 7 vs. O: 20 ± 3 to 137 ± 12 ml·min-1·100 g-1). However, in O vs. Y rats, BF was reduced in 6 (highly oxidative) and elevated in 8 (highly glycolytic) of the 28 individual hindquarter muscles or muscle parts examined ( P < 0.05). During Ex, BF to the spleen and stomach decreased ( P < 0.05) from rest in Y rats, whereas BF decreased in the kidneys, pancreas, spleen, stomach, as well as the small and large intestines of O rats. In conclusion, these data demonstrate that, despite similar increases in total hindlimb BF in Y and O rats during submaximal Ex, there is a profound BF redistribution from highly oxidative to highly glycolytic muscles.

The effect of endurance training on the resistance of the heart to left ventricular (LV) functional deficit and infarction after a transient regional ischemia and subsequent reperfusion was examined. Female Sprague-Dawley rats were randomly assigned to an endurance exercise training (Tr) group or a sedentary (Sed) control group. After 20 wk of training, hearts were excised, perfused, and instrumented for assessment of LV mechanical function, and the left anterior descending coronary artery was occluded to induce a transient regional ischemia (1 h) that was followed by 2 h of reperfusion. Throughout much of the regional ischemia-reperfusion protocol, coronary flow rates, diastolic function, and LV developed pressure were better preserved in hearts from Tr animals. During the regional ischemia, coronary flow to myocardium outside the ischemic zone at risk (ZAR) was maintained in Tr hearts, whereas it progressively fell in Sed hearts. On release of the coronary artery ligature, flow to the ZAR was greater in Tr than in Sed hearts. Infarct size, expressed as a percentage of the ischemic ZAR, was significantly smaller in hearts from Tr rats (24 ± 3 vs. 32 ± 2% of ZAR, P < 0.05). Mn- and CuZn-SOD protein expression were higher in the LV myocardium of Tr animals ( P < 0.05 for both isoforms). Our data indicate that long-term exercise training leads to infarct sparing and better maintenance of coronary flow and mechanical function after ischemia-reperfusion.

The effects of aging on muscle microvascular structure and function may play a key role in performance deficits and impairment of O2 exchange within skeletal muscle of senescent individuals. To determine the effects of aging on capillary geometry, red blood cell (RBC) hemodynamics, and hematocrit in a muscle of mixed fiber type, spinotrapezius muscles from Fischer 344 × Brown Norway hybrid rats aged 6–8 mo [young (Y); body mass 421 ± 10 g, n = 6] and 26–28 mo [old (O); 561 ± 12 g, n = 6] were observed by high-resolution transmission light microscopy under resting conditions. The percentage of RBC-perfused capillaries (Y: 78 ± 3%; O: 75 ± 2%) and degree of tortuosity and branching (Y: 13 ± 2%; O: 13 ± 2%, additional capillary length) were not different in O vs. Y muscles. Lineal density of RBC-perfused capillaries in O was significantly reduced (Y: 30.7 ± 1.8, O: 22.8 ± 3.1 capillaries/mm; P < 0.05). However, RBC-perfused capillaries from O rats ( n = 78) exhibited increased RBC velocity ( VRBC) (Y: 219 ± 12, O: 310 ± 14 μm/s; P < 0.05) and RBC flux ( FRBC) (Y: 27 ± 2, O: 41 ± 2 RBC/s; P < 0.05) vs. Y rats ( n = 66). Thus O2 delivery per unit of muscle was not different between groups (Y: 894 ± 111, O: 887 ± 118 RBC · s-1 · mm muscle-1). Capillary hematocrit was not different in Y vs. O rats (Y: 26 ± 1%, O: 28 ± 1%: P > 0.05). These data indicate that in resting spinotrapezius muscle, aging decreases the lineal density of RBC-perfused capillaries while increasing mean VRBC and FRBC within those capillaries. Whereas muscle conductive O2 delivery and capillary hematocrit were unchanged, elevated VRBC reduces capillary RBC transit time and may impair the diffusive transport of O2 from blood to myocyte particularly under exercise conditions.

To determine whether fibre type affects the O2 exchange characteristics of skeletal muscle at the microcirculatory level we tested the hypothesis that, following the onset of contractions, muscle comprising predominately type I fibres (soleus, Sol, 86 % type I) would, based on demonstrated blood flow responses, exhibit a blunted microvascular PO2 (PO2,m, which is determined by the O2 delivery (QO2) to O2 uptake (VO2) ratio) profile (assessed via phosphorescence quenching) compared to muscle of primarily type II fibres (peroneal, Per, 84 % type II). PO2,m was measured at rest, and following the rest-contractions (twitch, 1 Hz, 2-4 V for 120 s) transition in Sol (n = 6) and Per (n = 6) muscles of Sprague-Dawley rats. Both muscles exhibited a delay followed by a mono-exponential decrease in PO2,m to the steady state. However, compared with Sol, Per demonstrated (1) a larger change in baseline minus steady state contracting PO2,m (DeltaPO2,m) (Per, 13.4 +/- 1.7 mmHg; Sol, 8.6 +/- 0.9 mmHg, P < 0.05); (2) a faster mean response time (i.e. time delay (TD) plus time constant (tau); Per, 23.8 +/- 1.5 s; Sol, 39.6 +/- 4.3 s, P < 0.05); and therefore (3) a greater rate of PO2,m decline (DeltaPO2,m/tau; Per, 0.92 +/- 0.08 mmHg s-1; Sol, 0.42 +/- 0.05 mmHg s-1, P < 0.05). These data demonstrate an increased microvascular pressure head of O2 at any given point after the initial time delay for Sol versus Per following the onset of contractions that is probably due to faster QO2 dynamics relative to those of VO2.

Aim: During heart failure (HF), excess sodium retention is triggered by increased plasma renin-angiotensin-aldosterone activity and increased basal sympathetic nerve discharge (SND). Enhanced basal SND in the renal nerves plays a role in sodium retention. Therefore, as a hypothetical model for the central sympathetic control pathways that are dysregulated as a consequence of HF, the cental neural pathways regulating the sympathetic motor output to the kidney are reviewed in the context of their role during HF. Conclusion: From these findings, a model of the neuroanatomical circuitry that may be affected during HF is constructed.

This investigation tested the hypothesis that the dynamics of muscle microvascular O(2) pressure (PO(2)m, which reflects the ratio of O(2) utilization [V*O(2)] to O(2) delivery [Q*O(2)]) following the onset of contractions would be altered in chronic heart failure (CHF).Female Sprague-Dawley rats were subjected to a myocardial infarction (MI) or a sham operation (Sham). Six to 10 weeks post Sham (n=6) or MI (n=17), phosphorescence quenching techniques were utilized to determine PO(2)m dynamics at the onset of spinotrapezius muscle contractions (1 Hz).MI rats were separated into groups with Moderate (n=10) and Severe (n=7) CHF based upon the degree of left ventricular (LV) dysfunction as indicated by structural abnormalities (increased right ventricle weight and lung weight normalized to body weight). LV end-diastolic pressure was elevated significantly in both CHF groups compared with Sham (Sham, 3+/-1; Moderate CHF, 9+/-2; Severe CHF, 27+/-4 mmHg, P0.05). The PO(2)m response was modeled using time delay and exponential components to fit the PO(2)m response to the steady-state. Compared with Shams, the time constant (tau) of the primary PO(2)m response was significantly speeded in Moderate CHF (tau, Sham, 19.0+/-1.5; Moderate CHF, 13.2+/-1.9 s, P0.05) and slowed in Severe CHF (tau, 28.2+/-3.4 s, P0.05). Within the Severe CHF group, tau increased linearly with the product of right ventricular and lung weight (r=0.83, P0.05).These results suggest that CHF alters the dynamic matching of muscle V*O(2)-to-Q*O(2) across the transition from rest to contractions and that the nature of that perturbation is dependent upon the severity of cardiac dysfunction.

Technical limitations have precluded measurement of the V(O(2)) profile within contracting muscle (mV(O(2))) and hence it is not known to what extent V(O(2)) dynamics measured across limbs in humans or muscles in the dog are influenced by transit delays between the muscle microvasculature and venous effluent. Measurements of capillary red blood cell flux and microvascular P(O(2)) (P(O(2)m)) were combined to resolve the time course of mV(O(2)) across the rest-stimulation transient (1 Hz, twitch contractions). mV(O(2)) began to rise at the onset of contractions in a close to monoexponential fashion (time constant, J = 23.2 +/- 1.0 sec) and reached it's steady-state value at 4.5-fold above baseline. Using computer simulation in healthy and disease conditions (diabetes and chronic heart failure), our findings suggest that: (1) mV(O(2)) increases essentially immediately (< 2 sec) following exercise onset; (2) within healthy muscle the J blood flow (thus O(2) delivery, J Q(O(2)m)) is faster than JmV(O(2)) such that oxygen delivery is not limiting, and 3) a faster P(O(2)m) fall to a P(O(2)m) value below steady-state values within muscle from diseased animals is consistent with a relatively sluggish Q(O(2)m) response compared to that of mV(O(2)).

Recent investigations have suggested that changes in contractile protein expression contribute to reductions in skeletal muscle function during congestive heart failure (CHF). Myosin heavy chain (MHC), a major contractile protein, has been shown to undergo alterations in protein isoform expression during CHF. The purpose of this investigation was twofold: (1) to determine whether muscles of the same functional group undergo similar changes in MHC expression, and (2) determine whether the magnitude of alterations in MHC is related to the severity of CHF. Using the rat coronary ligation model, mild and severe forms of CHF were produced and muscles of the plantar flexor group were analyzed. Whole-muscle MHC isoform proportions were not altered in the soleus and white gastrocnemius muscle, however significant increases in the percentage of fast MHC isoforms (7-9% increases in MHC IIx and IIb expression) were found in the red gastrocnemius muscle. In addition, there were significant proportional increases (8%) in MHC type IIb at the expense of MHC type IIx in the plantaris muscle. Many of the changes in the proportions of MHC isoforms were significantly correlated with indices of CHF severity. This indicates that changes in skeletal muscle MHC isoform expression are related to the severity of CHF and suggests that some peripheral skeletal muscles are more susceptible to shifts in MHC expression due to CHF. These changes in MHC isoform expression may contribute to alterations in the physiological performance of skeletal muscle and exercise capacity during CHF.

Intrinsic skeletal muscle abnormalities decrease muscular endurance in chronic heart failure (CHF). In CHF patients, the number of skeletal muscle Na+-K+pumps that have a high affinity for ouabain (i.e., the concentration of [3H]ouabain binding sites) is reduced, and this reduction is correlated with peak oxygen uptake. The present investigation determined whether the concentration of skeletal muscle [3H]ouabain binding sites found during CHF is related to 1) severity of the disease state, 2) muscle fiber type composition, and/or 3) endurance capacity. Four muscles were chosen that represented slow-twitch oxidative (SO), fast-twitch oxidative glycolytic (FOG), fast-twitch glycolytic (FG), and mixed fiber types. Measurements were obtained 8–10 wk postsurgery in 23 myocardial infarcted (MI) and 18 sham-operated control (sham) rats. Eighteen rats had moderate left ventricular (LV) dysfunction [LV end-diastolic pressure (LVEDP) < 20 mmHg], and five had severe LV dysfunction (LVEDP > 20 mmHg). Rats with severe LV dysfunction had significant pulmonary congestion and were likely in a chronic state of compensated congestive failure as indicated by an approximately twofold increase in both lung and right ventricle weight. Run time to fatigue and maximal oxygen uptake (V˙o2 max) were significantly reduced (↓39 and ↓28%, respectively) in the rats with severe LV dysfunction and correlated with the magnitude of LV dysfunction as indicated by LVEDP (run time: r = 0.60, n = 21, P < 0.01 and V˙o2 max: r = 0.93, n = 13, P < 0.01). In addition, run time to fatigue was significantly correlated withV˙o2 max( r = 0.87, n = 15, P < 0.01). The concentration of [3H]ouabain binding sites (Bmax) was significantly reduced (21–28%) in the three muscles comprised primarily of oxidative fibers [soleus: 259 ± 14 vs. 188 ± 17; plantaris: 295 ± 17 vs. 229 ± 18; red portion of gastrocnemius: 326 ± 17 vs. 260 ± 14 pmol/g wet tissue wt]. In addition, Bmaxwas significantly correlated withV˙o2 max(soleus: r = 0.54, n = 15, P < 0.05; plantaris: r = 0.59, n = 15, P < 0.05; red portion of gastrocnemius: r = 0.65, n = 15, P < 0.01). These results suggest that downregulation of Na+-K+pumps that possess a high affinity for ouabain in oxidative skeletal muscle may play an important role in the exercise intolerance that attends severe LV dysfunction in CHF.

In humans, pulmonary oxygen uptake (.V(O2)) kinetics may be speeded by prior exercise in the heavy domain. This "speeding" arises potentially as the result of an increased muscle O(2) delivery (.Q(O2)) and/or a more rapid elevation of oxidative phosphorylation. We adapted phosphorescence quenching techniques to determine the.Q(O2)-to-O(2) utilization (.Q(O2)/.V(O2)) characteristics via microvascular O(2) pressure (P(O2,m)) measurements across sequential bouts of contractions in rat spinotrapezius muscle. Spinotrapezius muscles from female Sprague-Dawley rats (n = 6) were electrically stimulated (1 Hz twitch, 3-5 V) for two 3 min bouts (ST(1) and ST(2)) separated by 10 min rest. P(O2,m) responses were analysed using an exponential + time delay (TD) model. There was no significant difference in baseline and DeltaP(O2,m) between ST(1) and ST(2) (28.5 +/- 2.6 vs. 27.9 +/- 2.4 mmHg, and 13.9 +/- 1.8 vs. 14.1 +/- 1.3 mmHg, respectively). The TD was reduced significantly in the second contraction bout (ST(1), 12.2 +/- 1.9; ST(2), 5.7 +/- 2.2 s, P0.05), whereas the time constant of the exponential P(O2,m) decrease was unchanged (ST(1), 16.3 +/- 2.6; ST(2), 17.6 +/- 2.7 s, P0.1). The shortened TD found in ST(2) led to a reduced time to reach 63 % of the final response of ST(2) compared to ST(1) (ST(1), 28.3 +/- 3.0; ST(2), 20.2 +/- 1.8 s, P0.05). The speeding of the overall response in the absence of an elevated P(O2,m) baseline (which had it occurred would indicate an elevated.Q(O2)/.V(O2) or muscle blood flow suggests that some intracellular process(es) (e.g. more rapid increase in oxidative phosphorylation) may be responsible for the increased speed of P(O2,m) kinetics after prior contractions under these conditions.

It is thought that changes in sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) of skeletal muscle contribute to alterations in skeletal muscle function during congestive heart failure (CHF). It is well established that exercise training can improve muscle function. However, it is unclear whether similar adaptations will result from exercise training in a CHF patient. Therefore, the purpose of this study was to determine whether skeletal muscle during moderate CHF adapts to increased activity, utilizing the functional overload (FO) model. Significant increases in plantaris mass of the CHF-FO and sham-FO groups compared with the CHF and control (sham) groups were observed. Ca2+uptake rates were significantly elevated in the CHF group compared with all other groups. No differences were detected in Ca2+uptake rates between the CHF-FO, sham, and sham-FO groups. Increases in Ca2+uptake rates in moderate-CHF rats were not due to changes in SERCA isoform proportions; however, FO may have attenuated the CHF-induced increases through alterations in SERCA isoform expression. Therefore, changes in skeletal muscle Ca2+handling during moderate CHF may be due to alterations in regulatory mechanisms, which exercise may override, by possibly altering SERCA isoform expression.

Chronic heart failure (CHF) causes deficiencies in skeletal muscle blood flow resulting in compromised skeletal muscle capillary red blood cell (RBC) distribution and hemodynamics. These impairments are thought to be due, in part, to reductions in nitric oxide (NO) bioavailability within skeletal muscle. In healthy animals, nitrate (NO3-) supplementation via beetroot juice (BR) elevates skeletal muscle blood flow and raises the pressure head for capillary-myocyte O2 flux during exercise presumably following a stepwise reduction to NO in vivo. We tested the hypothesis that BR supplementation would increase the % of capillaries supporting RBC flow at rest and during contractions in CHF rats. CHF was induced in young adult male Sprague-Dawley rats via myocardial infarction (MI). Following a 5-week recovery period rats were given BR ([NO3-] 1 mmol/kg/day, CHF+BR) or water (CHF) for 5 days. MI size was not different between groups (CHF: 28 ± 5, CHF+BR: 28 ± 6 %). Intravital microscopy was used to study the in ...

Impaired vasomotor control in chronic heart failure (CHF) is due partly to decrements in nitric oxide synthase (NOS) mediated vasodilation. Exercising muscle blood flow (BF) is augmented with polyunsaturated fatty acid (PUFA) supplementation via fish oil (FO) in healthy rats. We hypothesized that FO would augment exercising muscle BF in CHF rats via increased NO-bioavailability. Myocardial infarction (coronary artery ligation) induced CHF in Sprague–Dawley rats which were subsequently randomized to dietary FO (20% docosahexaenoic acid, 30% eicosapentaenoic acid, n = 15) or safflower oil (SO, 5%, n = 10) for 6–8 weeks. Mean arterial pressure (MAP), blood [lactate], and hindlimb muscles BF (radiolabeled microspheres) were determined at rest, during treadmill exercise (20 m·min−1, 5% incline) and exercise + NG-nitro-l-arginine-methyl-ester (l-NAME) (a nonspecific NOS inhibitor). FO did not change left ventricular end-diastolic pressure (SO: 14 ± 2; FO: 11 ± 1 mm Hg, p > 0.05). During exercise, MAP (SO: 128 ± 3; FO: 132 ± 3 mm Hg) and blood [lactate] (SO: 3.8 ± 0.4; FO: 4.6 ± 0.5 mmol·L−1) were not different (p > 0.05). Exercising hindlimb muscle BF was lower in FO than SO (SO: 120 ± 11; FO: 93 ± 4 mL·min−1·100 g−1, p < 0.05) but was not differentially affected by l-NAME. Specifically, 17 of 28 individual muscle BF’s were lower (p < 0.05) in FO demonstrating that PUFA supplementation with FO in CHF rats does not augment muscle BF during exercise but may lower metabolic cost.