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Academic dishonesty is prevalent in universities in the form of cheating on examinations, with the problem being much greater in classes that have a large number of students that require close seating arrangements for in-class exams. The scenario described below was experienced during an in-class exam that included the possibility of an Honor Code violation between two students that was observed independently by three different faculty proctors. Herein we detail an objective, statistical approach taken to maintain exam and academic integrity that is compelling and transparent to students and the University Honor Council. Using the established error-similarity analysis for multiple-choice exams, it was determined that the number of identical incorrect answers found on the exams of the two individuals in question was sufficiently greater than the number expected by chance (probability of

Progress in understanding physiological mechanisms often consists of discrete discoveries made across different models and species. Accordingly, understanding the mechanistic bases for how altering nitric oxide (NO) bioavailability impacts exercise tolerance (or not) depends on integrating information from cellular energetics and contractile regulation through microvascular/vascular control of O

When exercising humans increase their oxygen uptake (V̇O2) 20-fold above rest the numbers are staggering: Each minute the O2 transport system - lungs, cardiovascular, active muscles – transports and utilizes 161 sextillion (10 21) O2 molecules. Leg extension exercise increases the quadriceps muscles’ blood flow 100-times; transporting 17 sextillion O2 molecules per kilogram per minute from microcirculation (capillaries) to mitochondria powering their cellular energetics. Within these muscles, the capillary network constitutes a prodigious blood-tissue interface essential to exchange O2 and carbon dioxide requisite for muscle function. In disease, microcirculatory dysfunction underlies the pathophysiology of heart failure, diabetes, hypertension, pulmonary disease, sepsis, stroke and senile dementia. Effective therapeutic countermeasure design demands knowledge of microvascular/capillary function in health to recognize and combat pathological dysfunction. Dated concepts of skeletal muscle capillary (from the Latin capillus meaning ‘hair’) function prevail despite rigorous data-supported contemporary models; hindering progress in the field for future and current students, researchers and clinicians. Following closely the 100th anniversary of August Krogh’s 1920 Nobel Prize for capillary function this Evidence Review presents an anatomical and physiological development of this dynamic field: Constructing a scientifically defensible platform for our current understanding of microcirculatory physiological function in supporting blood-mitochondrial O2 transport. New developments include: 1. Putative roles of red blood cell aquaporin and rhesus channels in determining tissue O2 diffusion. 2. Recent discoveries regarding intramyocyte O2 transport. 3. Developing a comprehensive capillary functional model for muscle O2 delivery-to-V̇O2 matching. 4. Use of kinetics analysis to discriminate control mechanisms from collateral or pathological phenomena.

Resting humans transport ~100 quintillion (10(18)) oxygen (O(2)) molecules every second to tissues for consumption. The final, short distance (< 50 μm) from capillary to the most distant mitochondria, in skeletal muscle where exercising O(2) demands may increase 100-fold, challenges our understanding of O(2) transport. To power cellular energetics O(2) reaches its muscle mitochondrial target by dissociating from hemoglobin, crossing the red cell membrane, plasma, endothelial surface layer, endothelial cell, interstitial space, myocyte sarcolemma and a variable expanse of cytoplasm before traversing the mitochondrial outer/inner membranes and reacting with reduced cytochrome c and protons. This past century our understanding of O(2)’s passage across the body’s final O(2) frontier has been completely revised. This review considers the latest structural and functional data, challenging entrenched notions: 1. That O(2) moves freely across blood cell membranes. 2. The Krogh-Erlang model whereby O(2) pressure decreases systematically from capillary to mitochondria. 3. Whether intramyocyte diffusion distances matter. 4. That mitochondria are separate organelles rather than coordinated and highly plastic syncytia. 5. The roles of free versus myoglobin-facilitated O(2) diffusion. 6. That myocytes develop anoxic loci. These questions, and the intriguing notions that 1. cellular membranes, including interconnected mitochondrial membranes, act as low resistance conduits for O(2), lipids and H(+) -electrochemical transport and 2. that myoglobin oxy/deoxygenation state controls mitochondrial oxidative function via nitric oxide, challenge established tenets of muscle metabolic control. These elements redefine muscle O(2) transport models essential for the development of effective therapeutic countermeasures to pathological decrements in O(2) supply and physical performance.

NEW FINDINGS What is the central question of this study? Does impairment in the dynamics of O2 transport in skeletal muscle during a series of contractions constitute a potential mechanism underlying reduced exercise capacity in pulmonary hypertension? What is the main finding and its importance? Pulmonary hypertension compromises the dynamic matching of skeletal muscle O2 delivery-to-utilization following contraction onset in the rat spinotrapezius muscle. These results implicate a role for vascular dysfunction in the slow VO2 kinetics and exercise intolerance present in pulmonary hypertension. ABSTRACT Pulmonary hypertension (PH) is characterized by pulmonary vascular dysfunction and exercise intolerance due, in part, to compromised pulmonary and cardiac function. We tested the hypothesis that there are peripheral (i.e., skeletal muscle) aberrations in O2 delivery ( QO2 )-to-O2 utilization ( VO2 ) matching and vascular control that might help to explain poor exercise tolerance in PH. Furthermore, we investigated the peripheral effects of nitric oxide (NO) in attenuating these decrements. Male Sprague-Dawley rats (n = 21) were administered monocrotaline (MCT; 50 mg/kg, i.p.) to induce PH. Disease progression was monitored via echocardiography. Phosphorescence quenching determined the O2 partial pressure in the interstitial space ( PO2is ) in the spinotrapezius muscle at rest and during contractions under control (SNP-) and NO-donor (sodium nitroprusside, SNP+) conditions. MCT rats displayed right ventricular (RV) hypertrophy (right ventricle/(left ventricle + septum): 0.44 (0.13) vs. 0.28 (0.05)), pulmonary congestion, increased RV systolic pressure (48 (18) vs. 20 (8) mmHg) and arterial hypoxaemia ( PaO2 : 64 (9) vs. 82 (9) mmHg) compared to healthy controls (HC) (P

Mechanical and metabolic signals associated with skeletal muscle contraction stimulate the sensory endings of thin fibre muscle afferents, which, in turn, generates reflex increases in sympathetic nerve activity (SNA) and blood pressure (the exercise pressor reflex; EPR). EPR activation in patients and animals with heart failure with reduced ejection fraction (HF-rEF) results in exaggerated increases in SNA and promotes exercise intolerance. In the healthy decerebrate rat, a subtype of acid sensing ion channel (ASIC) on the sensory endings of thin fibre muscle afferents, namely ASIC1a, has been shown to contribute to the metabolically sensitive portion of the EPR (i.e. metaboreflex), but not the mechanically sensitive portion of the EPR (i.e. the mechanoreflex). However, the role played by ASIC1a in evoking the EPR in HF-rEF is unknown. We hypothesized that, in decerebrate, unanaesthetized HF-rEF rats, injection of the ASIC1a antagonist psalmotoxin-1 (PcTx-1; 100 ng) into the hindlimb arterial supply would reduce the reflex increase in renal SNA (RSNA) evoked via 30 s of electrically induced static hindlimb muscle contraction, but not static hindlimb muscle stretch (model of mechanoreflex activation isolated from contraction-induced metabolite-production). We found that PcTx-1 reduced the reflex increase in RSNA evoked in response to muscle contraction (n = 8; mean (SD) ∫ΔRSNA pre: 1343 (588) a.u.; post: 816 (573) a.u.; P = 0.026) and muscle stretch (n = 6; ∫ΔRSNA pre: 688 (583) a.u.; post: 304 (370) a.u.; P = 0.025). Our data suggest that, in HF-rEF rats, ASIC1a contributes to activation of the exercise pressor reflex and that contribution includes a novel role for ASIC1a in mechanosensation that is not present in healthy rats. KEY POINTS: Skeletal muscle contraction results in exaggerated reflex increases in sympathetic nerve activity in heart failure patients compared to healthy counterparts, which likely contributes to increased cardiovascular risk and impaired tolerance for even mild exercise (i.e. activities of daily living) for patients suffering with this condition. Activation of acid sensing ion channel subtype 1a (ASIC1a) on the sensory endings of thin fibre muscle afferents during skeletal muscle contraction contributes to reflex increases in sympathetic nerve activity and blood pressure, at least in healthy subjects. In this study, we demonstrate that ASIC1a on the sensory endings of thin fibre muscle afferents plays a role in both the mechanical and metabolic components of the exercise pressor reflex in male rats with heart failure. The present data identify a novel role for ASIC1a in evoking the exercise pressor reflex in heart failure and may have important clinical implications for heart failure patients.

NEW FINDINGS What is the central question of this study? Do endoperoxide 4 and thromboxane A2 receptors, which are receptors for cyclooxygenase products of arachidonic metabolism, on thin fibre muscle afferents play a role in the chronic mechanoreflex sensitization present in rats with heart failure with reduced ejection fraction (HF-rEF)? What is the main finding and its importance? The data do not support a role for endoperoxide 4 receptors or thromboxane A2 receptors in the chronic mechanoreflex sensitization in HF-rEF rats. ABSTRACT We investigated the role of cyclooxygenase metabolite-associated endoperoxide 4 receptors (EP4-R) and thromboxane A2 receptors (TxA2 -R) on thin fibre muscle afferents in the chronic mechanoreflex sensitization in rats with myocardial infarction-induced heart failure with reduced ejection fraction (HF-rEF). We hypothesized that injection of either the EP4-R antagonist L-161,982 (1 µg) or the TxA2 -R antagonist daltroban (80 µg) into the arterial supply of the hindlimb would reduce the increase in blood pressure and renal sympathetic nerve activity (RSNA) evoked in response to 30 s of static hindlimb skeletal muscle stretch (a model of isolated mechanoreflex activation) in decerebrate, unanaesthetized HF-rEF rats but not sham-operated control rats (SHAM). Ejection fraction was significantly reduced in HF-rEF (45 ± 11%) compared to SHAM (83 ± 6%; P

August Krogh twice won the prestigious international Steegen Prize, for nitrogen metabolism (1906) and overturning the concept of active transport of gases across the pulmonary epithelium (1910). Despite this, at the beginning of 1920, the consummate experimentalist was relatively unknown worldwide and even among his own University of Copenhagen faculty. But, in early 1919, he had submitted three papers to Dr Langley, then editor of The Journal of Physiology in England. These papers coalesced anatomical observations of skeletal muscle capillary numbers with O2 diffusion theory to propose a novel active role for capillaries that explained the prodigious increase in blood-muscle O2 flux from rest to exercise. Despite his own appraisal of the first two papers as “rather dull” to his friend, the eminent Cambridge respiratory physiologist, Joseph Barcroft, Krogh believed that the third one, dealing with O2 supply and capillary regulation, was“interesting”. These papers, which won Krogh an unopposed Nobel Prize for Physiology or Medicine in 1920, form the foundation for this review. They single-handedly transformed the role of capillaries from passive conduit and exchange vessels, functioning at the mercy of their upstream arterioles, into independent contractile units that were predominantly closed at rest and opened actively during muscle contractions in a process he termed ‘capillary recruitment’. Herein we examine Krogh's findings and some of the experimental difficulties he faced. In particular, the boundary conditions selected for his model (e.g. heavily anaesthetized animals, negligible intramyocyte O2 partial pressure, binary open-closed capillary function) have not withstood the test of time. Subsequently, we update the reader with intervening discoveries that underpin our current understanding of muscle microcirculatory control and place a retrospectroscope on Krogh's discoveries. The perspective is presented that the imprimatur of the Nobel Prize, in this instance, may have led scientists to discount compelling evidence. Much as he and Marie Krogh demonstrated that active transport of gases across the blood-gas barrier was unnecessary in the lung, capillaries in skeletal muscle do not open and close spontaneously or actively, nor is this necessary to account for the increase in blood-muscle O2 flux during exercise. Thus, a contemporary model of capillary function features most muscle capillaries supporting blood flow at rest, and, rather than capillaries actively vasodilating from rest to exercise, increased blood-myocyte O2 flux occurs predominantly via elevating red blood cell and plasma flux in already flowing capillaries. Krogh is lauded for his brilliance as an experimentalist and for raising scientific questions that led to fertile avenues of investigation, including the study of microvascular function. (Figure presented.).

KEY POINTS: Oral sulphonylureas, widely prescribed in diabetes, inhibit pancreatic ATP-sensitive K+ (KATP ) channels to increase insulin release. However, KATP channels are also located within vascular (endothelium and smooth muscle) and muscle (cardiac and skeletal) tissue. We evaluated left ventricular function at rest, maximal aerobic capacity (VI‡O2 max) and submaximal exercise tolerance (i.e. speed-duration relationship) during treadmill running in rats, before and after systemic KATP channel inhibition via glibenclamide. Glibenclamide impaired critical speed proportionally more than VI‡O2 max but did not alter resting cardiac output. Vascular KATP channel function (topical glibenclamide superfused onto hindlimb skeletal muscle) resolved a decreased blood flow and interstitial PO2 during twitch contractions reflecting impaired O2 delivery-to-utilization matching. Our findings demonstrate that systemic KATP channel inhibition reduces VI‡O2 max and critical speed during treadmill running in rats due, in part, to impaired convective and diffusive O2 delivery, and thus VI‡O2 , especially within fast-twitch oxidative skeletal muscle. ABSTRACT: Vascular ATP-sensitive K+ (KATP ) channels support skeletal muscle blood flow and microvascular oxygen delivery-to-utilization matching during exercise, however, oral sulphonylurea treatment in diabetes inhibits pancreatic KATP channels to enhance insulin release. Herein we tested the hypotheses that i) systemic KATP channel inhibition via glibenclamide (GLI; 10 mg kg-1 i.p.) would decrease cardiac output at rest (echocardiography), maximal aerobic capacity (VI‡O2 max) and the speed-duration relationship (i.e. lower critical speed (CS)) during treadmill running and ii) local KATP channel inhibition (5 mg kg-1 GLI superfusion) would decrease blood flow (15 µm microspheres), interstitial space oxygen pressures (PO2 is; phosphorescence quenching) and convective and diffusive O2 transport (QI‡O2 and DO2 , respectively; Fick Principle and Law of Diffusion) in contracting fast-twitch oxidative mixed gastrocnemius muscle (MG: 9% type I+IIa fibres). At rest, GLI slowed LV relaxation (2.11 ± 0.59 vs. 1.70 ± 0.23 cm s-1 ) and decreased heart rate (321 ± 23 vs. 304 ± 22 bpm, both P 0.05). During exercise, GLI reduced VI‡O2 max (71.5 ± 1.0 vs. 68.0 ± 1.5 ml kg-1 min-1 ) and CS (35.9 ± 0.9 vs. 31.9 ± 1.1 m min-1 , both P

Females respond to baroreceptor stimulation with enhanced modulation of heart rate (HR) to regulate blood pressure and also express greater reliance on nitric oxide (NO) for vascular control compared to males. Sex differences in muscle oxygenation consequent to central hemodynamic challenge induced by systemic NO synthase (NOS) inhibition are unknown. We tested the hypotheses that systemic NOS inhibition would induce lower contracting skeletal muscle oxygenation in females compared to males. The spinotrapezius of Sprague-Dawley rats (females (♀) = 9, males (♂) = 9) was surgically exposed and contracted by electrical stimulation (180s, 1 Hz, ~6 V) under pentobarbital sodium anesthesia. Oxyphor G4 was injected into the muscle and phosphorescence quenching was used to measure the interstitial PO2 (PO2is, determined by O2 delivery-to-utilization matching) under control (Krebs-Henseleit solution) and after intra-arterial infusion of nitro- l -arginine methyl ester ( l -NAME; NOS blockade; 10 mg kg−1). At rest, females showed a greater PO2is increase (ΔPO2is/ΔMAP) and HR (ΔHR/ΔMAP) reduction than males in response to the elevated MAP induced by systemic NOS inhibition (both p l -NAME, during the contracting steady-state, females exhibited lower PO2is than males (♂: 17.1 ± 1.4 vs ♀: 10.8 ± 1.4 mmHg, p l -NAME-induced elevation of MAP via the baroreceptor reflex and provide new insights on how central hemodynamics affect skeletal muscle oxygenation in a sex-specific manner.

Whole body exercise tolerance is the consummate example of integrative physiological function among the metabolic, neuromuscular, cardiovascular, and respiratory systems. Depending on the animal selected, the energetic demands and flux through the oxygen transport system can increase two orders of magnitude from rest to maximal exercise. Thus, animal models in health and disease present the scientist with flexible, powerful, and, in some instances, purpose-built tools to explore the mechanistic bases for physiological function and help unveil the causes for pathological or age-related exercise intolerance. Elegant experimental designs and analyses of kinetic parameters and steady-state responses permit acute and chronic exercise paradigms to identify therapeutic targets for drug development in disease and also present the opportunity to test the efficacy of pharmacological and behavioral countermeasures during aging, for example. However, for this promise to be fully realized, the correct or optimal animal model must be selected in conjunction with reproducible tests of physiological function (e.g., exercise capacity and maximal oxygen uptake) that can be compared equitably across laboratories, clinics, and other proving grounds. Rigorously controlled animal exercise and training studies constitute the foundation of translational research. This review presents the most commonly selected animal models with guidelines for their use and obtaining reproducible results and, crucially, translates state-of-the-art techniques and procedures developed on humans to those animal models.Listen to this article’s corresponding podcast at: https://ajpheart.podbean.com/e/guidelines-for-animal-exercise-and-training-protocols/ .

Three sentinel parameters of aerobic performance are the maximal oxygen uptake ( V O 2 max ), critical power (CP) and speed of the V O 2 kinetics following exercise onset. Of these, the latter is, perhaps, the cardinal test of integrated function along the O2 transport pathway from lungs to skeletal muscle mitochondria. Fast V O 2 kinetics demands that the cardiovascular system distributes exercise-induced blood flow elevations among and within those vascular beds subserving the contracting muscle(s). Ideally, this process must occur at least as rapidly as mitochondrial metabolism elevates V O 2 . Chronic disease and ageing create an O2 delivery (i.e. blood flow × arterial [O2 ], Q O 2 ) dependency that slows V O 2 kinetics, decreasing CP and V O 2 max , increasing the O2 deficit and sowing the seeds of exercise intolerance. Exercise training, in contrast, does the opposite. Within the context of these three parameters (see Graphical Abstract), this brief review examines the training-induced plasticity of key elements in the O2 transport pathway. It asks how structural and functional vascular adaptations accelerate and redistribute muscle Q O 2 and thus defend microvascular O2 partial pressures and capillary blood-myocyte O2 diffusion across a ∼100-fold range of muscle V O 2 values. Recent discoveries, especially in the muscle microcirculation and Q O 2 -to- V O 2 heterogeneity, are integrated with the O2 transport pathway to appreciate how local and systemic vascular control helps defend V O 2 kinetics and determine CP and V O 2 max in health and how vascular dysfunction in disease predicates exercise intolerance. Finally, the latest evidence that nitrate supplementation improves vascular and therefore aerobic function in health and disease is presented.

In heart failure with reduced ejection fraction (HFrEF), nitric oxide-soluble guanylyl cyclase (sGC) pathway dysfunction impairs skeletal muscle arteriolar vasodilation and thus capillary hemodynamics, contributing to impaired oxygen uptake [Formula: see text] kinetics. Targeting this pathway with sGC activators offers a new treatment approach to HFrEF. We tested the hypotheses that sGC activator administration would increase the O(2) delivery [Formula: see text] ratio in the skeletal muscle interstitial space (PO(2)is) of HFrEF rats during twitch contractions due, in part, to increases in red blood cell (RBC) flux (f(RBC)), velocity (V(RBC)), and capillary hematocrit (Hct(cap)). HFrEF was induced in male Sprague-Dawley rats via myocardial infarction. After 3 weeks, rats were treated with 0.3 mg/kg of the sGC activator BAY 60–2770 (HFrEF + BAY; n = 11) or solvent (HFrEF; n = 9) via gavage b.i.d for 5 days prior to phosphorescence quenching (PO(2)is, in contracting muscle) and intravital microscopy (resting) measurements in the spinotrapezius muscle. Intravital microscopy revealed higher f(RBC) (70 ± 9 vs 25 ± 8 RBC/s), V(RBC) (490 ± 43 vs 226 ± 35 μm/s), Hct(cap) (16 ± 1 vs 10 ± 1%) and a greater number of capillaries supporting flow (91 ± 3 vs 82 ± 3%) in HFrEF + BAY vs HFrEF (all P < 0.05). Additionally, PO(2)is was especially higher during 12–34s of contractions in HFrEF + BAY vs HFrEF (P < 0.05). Our findings suggest that sGC activators improved resting [Formula: see text] via increased f(RBC), V(RBC), and Hct(cap) allowing for better [Formula: see text] matching during the rest-contraction transient, supporting sGC activators as a potential therapeutic to target skeletal muscle vasomotor dysfunction in HFrEF.

Pulmonary hypertension (PH) has previously been characterized as a disease of the pulmonary vasculature that subsequently results in myocardial dysfunction. Heart failure compromises skeletal muscle microvascular function, which contributes to exercise intolerance. Therefore, we tested the hypothesis that such changes might be present in PH. Thus, we investigated skeletal muscle oxygen (O(2)) transport in the rat model of PH to determine if O(2) delivery [Formula: see text] is impaired at the level of the microcirculation as evidenced via reduced red blood cell (RBC) flux, velocity, hematocrit, and percentage of capillaries flowing in quiescent muscle. Adult male Sprague-Dawley rats were randomized into healthy (n=9) and PH groups (n=9). Progressive PH was induced via a one-time intraperitoneal injection of monocrotaline (MCT; 50 mg/kg) and rats were monitored weekly via echocardiography. Intravital microscopy in the spinotrapezius muscle was performed when echocardiograms confirmed moderate PH (preceding right ventricular (RV) failure). At 25 ± 9 days post-MCT, PH rats displayed RV hypertrophy (RV/(Left ventricle+Septum): 0.28 ± 0.05 vs. 0.44 ± 0.11), pulmonary congestion, and increased right ventricular systolic pressure (21 ± 8 vs. 55 ± 14 mmHg) compared to healthy rats (all P < 0.05). Reduced capillary RBC velocity (403 ± 140 vs. 227 ± 84 μm/s; P = 0.01), RBC flux (33 ± 12 vs. 23 ± 5 RBCs/s; P = 0.04) and % of capillaries supporting continuous RBC flux at rest (79 ± 8 vs. 56 ± 13%; P = 0.01) were evident in PH rats compared to healthy rats. When [Formula: see text] within a given field of view was quantified (RBC flux x % of capillaries supporting continuous RBC flux), PH rats demonstrated lower overall [Formula: see text] (↓ 50%; P = 0.002). These data support that microcirculatory hemodynamic impairments (↓ [Formula: see text] and therefore altered [Formula: see text]-to- [Formula: see text] matching) may compromise blood-myocyte O(2) transport in PH. The mechanistic bases for decreased capillary RBC flux, velocity, and percentage of capillaries supporting RBC flow remains an important topic.

The oxygen partial pressure in the interstitial space (Po2 is) drives O2 into the myocyte via diffusion, thus supporting oxidative phosphorylation. Although crucial for metabolic recovery and the capacity to perform repetitive tasks, the time course of skeletal muscle Po2 is during recovery from contractions remains unknown. We tested the hypothesis that Po2 is would recover to resting values and display considerable on-off asymmetry (fast on-, slow off-kinetics), reflective of asymmetric capillary hemodynamics. Microvascular Po2 (Po2 mv) was also evaluated to test the hypothesis that a significant transcapillary gradient (ΔPo2 = Po2 mv − Po2 is) would be sustained during recovery. Po2 mv and Po2 is (expressed in mmHg) were determined via phosphorescence quenching in the exposed rat spinotrapezius muscle during and after submaximal twitch contractions ( n = 12). Po2 is rose exponentially ( P < 0.05) from end-contraction (11.1 ± 5.1), such that the end-recovery value (17.9 ± 7.9) was not different from resting Po2 is (18.5 ± 8.1; P > 0.05). Po2 is off-kinetics were slower than on-kinetics (mean response time: 53.1 ± 38.3 versus 18.5 ± 7.3 s; P < 0.05). A significant transcapillary ΔPo2 observed at end-contraction (16.6 ± 7.4) was maintained throughout recovery (end-recovery: 18.8 ± 9.6; P > 0.05). Consistent with our hypotheses, muscle Po2 is recovered to resting values with slower off-kinetics compared with the on-transient in line with the on-off asymmetry for capillary hemodynamics. Maintenance of a substantial transcapillary ΔPo2 during recovery supports that the microvascular-interstitium interface provides considerable resistance to O2 transport. As dictated by Fick’s law (V̇o2 = Do2 × ΔPo2), modulation of O2 flux (V̇o2) during recovery must be achieved via corresponding changes in effective diffusing capacity (Do2; mainly capillary red blood cell hemodynamics and distribution) in the face of unaltered ΔPo2. NEW & NOTEWORTHY Capillary blood-myocyte O2 flux (V̇o2) is determined by effective diffusing capacity (Do2; mainly erythrocyte hemodynamics and distribution) and microvascular-interstitial Po2 gradients (ΔPo2 = Po2 mv − Po2 is). We show that Po2 is demonstrates on-off asymmetry consistent with Po2 mv and erythrocyte kinetics during metabolic transitions. A substantial transcapillary ΔPo2 was preserved during recovery from contractions, indicative of considerable resistance to O2 diffusion at the microvascular-interstitium interface. This reveals that effective Do2 declines in step with V̇o2 during recovery, as per Fick’s law.

Background Respiratory muscle blood flows (BF) increase substantially during exercise in younger adult rats. As aging is associated with altered pulmonary function, we hypothesized that old rats will have greater intercostal muscle BF and vascular conductances (VC) than young rats during submaximal exercise. Methods Mean arterial pressure and respiratory muscle BFs (via carotid artery catheter and radiolabeled microspheres, respectively) were measured at rest and during submaximal exercise in young (n = 9) and old (n = 7) Fischer 344 X Brown Norway rats. Results At rest, diaphragm, intercostal, and transversus abdominis BFs and VCs were not different between groups (all, p > 0.10). During submaximal exercise, old compared to young rats had greater intercostal BF (40 ± 6 vs 25 ± 2 mL/min/100 g) and VC (0.30 ± 0.05 vs 0.18 ± 0.02 mL/min/mmHg/100 g) (both, p ≤ 0.01). Diaphragm and transversus abdominis BFs and VCs were not different between groups during exercise (all, p > 0.24). Conclusions These data demonstrate that intercostal muscle BF and VC are increased in old compared to young rats during submaximal exercise.

ATP‐sensitive K+ channels (KATP) have been implicated in the regulation of resting vascular smooth muscle membrane potential and tone. However, whether KATP channels modulate skeletal muscle microvascular hemodynamics at the capillary level (the primary site for blood‐myocyte O2 exchange) remains unknown. We tested the hypothesis that KATP channel inhibition would reduce the proportion of capillaries supporting continuous red blood cell (RBC) flow and impair RBC hemodynamics and distribution in perfused capillaries within resting skeletal muscle. RBC flux (fRBC), velocity (VRBC), and capillary tube hematocrit (Hctcap) were assessed via intravital microscopy of the rat spinotrapezius muscle (n = 6) under control (CON) and glibenclamide (GLI; KATP channel antagonist; 10 µM) superfusion conditions. There were no differences in mean arterial pressure (CON:120 ± 5, GLI:124 ± 5 mmHg; p > 0.05) or heart rate (CON:322 ± 32, GLI:337 ± 33 beats/min; p > 0.05) between conditions. The %RBC‐flowing capillaries were not altered between conditions (CON:87 ± 2, GLI:85 ± 1%; p > 0.05). In RBC‐perfused capillaries, GLI reduced fRBC (CON:20.1 ± 1.8, GLI:14.6 ± 1.3 cells/s; p 0.05). The absence of GLI effects on the %RBC‐flowing capillaries and Hctcap indicates preserved muscle O2 diffusing capacity (DO2m). In contrast, GLI lowered both fRBC and VRBC thus impairing perfusive microvascular O2 transport (Q̇m) and lengthening RBC capillary transit times, respectively. Given the interdependence between diffusive and perfusive O2 conductances (i.e., %O2 extraction∝DO2m/Q̇m), such GLI alterations are expected to elevate muscle %O2 extraction to sustain a given metabolic rate. These results support that KATP channels regulate capillary hemodynamics and, therefore, microvascular gas exchange in resting skeletal muscle.

Diaphragm muscle blood flow (BF) and vascular conductance (VC) are elevated with chronic heart failure (HF) during exercise. Exercise training (ExT) elicits beneficial respiratory muscle and pulmonary system adaptations in HF. We hypothesized that diaphragm BF and VC would be lower in HF rats following ExT than their sedentary counterparts (Sed). Respiratory muscle BFs and mean arterial pressure were measured via radiolabeled microspheres and carotid artery catheter, respectively, during submaximal treadmill exercise (20 m/min, 5 % grade). During exercise, no differences were present between HF + ExT and HF + Sed in diaphragm BFs (201 ± 36 vs. 227 ± 44 mL/min/100 g) or VCs (both, p 0.05). HF + ExT compared to HF + Sed had lower intercostal BF (27 ± 3 vs. 41 ± 5 mL/min/100 g) and VC (0.21 ± 0.02 vs. 0.31 ± 0.04 mL/min/mmHg/100 g) during exercise (both, p 0.05). Further, HF + ExT compared to HF + Sed had lower transversus abdominis BF (20 ± 1 vs. 35 ± 6 mL/min/100 g) and VC (0.14 ± 0.02 vs. 0.27 ± 0.05 mL/min/mmHg/100 g) during exercise (both, p 0.05). These data suggest that exercise training lowers the intercostal and transversus abdominis BF responses in HF rats during submaximal treadmill exercise.

Post-occlusive reactive hyperemia (PORH) is an accepted diagnostic tool for assessing peripheral macrovascular function. While conduit artery hemodynamics have been well defined, the impact of PORH on capillary hemodynamics remains unknown, despite the microvasculature being the dominant site of vascular control. Therefore, the purpose of this investigation was to determine the effects of 5 minutes of feed artery occlusion on capillary hemodynamics in skeletal muscle. We tested the hypothesis that, upon release of arterial occlusion, there would be: 1) an increased red blood cell flux (f(RBC)) and red blood cell velocity (V(RBC)), and 2) a decreased proportion of capillaries supporting RBC flow compared to the pre-occlusion condition. METHODS: In female Sprague-Dawley rats (n = 6), the spinotrapezius muscle was exteriorized for evaluation of capillary hemodynamics pre-occlusion, 5 min of feed artery occlusion (Occ), and 5 min of reperfusion (Post-Occ). RESULTS: There were no differences in mean arterial pressure (MAP) or capillary diameter (D(c)) between pre-occlusion and post-occlusion (P > 0.05). During 30s of PORH, capillary f(RBC) was increased (pre: 59 ± 4 vs 30s-post: 77 ± 2 cells/s; P < 0.05) and V(RBC) was not changed (pre: 300 ± 24 vs 30s post: 322 ± 25 μm/s; P > 0.05). Capillary hematocrit (Hct(cap)) was unchanged across the pre- to post-occlusion conditions (P > 0.05). Following occlusion, there was a 20–30% decrease in the number of capillaries supporting RBC flow at 30s and 300s-post occlusion (pre: 92 ± 2%; 30s-post: 66 ± 3%; 300s-post: 72 ± 6%; both P < 0.05). CONCLUSION: Short-term feed artery occlusion (i.e. 5 min) resulted in a more heterogeneous capillary flow profile with the presence of capillary no-reflow, decreasing the percentage of capillaries supporting RBC flow. A complex interaction between myogenic and metabolic mechanisms at the arteriolar level may play a role in the capillary no-reflow with PORH. Measurements at the level of the conduit artery mask significant alterations in blood flow distribution in the microcirculation.

Vascular ATP-sensitive K(+) (K(ATP)) channels support skeletal muscle blood flow (Q̇m), interstitial O(2) delivery (Q̇O(2))-utilization (V̇O(2)) matching (i.e., interstitial-myocyte O(2) flux driving pressure; PO(2)is) and exercise tolerance. Potential sex differences in skeletal muscle vascular K(ATP) channel function remain largely unexplored. We hypothesized that local skeletal muscle K(ATP) channel inhibition via glibenclamide superfusion (5 mg kg(−1) GLI; sulfonylurea diabetes medication) in anesthetized female Sprague-Dawley rats, compared to males, would demonstrate greater reductions in contracting (1 Hz, 7V, 180 s) fast-twitch oxidative mixed gastrocnemius (97% type IIA+IID/X+IIB) Q̇m (15 µm microspheres) and PO(2)is (phosphorescence quenching), resulting from more compromised convective (Q̇O(2)) and diffusive (DO(2)) O(2) conductances. Further that these GLI-induced reductions in ovary-intact females measured during proestrus would be diminished following ovariectomy (F+OVX). GLI similarly impaired mixed gastrocnemius V̇O(2) in both males (↓28%) and females (↓33%, both P

The primary purpose of this investigation was to determine the role played by endoperoxide 4 receptors (EP4-R) and thromboxane A(2) receptors (TxA(2)-R) during isolated dynamic muscle mechanoreflex activation in rats with heart failure with reduced ejection fraction (HF-rEF) and sham-operated healthy controls. We found that injection of the EP4-R antagonist L-161,982 (1μg) into the arterial supply of the hindlimb had no effect on the peak pressor response to dynamic hindlimb muscle stretch in HF-rEF (n=6, peak ΔMAP pre: 27±7; post: 27±4 mmHg; P=0.99) or sham (n=6, peak ΔMAP pre: 15±3; post: 13±3 mmHg; P=0.67) rats. In contrast, injection of the TxA(2)-R antagonist daltroban (80μg) into the arterial supply of the hindlimb reduced the pressor response to dynamic hindlimb muscle stretch in HF-rEF (n=11, peak ΔMAP pre: 28±4; post: 16±2 mmHg; P=0.02) but not sham (n=8, peak ΔMAP pre: 17±3; post: 16±3; P=0.84) rats. Our data suggest that TxA(2)-Rs on thin fibre muscle afferents contribute to the exaggerated mechanoreflex in HF-rEF.

The capillary bed constitutes the obligatory pathway for almost all oxygen (O(2)) and substrate molecules as they pass from blood to individual cells. As the largest organ, by mass, skeletal muscle contains a prodigious surface area of capillaries that have a critical role in metabolic homeostasis and must support energetic requirements that increase as much as 100-fold from rest to maximal exercise. In 1919 Krogh’s 3 papers, published in the Journal of Physiology, brilliantly conflated measurements of muscle capillary function at rest and during contractions with Agner K. Erlang’s mathematical model of O(2) diffusion. These papers single-handedly changed the perception of capillaries from passive vessels serving at the mercy of their upstream arterioles into actively contracting vessels that were recruited during exercise to elevate blood-myocyte O(2) flux. Although seminal features of Krogh’s model have not withstood the test of time and subsequent technological developments, Krogh is credited with helping found the field of muscle microcirculation and appreciating the role of the capillary bed and muscle O(2) diffusing capacity in facilitating blood-myocyte O(2) flux. Today, thanks in large part to Krogh, it is recognized that comprehending the role of the microcirculation, as it supports perfusive and diffusive O(2) conductances, is fundamental to understanding skeletal muscle plasticity with exercise training and resolving the mechanistic bases by which major pathologies including heart failure and diabetes cripple exercise tolerance and cerebrovascular dysfunction predicates impaired executive function.

Although mechanical ventilation (MV) is a life-saving intervention, prolonged MV can lead to deleterious effects on diaphragm function, including vascular incompetence and weaning failure. During MV, positive end-expiratory pressure (PEEP) is used to maintain small airway patency and mitigate alveolar damage. We tested the hypothesis that increased intrathoracic pressure with high levels of PEEP would increase diaphragm vascular resistance and decrease perfusion. Female Sprague-Dawley rats (~6 mo) were randomly divided into two groups receiving low PEEP (1 cmH2O; n = 10) or high PEEP (9 cmH2O; n = 9) during MV. Blood flow, via fluorescent microspheres, was determined during spontaneous breathing (SB), low-PEEP MV, high-PEEP MV, low-PEEP MV + surgical laparotomy (LAP), and high-PEEP MV + pneumothorax (PTX). Compared with SB, both low-PEEP MV and high-PEEP MV increased total diaphragm and medial costal vascular resistance (P ≤ 0.05) and reduced total and medial costal diaphragm blood flow (P ≤ 0.05). Also, during MV medial costal diaphragm vascular resistance was greater and blood flow lower with high-PEEP MV vs. low-PEEP MV (P ≤ 0.05). Diaphragm perfusion with high-PEEP MV+PTX and low-PEEP MV were not different (P > 0.05). The reduced total and medial costal diaphragmatic blood flow with low-PEEP MV appears to be independent of intrathoracic pressure changes and is attributed to increased vascular resistance and diaphragm quiescence. Mechanical compression of the diaphragm vasculature may play a role in the lower diaphragmatic blood flow at higher levels of PEEP. These reductions in blood flow to the quiescent diaphragm during MV could predispose critically ill patients to weaning complications. NEW & NOTEWORTHY This is the first study, to our knowledge, demonstrating that mechanical ventilation, with low and high positive-end expiratory pressure (PEEP), increases vascular resistance and reduces total and regional diaphragm perfusion. The rapid reduction in diaphragm perfusion and increased vascular resistance may initiate a cascade of events that predispose the diaphragm to vascular and thus contractile dysfunction with prolonged mechanical ventilation.

We investigated the role of cyclooxygenase metabolite-associated endoperoxide 4 receptors (EP4-R) and thromboxane A(2) receptors (TxA(2)-R) on thin fiber muscle afferents in the chronic mechanoreflex sensitization in rats with myocardial infarction-induced heart failure with reduced ejection fraction (HF-rEF). We hypothesized that injection of either the EP4-R antagonist L-161,982 (1 μg) or the TxA(2)-R antagonist daltroban (80 μg) into the arterial supply of the hindlimb would reduce the increase in blood pressure and renal sympathetic nerve activity (RSNA) evoked in response to 30 s of static hindlimb skeletal muscle stretch (a model of isolated mechanoreflex activation) in decerebrate, unanesthetized HF-rEF rats but not sham operated control rats (SHAM). Ejection fraction was significantly reduced in HF-rEF (45±11%) compared to SHAM (83±6%; P

KEY POINTS Within skeletal muscle the greatest resistance to oxygen transport is thought to reside across the short distance at the red blood cell-myocyte interface. These structures generate a significant transmural oxygen pressure (PO2 ) gradient in mixed fibre-type muscle. Increasing O2 flux across the capillary wall during exercise depends on: (i) the transmural O2 pressure gradient, which is maintained in mixed-fibre muscle, and/or (ii) elevating diffusing properties between microvascular and interstitial compartments resulting, in part, from microvascular haemodynamics and red blood cell distribution. We evaluated the PO2 within the microvascular and interstitial spaces of muscles spanning the slow- to fast-twitch fibre and high- to low-oxidative capacity spectrums, at rest and during contractions, to assess the magnitude of transcapillary PO2 gradients in rats. Our findings demonstrate that, across the metabolic rest-contraction transition, the transcapillary pressure gradient for O2 flux is: (i) maintained in all muscle types, and (ii) the lowest in contracting highly oxidative fast-twitch muscle. ABSTRACT In mixed fibre-type skeletal muscle transcapillary PO2 gradients (PO2 mv-PO2 is; microvascular and interstitial, respectively) drive O2 flux across the blood-myocyte interface where the greatest resistance to that O2 flux resides. We assessed a broad spectrum of fibre-type and oxidative-capacity rat muscles across the rest-to-contraction (1 Hz, 120 s) transient to test the novel hypotheses that: (i) slow-twitch PO2 is would be greater than fast-twitch, (ii) muscles with greater oxidative capacity have greater PO2 is than glycolytic counterparts, and (iii) whether PO2 mv-PO2 is at rest is maintained during contractions across all muscle types. PO2 mv and PO2 is were determined via phosphorescence quenching in soleus (SOL; 91% type I+IIa fibres and CSa: ∼21 μmol min-1 g-1 ), peroneal (PER; 33% and ∼20 μmol min-1 g-1 ), mixed (MG; 9% and ∼26 μmol min-1 g-1 ) and white gastrocnemius (WG; 0% and ∼8 μmol min-1 g-1 ) across the rest-contraction transient. PO2 mv was higher than PO2 is in each muscle (∼6-13 mmHg; P

Background: Recent evidence suggests prostate cancer independent of treatment has atrophic effects on whole heart and left ventricular (LV) masses, associated with reduced endurance exercise capacity. In a pre-clinical model, we tested the hypothesis that high-intensity training could prevent cardiac atrophy with prostate cancer and alter cardiac protein degradation mechanisms. Methods: Dunning R-3327 AT-1 prostate cancer cells (1×10(5)) were injected into the ventral prostate lobe of 5-6 mo immunocompetent Copenhagen rats (n=24). These animals were randomized into two groups, tumor-bearing exercise (TBEX, n=15) or tumor bearing sedentary (TBS, n=9). Five days after surgery, TBEX animals began exercise on a treadmill (25 m/min, 15° incline) for 45-60 min/day for 18±2 days. Pre-surgery (Pre), and post-exercise training (Post) echocardiographic evaluation (Vivid S6, GE Health Care), using the parasternal short axis view, was used to examine ventricle dimensions. Markers of protein degradation (muscle atrophy F-box, Cathepsin B, Cathepsin L) in the left ventricle were semi-quantified via Western Blot. Results: There were no significant differences in tumor mass between groups (TBEX 3.4±0.7, TBS 2.8±0.6 g, P=0.3), or body mass (TBEX 317±5, TBS 333±7 g, P=0.2). Heart-to-body mass ratio was lower in TBS group compared to TBEX (2.3±0.1 vs. 2.5±0.1 mg/g, P

Vascular ATP-sensitive K(+) (K(ATP)) channels support skeletal muscle blood flow and microvascular oxygen delivery-to-utilization matching during exercise. However, oral sulphonylurea treatment for diabetes inhibits pancreatic K(ATP) channels to enhance insulin release. Herein we tested the hypotheses that: i) systemic K(ATP) channel inhibition via glibenclamide (GLI; 10 mg kg(−1) i.p.) would decrease cardiac output at rest (echocardiography), maximal aerobic capacity [Formula: see text] and the speed–duration relationship (i.e. lower critical speed (CS)) during treadmill running; and ii) local K(ATP) channel inhibition (5 mg kg(−1) GLI superfusion) would decrease blood flow (15 μm microspheres), interstitial space oxygen pressures (PO(2)is; phosphorescence quenching) and convective and diffusive O(2) transport ([Formula: see text] and DO(2), respectively; Fick Principle and Law of Diffusion) in contracting fast-twitch oxidative mixed gastrocnemius muscle (MG: 9% type I+IIa fibres). At rest, GLI slowed left ventricular relaxation (2.11 ± 0.59 vs. 1.70 ± 0.23 cm s(−1)) and decreased heart rate (321 ± 23 vs. 304 ± 22 bpm, both P < 0.05) while cardiac output remained unaltered (219 ± 64 vs. 197 ± 39 ml min(−1), P > 0.05). During exercise, GLI reduced [Formula: see text] (71.5 ± 3.1 vs. 67.9 ± 4.8 ml kg(−1) min(−1)) and CS (35.9 ± 2.4 vs. 31.9 ± 3.1 m min(−1), both P < 0.05). Local K(ATP) channel inhibition decreased MG blood flow (52 ± 25 vs. 34 ± 13 ml min(−1) 100 g tissue(−1)) and PO(2)is(nadir) (5.9 ± 0.9 vs. 4.7 ± 1.1 mmHg) during twitch contractions. Furthermore, MG [Formula: see text] was reduced via impaired [Formula: see text] and DO(2) (P < 0.05 for each). Collectively, these data support that vascular K(ATP) channels help sustain submaximal exercise tolerance in healthy rats. For patients taking sulfonylureas, K(ATP) channel inhibition may exacerbate exercise intolerance.

Premenopausal women express reduced blood pressure and risk of cardiovascular disease relative to age-matched men. This purportedly relates to elevated estrogen levels increasing nitric oxide synthase (NOS) activity and NO-mediated vasorelaxation. We tested the hypotheses that female rat skeletal muscle would: 1) evince a higher O2delivery-to-utilization ratio (Q̇o2/V̇o2) during contractions; and 2) express greater modulation of Q̇o2/V̇o2with changes to NO bioavailability compared with male rats. The spinotrapezius muscle of Sprague-Dawley rats (females = 8, males = 8) was surgically exposed and electrically-stimulated (180 s, 1 Hz, 6 V). OxyphorG4 was injected into the muscle and phosphorescence quenching employed to determine the temporal profile of interstitial Po2(Po2is, determined by Q̇o2/V̇o2). This was performed under three conditions: control (CON), 300 µM sodium nitroprusside (SNP; NO donor), and 1.5 mM Nω-nitro-l-arginine methyl ester (l-NAME; NOS blockade) superfusion. No sex differences were found for the Po2iskinetics parameters in CON or l-NAME ( P > 0.05), but females elicited a lower baseline following SNP (males 42 ± 3 vs. females 36 ± 2 mmHg, P < 0.05). Females had a lower ΔPo2isduring contractions following SNP (males 22 ± 3 vs. females 17 ± 2 mmHg, P < 0.05), but there were no sex differences for the temporal response to contractions ( P > 0.05). The total NO effect (SNP minus l-NAME) on Po2iswas not different between sexes. However, the spread across both conditions was shifted to a lower absolute range for females (reduced SNP baseline and greater reduction following l-NAME). These data support that females have a greater reliance on basal NO bioavailability and males have a greater responsiveness to exogenous NO and less responsiveness to reduced endogenous NO.NEW & NOTEWORTHY Interstitial Po2(Po2is; determined by O2delivery-to-utilization matching) plays an important role for O2flux into skeletal muscle. We show that both sexes regulate Po2isat similar levels at rest and during skeletal muscle contractions. However, modulating NO bioavailability exposes sex differences in this regulation with females potentially having a greater reliance on basal NO bioavailability and males having a greater responsiveness to exogenous NO and less responsiveness to reduced endogenous NO.

Nitric oxide (NO) modulates oxygen delivery-utilization matching in resting and contracting skeletal muscle. Recent reports indicate that neuronal NO synthase (nNOS)-mediated vasoregulation during contractions is enhanced with exercise training and impaired with chronic heart failure (HF). Consequently, we tested the hypothesis that selective nNOS inhibition (S-methyl-l-thiocitrulline; SMTC, 2.1 µmol/kg) would produce attenuated reductions in muscle blood flow during moderate/heavy submaximal exercise in sedentary HF rats compared to their healthy counterparts. In addition, SMTC was expected to evoke greater reductions in exercising muscle blood flow in trained compared to sedentary healthy and HF rats. Blood flow during submaximal treadmill running (20 min/m, 5% grade) was determined via radiolabeled microspheres pre- and post-SMTC administration in healthy sedentary (Healthy + Sed, n = 8), healthy exercise trained (Healthy + ExT, n = 8), HF sedentary (HF + Sed, left ventricular end-diastolic pressure (LVEDP) = 12 ± 1 mmHg, n = 8), and HF exercise trained (HF + ExT, LVEDP = 16 ± 2 mmHg, n = 7) rats. nNOS contribution to exercising total hindlimb blood flow (ml/min/100 g) was not increased by training in either healthy or HF groups (Healthy + Sed: 105 ± 11 vs. 108 ± 16; Healthy + ExT: 96 ± 9 vs. 91 ± 7; HF + Sed: 124 ± 6 vs. 110 ± 12; HF + ExT: 107 ± 13 vs. 101 ± 8; control vs. SMTC, respectively; p > .05 for all). Similarly, SMTC did not reduce exercising blood flow in the majority of individual hindlimb muscles in any group (p > .05 for all, except for the semitendinosus and adductor longus in HF + Sed and the adductor longus in HF + ExT; p < .05). Contrary to our hypothesis, we find no support for either upregulation of nNOS function contributing to exercise hyperemia after training or its dysregulation with chronic HF.

KEY POINTS Oxygen pressure gradients across the microvascular walls are essential for oxygen diffusion from blood to tissue cells. At any given flux, the magnitude of these transmural gradients is proportional to the local resistance. The greatest resistance to oxygen transport into skeletal muscle is considered to reside in the short distance between red blood cells and myocytes. Although crucial to oxygen transport, little is known about transmural pressure gradients within skeletal muscle during contractions. We evaluated oxygen pressures within both the skeletal muscle microvascular and interstitial spaces to determine transmural gradients during the rest-contraction transient in anaesthetized rats. The significant transmural gradient observed at rest was sustained during submaximal muscle contractions. Our findings support that the blood-myocyte interface provides substantial resistance to oxygen diffusion at rest and during contractions and suggest that modulations in microvascular haemodynamics and red blood cell distribution constitute primary mechanisms driving increased transmural oxygen flux with contractions. ABSTRACT Oxygen pressure (PO2) gradients across the blood-myocyte interface are required for diffusive O2 transport, thereby supporting oxidative metabolism. The greatest resistance to O2 flux into skeletal muscle is considered to reside between the erythrocyte surface and adjacent sarcolemma, although this has not been measured during contractions. We tested the hypothesis that O2 gradients between skeletal muscle microvascular (PO2 mv ) and interstitial (PO2 is ) spaces would be present at rest and maintained or increased during contractions. PO2 mv and PO2 is were determined via phosphorescence quenching (Oxyphor probes G2 and G4, respectively) in the exposed rat spinotrapezius during the rest-contraction transient (1 Hz, 6 V; n = 8). PO2 mv was higher than PO2 is in all instances from rest (34.9 ± 6.0 versus 15.7 ± 6.4) to contractions (28.4 ± 5.3 versus 10.6 ± 5.2 mmHg, respectively) such that the mean PO2 gradient throughout the transient was 16.9 ± 6.6 mmHg (P 0.05). However, the speed of the PO2 is fall during contractions was slower than that of PO2 mv (time constant: 12.8 ± 4.7 versus 9.0 ± 5.1 s, respectively; P

The vascular ATP-sensitive K+ (KATP) channel is a mediator of skeletal muscle microvascular oxygenation (PO2mv) during contractions in health. We tested the hypothesis that KATP channel function is preserved in chronic heart failure (CHF) and therefore its inhibition would reduce PO2mv and exacerbate the time taken to reach the PO2mv steady-state during contractions of the spinotrapezius muscle. Moreover, we hypothesized that subsequent KATP channel activation would oppose the effects of this inhibition. Muscle PO2mv (phosphorescence quenching) was measured during 180 s of 1-Hz twitch contractions (~6 V) under control, glibenclamide (GLI, KATP channel antagonist; 5 mg/kg) and pinacidil (PIN, KATP channel agonist; 5 mg/kg) conditions in 16 male Sprague-Dawley rats with CHF induced via myocardial infarction (coronary artery ligation, left ventricular end-diastolic pressure: 18±1 mmHg). GLI reduced baseline PO2mv (control: 28.3±0.9, GLI: 24.8±1.0 mmHg, p

The oxygen partial pressure in the interstitial space (Po(2 is)) drives O(2) into the myocyte via diffusion, thus supporting oxidative phosphorylation. Although crucial for metabolic recovery and the capacity to perform repetitive tasks, the time course of skeletal muscle Po(2 is) during recovery from contractions remains unknown. We tested the hypothesis that Po(2 is) would recover to resting values and display considerable on-off asymmetry (fast on-, slow off-kinetics), reflective of asymmetric capillary hemodynamics. Microvascular Po(2) (Po(2 mv)) was also evaluated to test the hypothesis that a significant transcapillary gradient (ΔPo(2) = Po(2 mv) − Po(2 is)) would be sustained during recovery. Po(2 mv) and Po(2 is) (expressed in mmHg) were determined via phosphorescence quenching in the exposed rat spinotrapezius muscle during and after submaximal twitch contractions (n = 12). Po(2 is) rose exponentially (P < 0.05) from end-contraction (11.1 ± 5.1), such that the end-recovery value (17.9 ± 7.9) was not different from resting Po(2 is) (18.5 ± 8.1; P > 0.05). Po(2 is) off-kinetics were slower than on-kinetics (mean response time: 53.1 ± 38.3 versus 18.5 ± 7.3 s; P < 0.05). A significant transcapillary ΔPo(2) observed at end-contraction (16.6 ± 7.4) was maintained throughout recovery (end-recovery: 18.8 ± 9.6; P > 0.05). Consistent with our hypotheses, muscle Po(2 is) recovered to resting values with slower off-kinetics compared with the on-transient in line with the on-off asymmetry for capillary hemodynamics. Maintenance of a substantial transcapillary ΔPo(2) during recovery supports that the microvascular-interstitium interface provides considerable resistance to O(2) transport. As dictated by Fick’s law (V̇o(2) = Do(2) × ΔPo(2)), modulation of O(2) flux (V̇o(2)) during recovery must be achieved via corresponding changes in effective diffusing capacity (Do(2); mainly capillary red blood cell hemodynamics and distribution) in the face of unaltered ΔPo(2). NEW & NOTEWORTHY Capillary blood-myocyte O(2) flux (V̇o(2)) is determined by effective diffusing capacity (Do(2); mainly erythrocyte hemodynamics and distribution) and microvascular-interstitial Po(2) gradients (ΔPo(2) = Po(2 mv) − Po(2 is)). We show that Po(2 is) demonstrates on-off asymmetry consistent with Po(2 mv) and erythrocyte kinetics during metabolic transitions. A substantial transcapillary ΔPo(2) was preserved during recovery from contractions, indicative of considerable resistance to O(2) diffusion at the microvascular-interstitium interface. This reveals that effective Do(2) declines in step with V̇o(2) during recovery, as per Fick’s law.

Exercise intolerance is a primary symptom of heart failure (HF); however, the specific contribution of central and peripheral factors to this intolerance is not well described. The hyperbolic relationship between exercise intensity and time to exhaustion (speed-duration relationship) defines exercise tolerance but is underused in HF. We tested the hypotheses that critical speed (CS) would be reduced in HF, resting central functional measurements would correlate with CS, and the greatest HF-induced peripheral dysfunction would occur in more oxidative muscle. Multiple treadmill-constant speed runs to exhaustion were used to quantify CS and D′ (distance coverable above CS) in healthy control (Con) and HF rats. Central function was determined via left ventricular (LV) Doppler echocardiography [fractional shortening (FS)] and a micromanometer-tipped catheter [LV end-diastolic pressure (LVEDP)]. Peripheral O2 delivery-to-utilization matching was determined via phosphorescence quenching (interstitial Po2, Po2 is) in the soleus and white gastrocnemius during electrically induced twitch contractions (1 Hz, 8V). CS was lower in HF compared with Con (37 ± 1 vs. 44 ± 1 m/min, P < 0.001), but D′ was not different (77 ± 8 vs. 69 ± 13 m, P = 0.6). HF reduced FS (23 ± 2 vs. 47 ± 2%, P < 0.001) and increased LVEDP (15 ± 1 vs. 7 ± 1 mmHg, P < 0.001). CS was related to FS ( r = 0.72, P = 0.045) and LVEDP ( r = −0.75, P = 0.02) only in HF. HF reduced soleus Po2 is at rest and during contractions (both P < 0.01) but had no effect on white gastrocnemius Po2 is ( P > 0.05). We show in HF rats that decrements in central cardiac function relate directly with impaired exercise tolerance (i.e., CS) and that this compromised exercise tolerance is likely due to reduced perfusive and diffusive O2 delivery to oxidative muscles. NEW & NOTEWORTHY We show that critical speed (CS), which defines the upper boundary of sustainable activity, can be resolved in heart failure (HF) animals and is diminished compared with controls. Central cardiac function is strongly related with CS in the HF animals, but not controls. Skeletal muscle O2 delivery-to-utilization dysfunction is evident in the more oxidative, but not glycolytic, muscles of HF rats and is explained, in part, by reduced nitric oxide bioavailability.

Background Recent evidence suggests prostate cancer independent of treatment has atrophic effects on whole heart and left ventricular (LV) mass which are associated with reduced endurance exercise ...