Effects of exercise and doxorubicin on acute diaphragm neuromuscular transmission failure.

Doxorubicin (DOX) is a highly effective anthracycline antibiotic used to treat a wide variety of cancers including breast cancer, leukemia and lymphoma. Unfortunately, clinical use of DOX is limited due to adverse off-target effects resulting in fatigue, respiratory muscle weakness and dyspnea. The diaphragm is the primary muscle of inspiration and respiratory insufficiency is likely the result of both muscle weakness and neural impairment. However, the contribution of neuropathology to DOX-induced respiratory muscle dysfunction is unclear. We hypothesized that diaphragm weakness following acute DOX exposure is associated with neurotoxicity and that exercise preconditioning is sufficient to improve diaphragm muscle contractility by maintaining neuromuscular integrity. Adult female Sprague-Dawley rats were randomized into four experimental groups: 1) sedentary-saline, 2) sedentary-DOX, 3) exercise-saline or 4) exercise-DOX. Endurance exercise preconditioning consisted of treadmill running for 1 h/day at 30 m/min for 10 days. Twenty-four hours after the last bout of exercise, animals were treated with DOX (20 mg/kg, I.P.) or saline (equal volume). Our results demonstrate that 48-h following DOX administration diaphragm muscle specific force is reduced in sedentary-DOX rats in response to both phrenic nerve and direct diaphragm stimulation. Importantly, endurance exercise preconditioning in DOX-treated rats attenuated the decrease in diaphragm contractile function, reduced neuromuscular transmission failure and altered phrenic nerve morphology. These changes were associated with an exercise-induced reduction in circulating biomarkers of inflammation, nerve injury and reformation. Therefore, the results are consistent with exercise preconditioning as an effective way of reducing respiratory impairment via preservation of phrenic-diaphragm neuromuscular conduction.

Recovery from FOLFOX chemotherapy-induced systemic and skeletal muscle metabolic dysfunction in mice.

FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) chemotherapy is used to treat colorectal cancer and can acutely induce metabolic dysfunction. However, the lasting effects on systemic and skeletal muscle metabolism after treatment cessation are poorly understood. Therefore, we investigated the acute and lasting effects of FOLFOX chemotherapy on systemic and skeletal muscle metabolism in mice. Direct effects of FOLFOX in cultured myotubes were also investigated. Male C57BL/6J mice completed four cycles (acute) of FOLFOX or PBS. Subsets were allowed to recover for 4 wk or 10 wk. Comprehensive Laboratory Animal Monitoring System (CLAMS) metabolic measurements were performed for 5 days before study endpoint. C2C12 myotubes were treated with FOLFOX for 24 hr. Acute FOLFOX attenuated body mass and body fat accretion independent of food intake or cage activity. Acute FOLFOX decreased blood glucose, oxygen consumption (V̇o2), carbon dioxide production (V̇co2), energy expenditure, and carbohydrate (CHO) oxidation. Deficits in V̇o2 and energy expenditure remained at 10 wk. CHO oxidation remained disrupted at 4 wk but returned to control levels after 10 wk. Acute FOLFOX reduced muscle COXIV enzyme activity, AMPK(T172), ULK1(S555), and LC3BII protein expression. Muscle LC3BII/I ratio was associated with altered CHO oxidation (r = 0.75, P = 0.03). In vitro, FOLFOX suppressed myotube AMPK(T172), ULK1(S555), and autophagy flux. Recovery for 4 wk normalized skeletal muscle AMPK and ULK1 phosphorylation. Our results provide evidence that FOLFOX disrupts systemic metabolism, which is not readily recoverable after treatment cessation. FOLFOX effects on skeletal muscle metabolic signaling did recover. Further investigations are warranted to prevent and treat FOLFOX-induced metabolic toxicities that negatively impact survival and life quality of patients with cancer.NEW & NOTEWORTHY The present study demonstrates that FOLFOX chemotherapy induces long-lasting deficits in systemic metabolism. Interestingly, FOLFOX modestly suppressed skeletal muscle AMPK and autophagy signaling in vivo and in vitro. The FOLFOX-induced suppression of muscle metabolic signaling recovered after treatment cessation, independent of systemic metabolic dysfunction. Future research should investigate if activating AMPK during treatment can prevent long-term toxicities to improve health and quality of life of patients with cancer and survivors.

Impaired microvascular reactivity in patients treated with 5-fluorouracil chemotherapy regimens: Potential role of endothelial dysfunction.

Background: 5-fluorouracil (5-FU) is the second most common cancer chemotherapy associated with short- and long-term cardiotoxicity. Although the mechanisms mediating these toxicities are not well understood, patients often present with symptoms suggestive of microvascular dysfunction. We tested the hypotheses that patients undergoing cancer treatment with 5-FU based chemotherapy regimens would present with impaired microvascular reactivity and that these findings would be substantiated by decrements in endothelial nitric oxide synthase (eNOS) gene expression in 5-FU treated human coronary artery endothelial cells (HCAEC). Methods: We first performed a cross-sectional analysis of 30 patients undergoing 5-FU based chemotherapy treatment for cancer (5-FU) and 32 controls (CON) matched for age, sex, body mass index, and prior health history (excluding cancer). Cutaneous microvascular reactivity was evaluated by laser Doppler flowmetry in response to endothelium-dependent (local skin heating; acetylcholine iontophoresis, ACh) and -independent (sodium nitroprusside iontophoresis, SNP) stimuli. In vitro experiments in HCAEC were completed to assess the effects of 5-FU on eNOS gene expression. Results: 5-FU presented with diminished microvascular reactivity following eNOS-dependent local heating compared to CON (P = 0.001). Iontophoresis of the eNOS inhibitor L-NAME failed to alter the heating response in 5-FU (P = 0.95), despite significant reductions in CON (P = 0.03). These findings were corroborated by lower eNOS gene expression in 5-FU treated HCAEC (P < 0.01) compared to control. Peak vasodilation to ACh (P = 0.58) nor SNP (P = 0.39) were different between groups. Conclusions: The present findings suggest diminished microvascular function along the eNOS-NO vasodilatory pathway in patients with cancer undergoing treatment with 5-FU-based chemotherapy regimens and thus, may provide insight into the underlying mechanisms of 5-FU cardiotoxicity.

Head-up tilt does not enhance prostate tumor perfusion or oxygenation in young rats.

Solid tumors contain hypoxic regions that contribute to anticancer therapy resistance. Thus, mitigating tumor hypoxia may enhance the efficacy of radiation therapy which is commonly utilized for patients with prostate cancer. Increasing perfusion pressure in the prostate with head-up tilt (HUT) may augment prostate tumor perfusion and decrease hypoxia. The purpose of this study was to determine if an increase in the vascular hydrostatic gradient via 70° HUT increases tumor perfusion and decreases tumor hypoxia in a preclinical orthotopic model of prostate cancer. Male Copenhagen rats (n = 17) were orthotopically injected with Dunning R-3327 (AT-1) prostate adenocarcinoma cells to induce prostate tumors. After tumors were established, prostate tumor perfusion and hypoxia were measured in rats during level (0°) and 70° HUT positions. To compare the magnitude of the hydrostatic column to that present in humans, ultrasound was used to measure the heart to prostate distance in male human subjects to estimate the prostate vascular hydrostatic pressure with the upright posture. In young rats, no differences were detected in prostate tumor perfusion or prostate tumor hypoxia with 70° HUT versus the level position. However, from the retrospective study, young rats increased prostate vascular resistance to HUT, whereas aged rats lacked this response. Tumor vessels co-opted from existing functional vasculature in young rats may be sufficient to negate increases in perfusion pressure with HUT seen in aged rats. Additionally, in humans, the estimated hydrostatic column at the level of the prostate is five times greater than that of the rat. Therefore, 70° HUT may elicit increases in prostate/prostate tumor blood flow in humans that is not seen in rats.

Supplemental oxygen administration during mechanical ventilation reduces diaphragm blood flow and oxygen delivery.

During mechanical ventilation (MV), supplemental oxygen (O2) is commonly administered to critically ill patients to combat hypoxemia. Previous studies demonstrate that hyperoxia exacerbates MV-induced diaphragm oxidative stress and contractile dysfunction. Whereas normoxic MV (i.e., 21% O2) diminishes diaphragm perfusion and O2 delivery in the quiescent diaphragm, the effect of MV with 100% O2 is unknown. We tested the hypothesis that MV supplemented with hyperoxic gas (100% O2) would increase diaphragm vascular resistance and reduce diaphragmatic blood flow and O2 delivery to a greater extent than MV alone. Female Sprague-Dawley rats (4-6 mo) were randomly divided into two groups: 1) MV + 100% O2 followed by MV + 21% O2 (n = 9) or 2) MV + 21% O2 followed by MV + 100% O2 (n = 10). Diaphragmatic blood flow (mL/min/100 g) and vascular resistance were determined, via fluorescent microspheres, during spontaneous breathing (SB), MV + 100% O2, and MV + 21% O2. Compared with SB, total diaphragm vascular resistance was increased, and blood flow was decreased with both MV + 100% O2 and MV + 21% O2 (all P < 0.05). Medial costal diaphragmatic blood flow was lower with MV + 100% O2 (26 ± 6 mL/min/100 g) versus MV + 21% O2 (51 ± 15 mL/min/100 g; P < 0.05). Second, the addition of 100% O2 during normoxic MV exacerbated the MV-induced reductions in medial costal diaphragm perfusion (23 ± 7 vs. 51 ± 15 mL/min/100 g; P < 0.05) and O2 delivery (3.4 ± 0.2 vs. 6.4 ± 0.3 mL O2/min/100 g; P < 0.05). These data demonstrate that administration of supplemental 100% O2 during MV increases diaphragm vascular resistance and diminishes perfusion and O2 delivery to a significantly greater degree than normoxic MV. This suggests that prolonged bouts of MV (i.e., 6 h) with hyperoxia may accelerate MV-induced vascular dysfunction in the quiescent diaphragm and potentially exacerbate downstream contractile dysfunction.NEW & NOTEWORTHY This is the first study, to our knowledge, demonstrating that supplemental oxygen (i.e., 100% O2) during mechanical ventilation (MV) augments the MV-induced reductions in diaphragmatic blood flow and O2 delivery. The accelerated reduction in diaphragmatic blood flow with hyperoxic MV would be expected to potentiate MV-induced diaphragm vascular dysfunction and consequently, downstream contractile dysfunction. The data presented herein provide a putative mechanism for the exacerbated oxidative stress and diaphragm dysfunction reported with prolonged hyperoxic MV.

Prolonged mechanical ventilation increases diaphragm arteriole circumferential stretch without changes in stress/stretch: Implications for the pathogenesis of ventilator-induced diaphragm dysfunction.

INTRODUCTION: Prolonged mechanical ventilation (MV; ≥6 h) results in large, time-dependent reductions in diaphragmatic blood flow and shear stress. We tested the hypothesis that MV would impair the structural and material properties (ie, increased stress/stretch relation and/or circumferential stretch) of first-order arterioles (1A) from the medial costal diaphragm. METHODS: Shear stress was estimated from isolated arterioles and prior blood flow data from the diaphragm during spontaneous breathing (SB) and prolonged MV (6 h MV). Thereafter, female Sprague-Dawley rats (~5 months) were randomly divided into two groups, SB (n = 6) and 6 h MV (n = 6). Following SB and 6 h MV, 1A medial costal diaphragm arterioles were isolated, cannulated, and subjected to stepwise (0-140 cmH2 O) increases in intraluminal pressure in calcium-free Ringer's solution. Inner diameter and wall thickness were measured at each pressure step and used to calculate wall:lumen ratio, Cauchy-stress, and circumferential stretch. RESULTS: Compared to SB, there was a ~90% reduction in arteriolar shear stress with prolonged MV (9 ± 2 vs 78 ± 20 dynes/cm2 ; p ≤ .05). In the unloaded condition (0 cmH2 O), the arteriolar intraluminal diameter was reduced (37 ± 8 vs 79 ± 13 µm) and wall:lumen ratio was increased (120 ± 18 vs 46 ± 10%) compared to SB (p ≤ .05). There were no differences in the passive diameter responses or the circumferential stress/stretch relationship between groups (p > .05), but at each pressure step, circumferential stretch was increased with 6 h MV vs SB (p ≤ .05). CONCLUSION: During prolonged MV, medial costal diaphragm arteriolar shear stress is severely diminished. Despite no change in the material behavior (stress/stretch), prolonged MV resulted in altered structural and mechanical properties (ie, elevated circumferential stretch) of medial costal diaphragm arterioles. This provides important novel mechanistic insights into the impaired diaphragm blood flow capacity and vascular dysfunction following prolonged MV.

Effects of high-intensity training on prostate cancer-induced cardiac atrophy.

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 (1×105) 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<0.05). LV/body mass ratio was also lower in the TBS group (1.6±0.1 vs. 1.8±0.1 mg/g, P<0.05). From Pre-Post, TBEX had significant increases in SV (~20% P<0.05) whereas TBS had no significant change. There were no significant differences between groups for markers of protein degradation. CONCLUSION: This study suggests that high-intensity exercise can improve LV function and increase LV mass concurrent with prostate cancer development, versus sedentary counterparts. Given cardiac dysfunction often manifests with conventional anti-cancer treatments, a short-term high-intensity training program, prior to treatment, may improve cardiac function and fatigue resistance in cancer patients.

Angiotensin converting enzyme inhibition improves cerebrovascular control during exercise in male rats with heart failure.

We investigated the effects of chronic (∼7 weeks) treatment with the angiotensin converting enzyme (ACE) inhibitor Captopril in rats with heart failure with reduced ejection fraction (HF-rEF) on brain blood flow (BF; radiolabeled microspheres) at rest and during submaximal exercise. We hypothesized that middle cerebral, posterior cerebral, and cerebellar BF during submaximal exercise (20 m/min, 5% incline) would be reduced in rats with HF-rEF (n = 10) compared to healthy (SHAM, n = 10) controls and HF-rEF rats chronically treated with Captopril (HF-rEF + Cap., n = 20). During submaximal exercise middle cerebral (HF-rEF + Cap.: 274 ± 12; HF-rEF: 234 ± 23; SHAM: 248 ± 24 ml/min/100 g) and cerebellar (HF-rEF + Cap.: 222 ± 14; HF-rEF: 243 ± 22; SHAM: 214 ± 23 ml/min/100 g) BF increased from rest in all groups with no difference among groups (P > 0.24). Posterior cerebral BF increased from rest in all groups but was lower than SHAM (394 ± 46 ml/min/100 g; P = 0.03) in HF-rEF (298 ± 19 ml/min/100 g) but not HF-rEF + Cap. (356 ± 18 ml/min/100 g; P = 0.14), supporting the concept that ACE inhibition in HF-rEF elevates brain BF increases, at least to the posterior cerebral region, during moderate intensity exercise/physical activity.

Effects of elevated positive end-expiratory pressure on diaphragmatic blood flow and vascular resistance during mechanical ventilation.

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.

Impaired diaphragm resistance vessel vasodilation with prolonged mechanical ventilation.

Mechanical ventilation (MV) is a life-saving intervention, yet with prolonged MV (i.e., ≥6 h) there are time-dependent reductions in diaphragm blood flow and an impaired hyperemic response of unknown origin. Female Sprague-Dawley rats (4-8 mo, n = 118) were randomized into two groups; spontaneous breathing (SB) and 6-h (prolonged) MV. After MV or SB, vasodilation (flow-induced, endothelium-dependent and -independent agonists) and constriction (myogenic and α-adrenergic) responses were measured in first-order (1A) diaphragm resistance arterioles in vitro, and endothelial nitric oxide synthase (eNOS) mRNA expression was quantified. Following prolonged MV, there was a significant reduction in diaphragm arteriolar flow-induced (SB, 34.7 ± 3.8% vs. MV, 22.6 ± 2.0%; P ≤ 0.05), endothelium-dependent (via acetylcholine; SB, 64.3 ± 2.1% vs. MV, 36.4 ± 2.3%; P ≤ 0.05) and -independent (via sodium nitroprusside; SB, 65.0 ± 3.1% vs. MV, 46.0 ± 4.6%; P ≤ 0.05) vasodilation. Compared with SB, there was reduced eNOS mRNA expression (P ≤ 0.05). Prolonged MV diminished phenylephrine-induced vasoconstriction (SB, 37.3 ± 6.7% vs. MV, 19.0 ± 1.9%; P ≤ 0.05) but did not alter myogenic or passive pressure responses. The severe reductions in diaphragmatic blood flow at rest and during contractions, with prolonged MV, are associated with diaphragm vascular dysfunction which occurs through both endothelium-dependent and endothelium-independent mechanisms.NEW & NOTEWORTHY Following prolonged mechanical ventilation, vascular alterations occur through both endothelium-dependent and -independent pathways. This is the first study, to our knowledge, demonstrating that diaphragm arteriolar dysfunction occurs consequent to prolonged mechanical ventilation and likely contributes to the severe reductions in diaphragmatic blood flow and weaning difficulties.

Central and peripheral factors mechanistically linked to exercise intolerance in heart failure with reduced ejection fraction.

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.

Prostate cancer cell growth characteristics in serum and prostate-conditioned media from moderate-intensity exercise-trained healthy and tumor-bearing rats.

Physical activity is associated with diminished risk of several cancers, and preclinical studies suggest exercise training may alter tumor cell growth in certain tissue(s) (e.g., adipose). From moderate-intensity exercise-trained rats versus sedentary controls, we hypothesized 1) there will be a decreased prostate cancer cell viability and migration in vitro and, within the prostate, a reduced 5α-reductase 2 (5αR2) and increased caspase-3 expression, and 2) that exercise training in tumor-bearing (TB) animals will demonstrate a reduced tumor cell viability in prostate-conditioned media. Serum and prostate were harvested from sedentary or exercise-trained (treadmill running, 10-11 weeks) immune-competent (Copenhagen; n = 20) and -deficient (Nude; n = 18) rats. AT-1 and PC-3 prostate cancer cells were grown in one or more of the following: serum-supplemented media (SSM), SSM from TB rats (SSM-TB), prostate-conditioned media (PCM) or PCM from TB rats (PCM-TB) for 24-96 h under normoxic (18.6% O2) or hypoxic (5% O2) conditions. Under normoxic condition, there was a decreased AT-1 cell viability in SSM and PCM from the exercise-trained (ET) immune-competent rats, but no difference in PC-3 cell viability in SSM and PCM from ET Nude rats versus the sedentary (SED) group, or in SSM-TB from ET-TB Nude rats versus the SED-TB group. However, there was a decreased PC-3 cell viability in the PCM-TB of the ET-TB group versus SED-TB group. PC-3 cell viability in all conditioned media types was not altered between groups with hypoxia. In the prostate, exercise training did not alter 5αR2 expression levels, but increased caspase-3 expression levels. In conclusion, prior exercise status reduced prostate cancer cell viability in the serum and prostate of trained rats but did not modify several other key prostate tumor cell growth characteristics (e.g., migration, cell cycle except in S phase of PC-3 cells in PCM-TB). Importantly, once the tumor was established, exercise training reduced tumor cell viability in the surrounding prostate, which may help explain the reduced severity of the disease in patients that exercise.

Impact of Acute Dietary Nitrate Supplementation during Exercise in Hypertensive Women.

INTRODUCTION: the aim of the current investigation was to examine if dietary nitrate supplementation would improve vascular control in hypertensive postmenopausal women (PMW). We tested the hypotheses that acute dietary nitrate supplementation would 1) significantly decrease arterial blood pressure (BP) at rest and during exercise, 2) increase limb blood flow during steady-state (SS) exercise, and 3) improve functional sympatholysis during SS exercise. METHODS: Ten hypertensive PMW underwent a randomized, double-blind, placebo-controlled trial with a nitrate-rich (NR) or nitrate-poor (NP) supplement. Beat-by-beat BP and heart rate were recorded throughout the trial on the nonexercising limb. Forearm blood flow was measured via ultrasonography on the brachial artery of the exercising limb. All patients performed a resting cold pressor test (CPT) (2 min) and then 7 min of submaximal handgrip exercise with a CPT applied during minutes 5-7. RESULTS: SS systolic (NR, 170 ± 7; NP, 171 ± 37 mm Hg), diastolic (NR, 89 ± 2; NP, 92 ± 2 mm Hg), and mean arterial (NR, 121 ± 4; NP, 123 ± 2 mm Hg) pressures were not different between NP and NR treatment conditions (P > 0.05). During SS exercise, forearm blood flow (NR, 189 ± 8; NP, 218 ± 8 mL·min; P = 0.03) in the NR treatment was significantly lower compared with NP. When the CPT was applied during minutes 6-7 of exercise, forearm vascular conductance was reduced by 15% in the NR condition, but only 7% in the NR condition. CONCLUSIONS: In summary, an acute NR supplement improved functional sympatholysis by ~50% versus an NP placebo condition. Improvements in functional sympatholysis may have important implications regarding exercise tolerance in hypertensive PMW.

Effects of prostate cancer and exercise training on left ventricular function and cardiac and skeletal muscle mass.

Prostate cancer was found to reduce cardiac and left ventricle (LV) masses in association with diminished exercise capacity in rats. We tested the hypothesis that exercise training will mitigate prostate cancer-induced cardiac and skeletal muscle atrophy and improve LV function versus sedentary tumor-bearing counterparts. Copenhagen rats ( n = 39; ~5 mo old) were randomized into four groups: exercise-trained tumor-bearing (EXTB) or control (EXCON) and sedentary tumor-bearing (SEDTB) or control (SEDCON). Dunning R-3327 prostate cancer cells were injected orthotopically in 19 of the 39 animals. Treadmill exercise training was performed for 60 min/day for ~30 days. Animals underwent echocardiography to examine ventricle dimensions "Pre-" cancer injection or exercise (PRE) and 15 (Post 1) and 32-35 (Post 2) days after cancer cell injection with tissues collected after Post 2. LV TNF-α and IL-6 concentrations were measured post mortem. Cardiac and LV mass of SEDTB animals were lower than all groups ( P < 0.05). Tumor mass was negatively correlated with LV mass in EXTB (-0.75, P < 0.02) and SEDTB animals (-0.72, P < 0.02). EXCON group had higher stroke volume Post 2 assessment compared with both sedentary groups ( P < 0.05) but not EXTB animals. No difference in LV [IL-6] or [TNF-α] was found between the cancer groups. The current investigation demonstrates prostate cancer, independent of anticancer treatment, significantly reduces cardiac mass and LV mass as well as locomotor muscle masses. However, moderate-intensity exercise training can mitigate cardiac and skeletal muscle atrophy with prostate cancer and preserve the cardiac phenotype (i.e., mass and function) to that of the healthy sedentary group. NEW & NOTEWORTHY This study demonstrates the atrophic effects of prostate cancer on cardiac and skeletal muscle mass independent of anticancer treatment(s) that can be mitigated with moderate-intensity exercise. These findings have important implications for potentially improving the quality of life as well as therapeutic outcomes for patients with prostate cancer.

Exercise and the Tumor Microenvironment: Potential Therapeutic Implications.

An imbalance in oxygen delivery to demand in solid tumors results in local areas of hypoxia leading to poor prognosis for the patient. We hypothesize that aerobic exercise increases tumor blood flow, recruits previously nonperfused tumor blood vessels, and thereby augments blood-tumor O2 transport and diminishes tumor hypoxia. When combined with conventional anticancer treatments, aerobic exercise can significantly improve the outcomes for several types of cancers.

Left ventricular strain rate is reduced during voluntary apnea in healthy humans.

During an apneic event, sympathetic nerve activity increases resulting in subsequent increases in left ventricular (LV) afterload and myocardial work. It is unknown how cardiac mechanics are acutely impacted by the increased myocardial work during an apneic event. Ten healthy individuals (23 ± 3 yr) performed multiple voluntary end-expiratory apnea (VEEA) maneuvers exposed to room air, while a subset ( n = 7) completed multiple VEEA exposed to hyperoxic air (100% [Formula: see text]). Beat-by-beat blood pressure, heart rate, and stroke volume were measured continuously. Effective arterial elastance (EA) was calculated as an index of cardiac afterload, and myocardial work was calculated as the rate pressure product (RPP). Tissue Doppler echocardiography was used to measure LV tissue velocities, deformation via strain, and strain rate (SR). Systolic blood pressure (Δ18 ± 13 mmHg, P < 0.01), EA (Δ0.13 ± 0.10 mmHg/ml, P < 0.01), and RPP (Δ9 ± 10 beats/min × mmHg 10-2, P < 0.01) significantly increased with room air VEEA. This occurred in parallel with decreases in peak longitudinal systolic (Δ-0.62 ± 0.41 cm/s, P < 0.01) and early LV filling (Δ-2.81 ± 1.99 cm/s, P < 0.01) myocardial velocities. Longitudinal SR (Δ-0.30 ± 0.32 1/s, P = 0.01) was significantly decreased during room air VEEA. VEEA with hyperoxia did not alter ( P > 0.18) EA or RPP and attenuated the systolic blood pressure response compared with room air. Myocardial velocities and LV strain rate response to VEEA were unchanged ( P = 0.30) with hyperoxia. Consistent with our hypotheses, VEEA-induced increases in EA and myocardial work impact LV mechanics, which may depend, in part, on stimulation of peripheral chemoreceptors. NEW & NOTEWORTHY Transient increases in arterial blood pressure and systemic vascular resistance occur during sleep apnea events and may contribute to the associated daytime hypertension and risk of overt cardiovascular disease. To date, the link between this apnea pressor response and acute changes in left ventricular function remains poorly understood. We demonstrate that in parallel to increases in cardiac afterload a depressed left ventricular systolic function occurs at end apnea.

Prostate cancer reduces endurance exercise capacity in association with reductions in cardiac and skeletal muscle mass in the rat.

Exercise capacity is reduced in prostate cancer patients concurrently treated with androgen deprivation therapy compared to healthy counterparts. We tested the hypothesis that prostate cancer independently reduces endurance exercise capacity in a preclinical orthotopic prostate tumor model. Male Copenhagen rats performed an initial treadmill running test to exhaustion. The rats' prostates were subsequently injected with either prostate tumor cells (R-3327 AT-1, tumor bearing, n=9) or vehicle control (sham, n=9) and the treadmill tests were repeated four and eight weeks post-surgery. Left ventricle contractility (LV Δpressure/Δtime) was subsequently measured under anesthesia and the heart and select hindlimb muscles were dissected and weighed. Initial times to exhaustion were not different between groups (sham: 28.24±1.26, tumor bearing: 28.63±2.49 min, P=0.90). Time to exhaustion eight weeks post-surgery was reduced compared to initial values for both groups but was significantly lower in the tumor bearing (13.25±1.44 min) versus the sham (21.17±1.87 min, P<0.01) group. Within the tumor bearing group, LV Δpressure/Δtime was significantly negatively correlated with tumor mass (-0.71, P<0.05). Body mass at eight weeks post-surgery was not different between groups (P=0.26) but LV mass (↓17%, P<0.01), as well as the mass of select hindlimb skeletal muscles, was significantly lower in the tumor bearing versus sham group. Within the tumor bearing group, LV muscle mass was significantly negatively correlated with prostate tumor mass (r=-0.85, P<0.01). Prostate cancer reduced endurance exercise capacity in the rat and reductions in cardiac function and mass and skeletal muscle mass may have played an important role in this impairment.