ABSTRACT
Acute heat exposure improves microvascular function in aged adults as assessed using reactive hyperemia. The cutaneous and skeletal muscle microcirculations are thought to contribute to this response, but this has never been confirmed due to the methodological challenges associated with differentiating blood flow between these vascular beds. We hypothesized that acute hot water immersion would improve endothelial-dependent, but not endothelial-independent vasodilation in the microcirculation of the vastus lateralis muscle in healthy aged adults. Participants (70 ± 5 yr) were immersed for 60 min in thermoneutral (36°C) or hot (40°C) water. Ninety minutes following immersion, skeletal muscle microdialysis was used to bypass the cutaneous circulation and directly assess endothelial-dependent and endothelial-independent vasodilation by measuring the local hyperemic response to graded infusions of acetylcholine (ACh, 27.5 and 55.0 mM) and sodium nitroprusside (SNP, 21 and 42 mM), respectively. The hyperemic response to 27.5 mM ACh did not differ between thermal conditions (P = 0.9). However, the hyperemic response to 55.0 mM ACh was increased with prior hot water immersion (thermoneutral immersion, 43.9 ± 23.2 mL/min/100 g vs. hot water immersion, 66.5 ± 25.5 mL/min/100 g; P < 0.01). Similarly, the hyperemic response to 21 mM SNP did not differ between thermal conditions (P = 0.3) but was increased following hot water immersion with the infusion of 42 mM SNP (thermoneutral immersion, 48.8 ± 25.6 mL/min/100 g vs. hot water immersion, 90.7 ± 53.5 mL/min/100 g; P < 0.01). These data suggest that acute heat exposure improves microvascular function in skeletal muscle of aged humans.NEW & NOTEWORTHY Acute heat exposure improves microvascular function in aged adults as assessed using reactive hyperemia. The cutaneous and skeletal muscle microcirculations are thought to contribute to this response, but this has never been confirmed due to the methodological challenges associated with differentiating blood flow between these vascular beds. Using the microdialysis technique to bypass the cutaneous circulation, we demonstrated that heat exposure improves endothelial-dependent and endothelial-independent vasodilation in the microcirculation of skeletal muscle in aged humans.
Subject(s)
Hyperthermia, Induced/methods , Microcirculation , Muscle, Skeletal/blood supply , Aged , Female , Humans , Male , Microvessels/physiology , Muscle, Skeletal/growth & development , VasodilationABSTRACT
Nonpharmacological therapies that protect against endothelial ischemia-reperfusion injury (I/R) remain limited in aged adults. Acute heat exposure protects against endothelial I/R injury in young adults, but its efficacy has never been explored in aged adults. Therefore, we tested the hypothesis that acute heat exposure would prevent the attenuation of endothelium-dependent vasodilation after I/R injury in aged adults. Nine (2 men, 69 ± 8 yr) aged adults were exposed to a thermoneutral control condition or whole body passive heating (water-perfused suit) sufficient to increase body core temperature by 1.2°C. Experiments were separated by at least 7 days. Heat exposure was always performed first to time match the thermoneutral control condition. Endothelium-dependent vasodilation was assessed via flow-mediated dilation of the brachial artery before (pre-I/R) and after I/R injury (post-I/R), which was induced by 20 min of arm ischemia followed by 20 min of reperfusion. Flow-mediated dilation was reduced following I/R injury for the thermoneutral control condition (pre-I/R, 4.5 ± 2.9% vs. post-I/R, 0.9 ± 2.8%, P < 0.01), but was well maintained with prior heat exposure (pre-I/R, 4.4 ± 2.8% vs. post-I/R, 3.5 ± 2.8%, P = 0.5). Taken together, acute heat exposure protects against endothelial I/R injury in aged adults. These results highlight the therapeutic potential of heat therapy to prevent endothelial dysfunction associated with I/R injury in aged adults who are most at risk for an ischemic event.
Subject(s)
Body Temperature , Hot Temperature , Reperfusion Injury/prevention & control , Aged , Brachial Artery , Endothelium, Vascular , Female , Humans , Male , Middle Aged , VasodilationABSTRACT
Prior data suggest that, relative to the early follicular phase, women in the late follicular phase are protected against endothelial ischemia-reperfusion (I/R) injury when estradiol concentrations are highest. In addition, endothelial I/R injury is consistently observed in men with naturally low endogenous estradiol concentrations that are similar to those of women in the early follicular phase. Therefore, the purpose of this study was to determine whether the vasodeleterious effect of I/R injury differs between women in the early follicular phase of the menstrual cycle and age-matched men. We tested the hypothesis that I/R injury would attenuate endothelium-dependent vasodilation to the same extent in women and age-matched men with similar circulating estradiol concentrations. Endothelium-dependent vasodilation was assessed via brachial artery flow-mediated dilation (duplex ultrasound) in young healthy men (n = 22) and women (n = 12) before (pre-I/R) and immediately after (post-I/R) I/R injury, which was induced via 20 min of arm circulatory arrest followed by 20-min reperfusion. Serum estradiol concentrations did not differ between sexes (men 115.0 ± 33.9 pg·mL-1 vs. women 90.5 ± 40.8 pg·mL-1; P = 0.2). The magnitude by which I/R injury attenuated endothelium-dependent vasodilation did not differ between men (pre-I/R 5.4 ± 2.4% vs. post-I/R 3.0 ± 2.7%) and women (pre-I/R 6.1 ± 2.8% vs. post-I/R 3.7 ± 2.7%; P = 0.9). Our data demonstrate that I/R injury similarly reduces endothelial function in women in the early follicular phase of the menstrual cycle and age-matched men with similar estradiol concentrations.
Subject(s)
Arm/blood supply , Brachial Artery/physiopathology , Endothelium, Vascular/physiopathology , Estradiol/blood , Follicular Phase/blood , Reperfusion Injury/physiopathology , Vasodilation , Adult , Brachial Artery/diagnostic imaging , Female , Humans , Male , Reperfusion Injury/blood , Reperfusion Injury/diagnostic imaging , Sex Factors , Young AdultABSTRACT
There is a sustained reduction in arterial blood pressure that occurs in aged adults following exposure to acute leg heating. We tested the hypothesis that acute leg heating would decrease arterial blood pressure in aged adults secondary to sympathoinhibition. We exposed 13 young and 10 aged adults to 45 min of leg heating. Muscle sympathetic nerve activity (radial nerve) was measured before leg heating (preheat) and 30 min after (recovery) and is expressed as burst frequency. Neurovascular transduction was examined by assessing the slope of the relation between muscle sympathetic nerve activity and leg vascular conductance measured at rest and during isometric handgrip exercise performed to fatigue. Arterial blood pressure was well maintained in young adults (preheat, 86 ± 6 mmHg vs. recovery, 88 ± 7 mmHg; P = 0.4) due to increased sympathetic nerve activity (preheat, 16 ± 7 bursts/min vs. recovery, 22 ± 10 bursts/min; P < 0.01). However, in aged adults, sympathetic nerve activity did not differ from preheat (37 ± 5 bursts/min) to recovery (33 ± 6 bursts/min, P = 0.1), despite a marked reduction in arterial blood pressure (preheat, 101 ± 7 mmHg vs. recovery, 94 ± 6 mmHg; P < 0.01). Neurovascular transduction did not differ from preheat to recovery for either age group (P ≥ 0.1). The reduction in arterial blood pressure that occurs in aged adults following exposure to acute leg heating is mediated, in part, by a sympathoinhibitory effect that alters the compensatory neural response to hypotension.NEW & NOTEWORTHY There is a sustained reduction in arterial blood pressure that occurs in aged adults following exposure to acute leg heating. However, the neurovascular mechanisms mediating this response remain unknown. Our findings demonstrate for the first time that this reduction in arterial blood pressure is mediated, in part, by a sympathoinhibitory effect that alters the compensatory neural response to hypotension in aged adults.
Subject(s)
Aging/physiology , Blood Pressure , Heat-Shock Response , Sympathetic Nervous System/physiology , Adult , Aged , Female , Hand Strength , Humans , Leg/growth & development , Leg/physiology , Male , Middle Aged , Muscle, Smooth, Vascular/growth & development , Muscle, Smooth, Vascular/physiology , Neural Conduction , Sympathetic Nervous System/growth & developmentABSTRACT
Endoplasmic reticulum stress contributes to ischemia-reperfusion (I/R) injury in rodent and cell models. However, the contribution of endoplasmic reticulum stress in the pathogenesis of endothelial I/R injury in humans is unknown. We tested the hypothesis that compared with placebo, inhibition of endoplasmic reticulum stress via ingestion of tauroursodeoxycholic acid would prevent the attenuation of endothelium-dependent vasodilation following I/R injury. Twelve young adults (6 women) were studied following ingestion of a placebo or 1,500 mg tauroursodeoxycholic acid (TUDCA). Endothelium-dependent vasodilation was assessed via brachial artery flow-mediated dilation (duplex ultrasonography) before and after I/R injury, which was induced by 20 min of arm ischemia followed by 20 min of reperfusion. Endothelium-independent vasodilation (glyceryl trinitrate-mediated vasodilation) was also assessed after I/R injury. Compared with placebo, TUDCA ingestion increased circulating plasma concentrations by 145 ± 90 ng/ml and increased concentrations of the taurine unconjugated form, ursodeoxycholic acid, by 560 ± 156 ng/ml (both P < 0.01). Ischemia-reperfusion injury attenuated endothelium-dependent vasodilation, an effect that did not differ between placebo (pre-I/R, 5.0 ± 2.1% vs. post-I/R, 3.5 ± 2.2%) and TUDCA (pre-I/R, 5.6 ± 2.1% vs. post-I/R, 3.9 ± 2.1%; P = 0.8) conditions. Similarly, endothelium-independent vasodilation did not differ between conditions (placebo, 19.6 ± 4.8% vs. TUDCA, 19.7 ± 6.1%; P = 0.9). Taken together, endoplasmic reticulum stress does not appear to contribute to endothelial I/R injury in healthy young adults.
Subject(s)
Brachial Artery/physiopathology , Endoplasmic Reticulum Stress , Endothelium, Vascular/physiopathology , Reperfusion Injury/physiopathology , Upper Extremity/blood supply , Vasodilation , Adult , Brachial Artery/drug effects , Brachial Artery/metabolism , Endoplasmic Reticulum Stress/drug effects , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Female , Humans , Male , Random Allocation , Reperfusion Injury/blood , Single-Blind Method , Taurochenodeoxycholic Acid/administration & dosage , Taurochenodeoxycholic Acid/blood , Vasodilation/drug effects , Young AdultABSTRACT
NEW FINDINGS: ⢠What is the central question of this study? What is the effect of lower leg hot water immersion on vascular ischaemia-reperfusion injury induced in the arm of young healthy humans? ⢠What is the main finding and its importance? Lower leg hot water immersion successfully protects against vascular ischaemia-reperfusion injury in humans. This raises the possibility that targeted heating of the lower legs may be an alternative therapeutic approach to whole-body heating that is equally efficacious at protecting against vascular ischaemia-reperfusion injury. ABSTRACT: Reperfusion that follows a period of ischaemia paradoxically reduces vasodilator function in humans and contributes to the tissue damage associated with an ischaemic event. Acute whole-body hot water immersion protects against vascular ischaemia-reperfusion (I-R) injury in young healthy humans. However, the effect of acute lower leg heating on I-R injury is unclear. Therefore, the purpose of this study was to test the hypothesis that, compared with thermoneutral control immersion, acute lower leg hot water immersion would prevent the decrease in macro- and microvascular dilator functions following I-R injury in young healthy humans. Ten young healthy subjects (5 female) immersed their lower legs into a circulated water bath for 60 min under two randomized conditions: (1) thermoneutral control immersion (â¼33°C) and (2) hot water immersion (â¼42°C). Macrovascular (brachial artery flow-mediated dilatation) and microvascular (forearm reactive hyperaemia) dilator functions were assessed using Doppler ultrasound at three time points: (1) pre-immersion, (2) 60 min post-immersion, and (3) post-I/R (20 min of arm ischaemia followed by 20 min of reperfusion). Ischaemia-reperfusion injury reduced macrovascular dilator function following control immersion (pre-immersion 6.0 ± 2.1% vs. post-I/R 3.6 ± 2.1%; P < 0.05), but was well-maintained with prior hot water immersion (pre-immersion 5.8 ± 2.1% vs. post-I/R 5.3 ± 2.1%; P = 0.8). Microvascular dilator function did not differ between conditions or across time. Taken together, acute lower leg hot water immersion prevents the decrease in macrovascular dilator function that occurs following I-R injury in young healthy humans.
Subject(s)
Brachial Artery/physiology , Hyperthermia, Induced/methods , Immersion , Leg/blood supply , Reperfusion Injury/physiopathology , Vasodilation/physiology , Adult , Blood Flow Velocity/physiology , Female , Forearm/blood supply , Forearm/physiology , Humans , Leg/physiology , Male , Microvessels/physiology , Regional Blood Flow/physiology , Reperfusion Injury/prevention & control , Water , Young AdultABSTRACT
Acute heat exposure increases skeletal muscle blood flow in humans. However, the mechanisms mediating this hyperemic response remain unknown. The cyclooxygenase pathway is active in skeletal muscle, is heat sensitive, and contributes to cutaneous thermal hyperemia in young healthy humans. Therefore, the purpose of this study was to test the hypothesis that cyclooxygenase inhibition would attenuate blood flow in the vastus lateralis muscle during localized heating. Twelve participants (6 women) were studied on two separate occasions: 1) time control (i.e., no ibuprofen); and 2) ingestion of 800 mg ibuprofen, a nonselective cyclooxygenase inhibitor. Experiments were randomized, counter-balanced, and separated by at least 10 days. Pulsed short-wave diathermy was used to induce unilateral deep heating of the vastus lateralis for 90 min, whereas the contralateral leg served as a thermoneutral control. Microdialysis was utilized to bypass the cutaneous circulation and directly measure local blood flow in the vastus lateralis muscle of each leg via the ethanol washout technique. Heat exposure increased muscle temperature and local blood flow (both P < 0.01 vs. baseline). However, the thermal hyperemic response did not differ between control and ibuprofen conditions (P ≥ 0.2). Muscle temperature slightly decreased for the thermoneutral leg (P < 0.01 vs. baseline), yet local blood flow remained relatively unchanged across time for control and ibuprofen conditions (both P ≥ 0.7). Taken together, our data suggest that inhibition of cyclooxygenase-derived vasodilator prostanoids does not blunt thermal hyperemia in skeletal muscle of young healthy humans.NEW & NOTEWORTHY Acute heat exposure increases skeletal muscle blood flow in humans. However, the mechanisms mediating this hyperemic response remain unknown. Using a pharmacological approach combined with microdialysis, we found that thermal hyperemia in the vastus lateralis muscle was well maintained despite the successful inhibition of cyclooxygenase. Our results suggest that cyclooxygenase-derived vasodilator prostanoids do not contribute to thermal hyperemia in skeletal muscle of young healthy humans.
Subject(s)
Hyperemia , Humans , Female , Ibuprofen/pharmacology , Muscle, Skeletal/physiology , Vasodilator Agents/pharmacology , Cyclooxygenase 2 , Prostaglandins/pharmacology , Regional Blood FlowABSTRACT
The pressor response induced by a voluntary hypoxic apnea is mediated largely by increased sympathetic outflow. The neural control of blood pressure is altered in recovery from acute heat exposure, but its effect on the pressor response to a voluntary hypoxic apnea has never been explored. Therefore, we tested the hypothesis that prior heat exposure would attenuate the pressor response induced by a voluntary hypoxic apnea. Eleven healthy adults (five women) were exposed to whole body passive heating (water-perfused suit) sufficient to increase body core temperature by 1.2°C. Voluntary hypoxic apneas were performed at baseline and in recovery when body core temperature returned to ≤ 0.3°C of baseline. Participants breathed gas mixtures of varying [Formula: see text] (21%, 16%, and 12%; randomized) for 1 min followed by a 15-s end-expiratory apnea. The change in arterial oxygen saturation during each apnea did not differ from baseline to recovery (P = 0.6 for interaction), whereas the pressor response induced by a voluntary hypoxia apnea was reduced ([Formula: see text] 21%, baseline 17 ± 7 mmHg vs. recovery 14 ± 7 mmHg; [Formula: see text] 16%, baseline 24 ± 8 mmHg vs. recovery 18 ± 7 mmHg; [Formula: see text] 12%, baseline 28 ± 11 mmHg vs. recovery 24 ± 11 mmHg; P = 0.01 for main effect of time). These data suggest that prior heat exposure induces a cross-stressor effect such that the pressor response to a voluntary hypoxic apnea is attenuated.NEW & NOTEWORTHY The pressor response induced by a voluntary hypoxic apnea is mediated by increased sympathetic outflow. The neural control of blood pressure is altered in recovery from acute heat exposure, but its effect on the pressor response to a voluntary hypoxic apnea has never been explored. Our data suggest that prior heat exposure induces a cross-stressor effect such that the pressor response to a voluntary hypoxic apnea is attenuated.
Subject(s)
Apnea , Hot Temperature , Adult , Humans , Female , Sympathetic Nervous System/physiology , Blood Pressure/physiology , HypoxiaABSTRACT
Acute heat exposure protects against endothelial ischemia-reperfusion (I/R) injury in humans. However, the mechanism/s mediating this protective effect remain unclear. We tested the hypothesis that inhibiting the increase in shear stress induced by acute heat exposure would attenuate the protection of endothelial function following I/R injury. Nine (3 women) young healthy participants were studied under three experimental conditions: 1) thermoneutral control; 2) whole body heat exposure to increase body core temperature by 1.2°C; and 3) heat exposure + brachial artery compression to inhibit the temperature-dependent increase in shear stress. Endothelial function was assessed via brachial artery flow-mediated dilatation before (pre-I/R) and after (post-I/R) 20 min of arm ischemia followed by 20 min of reperfusion. Brachial artery shear rate was increased during heat exposure (681 ± 359 s-1), but not for thermoneutral control (140 ± 63 s-1; P < 0.01 vs. heat exposure) nor for heat + brachial artery compression (139 ± 60 s-1; P < 0.01 vs. heat exposure). Ischemia-reperfusion injury reduced flow-mediated dilatation following thermoneutral control (pre-I/R, 5.5 ± 2.9% vs. post-I/R, 3.8 ± 2.9%; P = 0.06), but was protected following heat exposure (pre-I/R, 5.8 ± 2.9% vs. post-I/R, 6.1 ± 2.9%; P = 0.5) and heat + arterial compression (pre-I/R, 4.4 ± 2.8% vs. post-I/R, 5.8 ± 2.8%; P = 0.1). Contrary to our hypothesis, our findings demonstrate that shear stress induced by acute heat exposure is not obligatory to protect against endothelial I/R injury in humans.NEW & NOTEWORTHY Acute heat exposure protects against endothelial ischemia-reperfusion injury in humans. However, the mechanism/s mediating this protective effect remain unclear. We utilized arterial compression to inhibit the temperature-dependent increase in brachial artery blood velocity that occurs during acute heat exposure to isolate the contribution of shear stress to the protection of endothelial function following ischemia-reperfusion injury. Our findings demonstrate that shear stress induced by acute heat exposure is not obligatory to protect against endothelial I/R injury.
Subject(s)
Hot Temperature , Reperfusion Injury , Brachial Artery , Endothelium, Vascular , Female , Humans , Reperfusion Injury/prevention & control , Stress, Mechanical , VasodilationABSTRACT
BACKGROUND: Tourniquets impose ischemia on distal musculature. Resuscitation with pyruvate, an energy substrate and antioxidant, may ameliorate muscle ischemia-reperfusion injury. METHODS: After goats were exsanguinated to lower mean arterial pressure to 48 mmHg, femoral vessels were occluded for 90 minutes to impose hindlimb ischemia. Lactate Ringer's (LR) or pyruvate Ringer's (PR) solution was infused from 30 minutes ischemia until 30 minutes reperfusion. Pro- and antiapoptotic proteins and injury markers were measured in gastrocnemius at 4 hours reperfusion. RESULTS: Pro-oxidant NADPH oxidase activity and nitrotyrosine content, a footprint of nitrosative stress, doubled, and poly (ADP-ribose) polymerase cleavage, an early apoptotic event, increased 80% in LR-resuscitated vs. sham muscle, but PR prevented these increases. Antiapoptotic Bcl-X(L) content fell in LR-treated vs. sham and PR-treated muscle. Water content increased in LR- but not PR-resuscitated muscle. CONCLUSIONS: LR resuscitation imposed oxido-nitrosative stress and initiated proapoptotic mechanisms, while PR blunted these harmful consequences of muscle ischemia-reperfusion.
Subject(s)
Pyruvic Acid/metabolism , Reperfusion Injury/prevention & control , Animals , Fluid Therapy , Goats , Hindlimb , Isotonic Solutions , Male , Muscle, Skeletal/chemistry , Muscle, Skeletal/enzymology , Reperfusion , Ringer's LactateABSTRACT
OBJECTIVES: To determine whether controlled resuscitation with pyruvate-fortified Ringer's (PR) solution vs. conventional lactate Ringer's (LR) more effectively stabilizes mean arterial pressure (MAP) and suppresses myocardial inflammation postresuscitation. METHODS: Goats were hemorrhaged (255 +/- 22 ml) to lower MAP to 48 +/- 1 mmHg. Next, the right femoral vessels were occluded for 90 min to model tourniquet application. Beginning at 30 min occlusion, LR or PR was infused i.v. at 10 ml/min for 90 min. The femoral occlusions were released at 60 min infusion. RESULTS: At 4 h postocclusion, MAP (mmHg) was increased in PR (59 +/- 4) vs. LR (47 +/- 3) resuscitated goats (p < 0.05). PR also more effectively augmented circulating HCO3 and total base excess. Nitrosative stress, detected in myocardium 4 h after LR resuscitation, was suppressed by PR. Finally, PR prevented the increase in circulating neutrophils that accompanied LR resuscitation. CONCLUSIONS: Relative to LR, resuscitation with PR more effectively stabilized MAP, suppressed myocardial nitrosative stress and minimized systemic inflammation after hemorrhagic shock with hindlimb ischemia-reperfusion.
Subject(s)
Fluid Therapy/methods , Hemodynamics/physiology , Inflammation/therapy , Myocardium/metabolism , Oxidative Stress , Pyruvic Acid/administration & dosage , Shock, Hemorrhagic/complications , Animals , Disease Models, Animal , Drug Combinations , Goats , Hemodynamics/drug effects , Inflammation/etiology , Infusions, Intravenous , Isotonic Solutions/administration & dosage , Isotonic Solutions/pharmacokinetics , Lactates/metabolism , Leukocyte Count , Male , Neutrophils , Pyruvic Acid/pharmacokinetics , Resuscitation/methods , Ringer's Lactate , Shock, Hemorrhagic/metabolism , Shock, Hemorrhagic/therapy , Treatment Outcome , Tyrosine/analogs & derivatives , Tyrosine/metabolismABSTRACT
Goats are used as animal models for surgery and trauma research. The authors discuss appropriate methods for induction of anesthetics, intubation and surgical maintenance of the goat during acute experimentation. Risks imposed by the Q fever pathogen Coxiella burnetii are described, as well as measures that have proven effective in minimizing zoonotic transmission of this pathogen to laboratory personnel. With appropriate knowledge of its applications, peri- and intra-operative management and limitations, the goat is a suitable animal model for a variety of biomedical research applications.
Subject(s)
Goats/surgery , Intraoperative Care/veterinary , Shock, Hemorrhagic/veterinary , Surgical Procedures, Operative/veterinary , Anesthesia/methods , Anesthesia/veterinary , Animals , Intraoperative Care/methods , Intubation, Intratracheal/methods , Intubation, Intratracheal/veterinary , Models, Animal , Preoperative Care/methods , Preoperative Care/veterinary , Shock, Hemorrhagic/surgery , Surgical Procedures, Operative/methodsABSTRACT
Pyruvate-fortified cardioplegia protects myocardium and hastens postsurgical recovery of patients undergoing cardiopulmonary bypass (CPB). Pyruvate reportedly suppresses degradation of the alpha-subunit of hypoxia-inducible factor-1 (HIF-1), an activator of the gene encoding the cardioprotective cytokine erythropoietin (EPO). This study tested the hypothesis that pyruvate-enriched cardioplegia evoked EPO expression and mobilized EPO signaling mechanisms in myocardium. Hearts of pigs maintained on CPB were arrested for 60 min with 4:1 blood-crystalloid cardioplegia. The crystalloid component contained 188 mM glucose + or - 24 mM pyruvate. After 30-min cardiac reperfusion with cardioplegia-free blood, the pigs were weaned from CPB. Left ventricular myocardium was sampled 4 h after CPB for immunoblot assessment of HIF-1alpha, EPO and its receptor, the signaling kinases Akt and ERK, and endothelial nitric oxide synthase (eNOS), an effector of EPO signaling. Pyruvate-fortified cardioplegia stabilized arterial pressure post-CPB, induced myocardial EPO mRNA expression, and increased HIF-1alpha, EPO, and EPO-R protein contents by 60, 58, and 123%, respectively, vs. control cardioplegia (P < 0.05). Pyruvate cardioplegia also increased ERK phosphorylation by 61 and 118%, respectively, vs. control cardioplegia-treated and non-CPB sham myocardium (P < 0.01), but did not alter Akt phosphorylation. Nitric oxide synthase (NOS) activity and eNOS content fell 32% following control CPB vs. sham, but pyruvate cardioplegia prevented these declines, yielding 49 and 80% greater NOS activity and eNOS content vs. respective control values (P < 0.01). Pyruvate-fortified cardioplegia induced myocardial EPO expression and mobilized the EPO-ERK-eNOS mechanism. By stabilizing HIF-1alpha, pyruvate-fortified cardioplegia may evoke sustained activation of EPO's cardioprotective signaling cascade in myocardium.
Subject(s)
Cardioplegic Solutions/pharmacology , Cardiopulmonary Bypass , Erythropoietin/metabolism , Heart Arrest, Induced/methods , Heart Diseases/prevention & control , Myocardium/metabolism , Pyruvic Acid/pharmacology , Signal Transduction/drug effects , Animals , Blood Pressure/drug effects , Cardioplegic Solutions/metabolism , Cardiopulmonary Bypass/adverse effects , Edema, Cardiac/etiology , Edema, Cardiac/metabolism , Edema, Cardiac/prevention & control , Energy Metabolism , Erythropoietin/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Glutathione/metabolism , Heart Arrest, Induced/adverse effects , Heart Diseases/etiology , Heart Diseases/metabolism , Heart Diseases/physiopathology , Heart Rate/drug effects , Heart Ventricles/drug effects , Heart Ventricles/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Male , Models, Animal , Nitric Oxide Synthase Type III/metabolism , Oxidation-Reduction , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Pyruvic Acid/metabolism , RNA, Messenger/metabolism , Receptors, Erythropoietin/metabolism , Swine , Time Factors , Up-RegulationABSTRACT
Shunts are commonly employed to treat hydrocephalus, a severe central nervous disease caused by the buildup of cerebrospinal fluid in the brain. These shunts divert excessive cerebrospinal fluid from brain ventricles to other body cavities, thereby relieving the symptoms. However, these shunts are highly prone to failure due to obstruction from cellular debris, leading to cerebrospinal fluid accumulation in the brain and exacerbation of neurological symptoms. Therefore, there is a clinical need for a reliable, non-invasive method of monitoring shunt performance. Recently, a simple inline flow sensor was reported for monitoring ventriculoperitoneal shunting of cerebrospinal fluid in hydrocephalus treatment. The present work aimed to evaluate performance of the device in an animal model of hydrocephalus. Sensor-equipped shunt tubes were placed in anesthetized, juvenile swine. The flows reported by the sensor were compared with gravimetric flow measurements. Robust correlations (râ¯≈â¯0.87-0.96) between the gravimetric and sensor-reported flows were obtained in 4 of the 6 experiments. The mean slope of the linear relationship of the gravimetrically determined vs. sensor flow rates was 0.98 ± 0.09 in the 6 experiments, indicating the sensor accurately reported shunt flows up to 35â¯ml/h. The sensor responded immediately to abrupt flow changes following cerebroventricular fluid injections. Minor hardware problems were identified and corrected. These experiments provide practical guidance for future preclinical testing of the device.
Subject(s)
Hydrodynamics , Ventriculoperitoneal Shunt/instrumentation , Animals , Calibration , Hydrocephalus/cerebrospinal fluid , Hydrocephalus/surgery , SwineABSTRACT
Cardiac contractile function is adenosine-5'-triphosphate (ATP)-intensive, and the myocardium's high demand for oxygen and energy substrates leaves it acutely vulnerable to interruptions in its blood supply. The myriad cardioprotective properties of the natural intermediary metabolite pyruvate make it a potentially powerful intervention against the complex injury cascade ignited by myocardial ischemia-reperfusion. A readily oxidized metabolic substrate, pyruvate augments myocardial free energy of ATP hydrolysis to a greater extent than the physiological fuels glucose, lactate and fatty acids, particularly when it is provided at supra-physiological plasma concentrations. Pyruvate also exerts antioxidant effects by detoxifying reactive oxygen and nitrogen intermediates, and by increasing nicotinamide adenine dinucleotide phosphate reduced form (NADPH) production to maintain glutathione redox state. These enhancements of free energy and antioxidant defenses combine to augment sarcoplasmic reticular Ca2+ release and re-uptake central to cardiac mechanical performance and to restore ß-adrenergic signaling of ischemically stunned myocardium. By minimizing Ca2+ mismanagement and oxidative stress, pyruvate suppresses inflammation in post-ischemic myocardium. Thus, pyruvate administration stabilized cardiac performance, augmented free energy of ATP hydrolysis and glutathione redox systems, and/or quelled inflammation in a porcine model of cardiopulmonary bypass, a canine model of cardiac arrest-resuscitation, and a caprine model of hypovolemia and hindlimb ischemia-reperfusion. Pyruvate's myriad benefits in preclinical models provide the mechanistic framework for its clinical application as metabolic support for myocardium at risk. Phase one trials have demonstrated pyruvate's safety and efficacy for intravenous resuscitation for septic shock, intracoronary infusion for heart failure and as a component of cardioplegia for cardiopulmonary bypass. The favorable outcomes of these trials, which argue for expanded, phase three investigations of pyruvate therapy, mirror findings in isolated, perfused hearts, underscoring the pivotal role of preclinical research in identifying clinical interventions for cardiovascular diseases. Impact statement This article reviews pyruvate's cardioprotective properties as an energy-yielding metabolic fuel, antioxidant and anti-inflammatory agent in mammalian myocardium. Preclinical research has shown these properties make pyruvate a powerful intervention to curb the complex injury cascade ignited by ischemia and reperfusion. In ischemically stunned isolated hearts and in large mammal models of cardiopulmonary bypass, cardiac arrest-resuscitation and hypovolemia, intracoronary pyruvate supports recovery of myocardial contractile function, intracellular Ca2+ homeostasis and free energy of ATP hydrolysis, and its antioxidant actions restore ß-adrenergic signaling and suppress inflammation. The first clinical trials of pyruvate for cardiopulmonary bypass, fluid resuscitation and intracoronary intervention for congestive heart failure have been reported. Receiver operating characteristic analyses show remarkable concordance between pyruvate's beneficial functional and metabolic effects in isolated, perfused hearts and in patients recovering from cardiopulmonary bypass in which they received pyruvate- vs. L-lactate-fortified cardioplegia. This research exemplifies the translation of mechanism-oriented preclinical studies to clinical application and outcomes.
Subject(s)
Cardiovascular Agents/administration & dosage , Cardiovascular Agents/pharmacology , Myocardial Reperfusion Injury/drug therapy , Pyruvic Acid/administration & dosage , Pyruvic Acid/pharmacology , Adenosine Triphosphate/metabolism , Animals , Antioxidants/administration & dosage , Antioxidants/pharmacology , Cardiovascular Agents/adverse effects , Clinical Trials, Phase I as Topic , Disease Models, Animal , Dogs , Goats , Heart/drug effects , Humans , Oxidation-Reduction , Pyruvic Acid/adverse effects , SwineABSTRACT
This commentary addresses the recent retraction of an article which reported favorable outcomes in septic patients treated with intravenous pyruvate. The retracted report was cited in the authors' recent minireview on the cellular mechanisms and clinical application of pyruvate to improve cardiac performance. Because the retracted article reports pyruvate-enhanced resuscitation of critically ill patients, the authors wish to inform the readership, especially critical care providers, that this particular clinical application of pyruvate is not now supported by robust evidence. After discussing the retraction's implications for the clinical application of pyruvate-enriched resuscitation for sepsis, this commentary summarizes the extensive preclinical evidence of the efficacy and mechanisms of pyruvate resuscitation in animal models of hemorrhagic and septic shock, which argues for renewed clinical investigation of pyruvate-enriched resuscitation. Impact statement This commentary addresses the recent retraction of a clinical report of significant benefits of intravenous pyruvate resuscitation in septic patients, including sharply lowered mortality and decreased circulating pro-inflammatory cytokines, which was cited in the authors' minireview in Experimental Biology and Medicine. The potential implications of the retraction, and the extensive preclinical evidence supporting the use of pyruvate-enriched resuscitation for shock states, are summarized and discussed.
Subject(s)
Pyruvic Acid/administration & dosage , Resuscitation/methods , Shock, Hemorrhagic/drug therapy , Shock, Septic/drug therapy , Administration, Intravenous , Animals , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Treatment OutcomeABSTRACT
Pyruvate, a natural metabolic fuel and antioxidant in myocardium and other tissues, exerts a variety of cardioprotective actions when provided at supraphysiological concentrations. Pyruvate increases cardiac contractile performance and myocardial energy state, bolsters endogenous antioxidant systems, and protects myocardium from ischemia-reperfusion injury and oxidant stress. This article reviews and discusses basic and clinically oriented research conducted over the last several years that has yielded fundamental information on pyruvate's inotropic and cardioprotective mechanisms. Particular attention is placed on pyruvate's enhancement of sarcoplasmic reticular Ca2+ transport, its antioxidant properties, and its ability to mitigate reversible and irreversible myocardial injury. These research efforts are establishing the essential foundation for clinical application of pyruvate therapy in numerous settings including cardiopulmonary bypass surgery, cardiopulmonary resuscitation, myocardial stunning, and cardiac failure.
Subject(s)
Cardiomyopathies/drug therapy , Cardiotonic Agents/metabolism , Cardiotonic Agents/therapeutic use , Myocardium/metabolism , Pyruvic Acid/metabolism , Pyruvic Acid/therapeutic use , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Antioxidants/therapeutic use , Cardiomyopathies/prevention & control , Cardiotonic Agents/pharmacology , Humans , Pyruvic Acid/pharmacologyABSTRACT
Clear cell "sugar" tumors of the lung are rare pulmonary tumors. This case study illustrates a patient who was found to have a persistent nodule in the left-upper lobe of the lung. Positron emission tomographic scanning showed mild-moderate 18-fluorodeoxyglucose uptake. Based on these findings, a video-assisted resection of the tumor was undertaken. The mass was identified histologically, as a clear cell "sugar" tumor of the lung. This case report discusses the benign versus malignant nature of this rare tumor.
Subject(s)
Lung Neoplasms/pathology , Lung Neoplasms/surgery , Perivascular Epithelioid Cell Neoplasms/pathology , Perivascular Epithelioid Cell Neoplasms/surgery , Thoracic Surgery, Video-Assisted , Adult , Diagnosis, Differential , Female , Fluorodeoxyglucose F18 , Humans , Multimodal Imaging , Positron-Emission Tomography , Radiopharmaceuticals , Tomography, X-Ray ComputedABSTRACT
Cardiac arrest remains a leading cause of death and permanent disability worldwide. Although many victims are initially resuscitated, they often succumb to the extensive ischemia-reperfusion injury inflicted on the internal organs, especially the brain. Cardiac arrest initiates a complex cellular injury cascade encompassing reactive oxygen and nitrogen species, Ca(2+) overload, ATP depletion, pro- and anti-apoptotic proteins, mitochondrial dysfunction, and neuronal glutamate excitotoxity, which injures and kills cells, compromises function of internal organs and ignites a destructive systemic inflammatory response. The sheer complexity and scope of this cascade challenges the development of experimental models of and effective treatments for cardiac arrest. Many experimental animal preparations have been developed to decipher the mechanisms of damage to vital internal organs following cardiac arrest and cardiopulmonary resuscitation (CPR), and to develop treatments to interrupt the lethal injury cascades. Porcine models of cardiac arrest and resuscitation offer several important advantages over other species, and outcomes in this large animal are readily translated to the clinical setting. This review summarizes porcine cardiac arrest-CPR models reported in the literature, describes clinically relevant phenomena observed during cardiac arrest and resuscitation in pigs, and discusses numerous methodological considerations in modeling cardiac arrest/CPR. Collectively, published reports show the domestic pig to be a suitable large animal model of cardiac arrest which is responsive to CPR, defibrillatory countershocks and medications, and yields extensive information to foster advances in clinical treatment of cardiac arrest.
ABSTRACT
Cardiac electromechanical dysfunction may compromise recovery of patients who are initially resuscitated from cardiac arrest, and effective treatments remain elusive. Pyruvate, a natural intermediary metabolite, energy substrate, and antioxidant, has been found to protect the heart from ischemia-reperfusion injury. This study tested the hypothesis that pyruvate-enriched resuscitation restores hemodynamic, metabolic, and electrolyte homeostasis following cardiac arrest. Forty-two Yorkshire swine underwent pacing-induced ventricular fibrillation and, after 6 min pre-intervention arrest, 4 min precordial compressions followed by transthoracic countershocks. After defibrillation and recovery of spontaneous circulation, the pigs were monitored for another 4 h. Sodium pyruvate or NaCl were infused i.v. (0.1 mmol·kg(-1)·min(-1)) throughout precordial compressions and the first 60 min recovery. In 8 of the 24 NaCl-infused swine, the first countershock converted ventricular fibrillation to pulseless electrical activity unresponsive to subsequent countershocks, but only 1 of 18 pyruvate-treated swine developed pulseless electrical activity (relative risk 0.17; 95% confidence interval 0.13-0.22). Pyruvate treatment also lowered the dosage of vasoconstrictor phenylephrine required to maintain systemic arterial pressure at 15-60 min recovery, hastened clearance of excess glucose, elevated arterial bicarbonate, and raised arterial pH; these statistically significant effects persisted up to 3 h after sodium pyruvate infusion, while infusion-induced hypernatremia subsided. These results demonstrate that pyruvate-enriched resuscitation achieves electrocardiographic and hemodynamic stability in swine during the initial recovery from cardiac arrest. Such metabolically based treatment may offer an effective strategy to support cardiac electromechanical recovery immediately after cardiac arrest.