Lori J. Gilligan

Aerobic interval training vs. continuous moderate exercise in the metabolic syndrome of rats artificially selected for low aerobic capacity

AIMS The recent development of a rat model that closely resembles the metabolic syndrome allows to study the mechanisms of amelioration of the syndrome by exercise training. Here, we compared the effectiveness for reducing cardiovascular risk factors by exercise training programmes of different exercise intensities. METHODS AND RESULTS Metabolic syndrome rats were subjected to either continuous moderate-intensity exercise (CME) or high-intensity aerobic interval training (AIT). AIT was more effective than CME at reducing cardiovascular disease risk factors linked to the metabolic syndrome. Thus, AIT produced a larger stimulus than CME for increasing maximal oxygen uptake (VO(2max); 45 vs. 10%, P < 0.01), reducing hypertension (20 vs. 6 mmHg, P < 0.01), HDL cholesterol (25 vs. 0%, P < 0.05), and beneficially altering metabolism in fat, liver, and skeletal muscle tissues. Moreover, AIT had a greater beneficial effect than CME on sensitivity of aorta ring segments to acetylcholine (2.7- vs. 2.0-fold, P < 0.01), partly because of intensity-dependent effects on expression levels of nitric oxide synthase and the density of caveolae, and a greater effect than CME on the skeletal muscle Ca2+ handling (50 vs. 0%, P < 0.05). The two exercise training programmes, however, were equally effective at reducing body weight and fat content. CONCLUSION High-intensity exercise training was more beneficial than moderate-intensity exercise training for reducing cardiovascular risk in rats with the metabolic syndrome. This was linked to more superior effects on VO(2max), endothelial function, blood pressure, and metabolic parameters in several tissues. These results demonstrate that exercise training reduces the impact of the metabolic syndrome and that the magnitude of the effect depends on exercise intensity.

Intrinsic Aerobic Capacity Sets a Divide for Aging and Longevity

Rationale: Low aerobic exercise capacity is a powerful predictor of premature morbidity and mortality for healthy adults as well as those with cardiovascular disease. For aged populations, poor performance on treadmill or extended walking tests indicates closer proximity to future health declines. Together, these findings suggest a fundamental connection between aerobic capacity and longevity. Objectives: Through artificial selective breeding, we developed an animal model system to prospectively test the association between aerobic exercise capacity and survivability (aerobic hypothesis). Methods and Results: Laboratory rats of widely diverse genetic backgrounds (N:NIH stock) were selectively bred for low or high intrinsic (inborn) treadmill running capacity. Cohorts of male and female rats from generations 14, 15, and 17 of selection were followed for survivability and assessed for age-related declines in cardiovascular fitness including maximal oxygen uptake (VO2max), myocardial function, endurance performance, and change in body mass. Median lifespan for low exercise capacity rats was 28% to 45% shorter than high capacity rats (hazard ratio, 0.06; P<0.001). VO2max, measured across adulthood was a reliable predictor of lifespan (P<0.001). During progression from adult to old age, left ventricular myocardial and cardiomyocyte morphology, contractility, and intracellular Ca2+ handling in both systole and diastole, as well as mean blood pressure, were more compromised in rats bred for low aerobic capacity. Physical activity levels, energy expenditure (VO2), and lean body mass were all better sustained with age in rats bred for high aerobic capacity. Conclusions: These data obtained from a contrasting heterogeneous model system provide strong evidence that genetic segregation for aerobic exercise capacity can be linked with longevity and are useful for deeper mechanistic exploration of aging.

Volatile anesthetic modulation of lung injury and outcome in a murine model of multiple organ dysfunction syndrome

General anesthesia has been shown to have a significant impact on the inflammatory response. We hypothesized that lung pathophysiology will be attenuated in a mouse model of secondary multiple organ dysfunction syndrome (MODS) elicited by intraperitoneal zymosan suspension in saline. CD-1 mice were anesthetized for 6 h with either 1% halothane or 1.5% isoflurane in 30% oxygen in N2 carrier gas. Another group of mice was exposed to 30% oxygen in N2 carrier gas only. The inflammatory response to zymosan was quantified by measuring lung myeloperoxidase activity (neutrophil recruitment). Lung injury was estimated by determining the degree of lung permeability to radioactive albumin (permeability index). Unanesthetized injured mice exhibited maximal lung myeloperoxidase activity 2 h after zymosan injection (.671 +/- .07 delta OD.min-1), which was significantly attenuated (p < .01) in injured mice anesthetized with halothane (.369 +/- .054) and isoflurane (.324 +/- .055). The maximum lung permeability index occurred 8 h after injection in the unanesthetized, injured mice (.398 +/- .019), and was attenuated (p < .01) in injured mice anesthetized with halothane (.255 +/- .02) and isoflurane (.224 +/- .019). Histopathological findings corresponded to the quantitative myeloperoxidase and permeability index values. Halothane and isoflurane attenuate lung inflammation and injury in this mouse model of multiple organ dysfunction syndrome. This attenuation may be related to modulation of the inflammatory response by volatile anesthetics.

Coronary perfusion pressure during cardiopulmonary resuscitation after spinal anesthesia in dogs.

Cardiac arrest during spinal anesthesia is a rare event, but when it does happen cardiopulmonary resuscitation (CPR) is often ineffectual. This study examines the effect of spinal anesthesia on coronary perfusion pressure (CPP) during CPR and the subsequent response of CPP to epinephrine administration. Twenty mongrel dogs were anesthetized, and randomly assigned to a spinal injection with either 0.5 mg/kg bupivacaine or with an equivalent volume of normal saline. Twenty minutes later, ventricular fibrillation was electrically induced and after 1 min CPR was started. CPP was measured every minute. After 4 min of CPR, epinephrine 0.01 mg/kg was given followed by 0.1, 0.2, and 0.4 mg/kg epinephrine intravenously (IV) at 6, 8, 10 min of CPR, respectively. The bupivacaine (n = 11) group had significantly less CPP than the sham spinal (n = 8) group, 12-13 mm Hg as compared to 27-34 mm Hg. Only 4/11 dogs (36%) in the bupivacaine group had CPP > or = 15 mm Hg during the first 4 min after arrest as compared to 8/8 (100%) in the sham spinal group. This increased to 7/11 dogs (64%) after 0.01 mg/kg epinephrine and to 9/11 after 0.1 mg/kg epinephrine. Total spinal anesthesia decreases CPP and thus the efficacy of CPR in dogs below the threshold previously established for predicting successful resuscitation. Epinephrine is effective in increasing CPP during CPR above the critical threshold. These data suggest that if cardiac arrest occurs during spinal anesthesia, epinephrine should be given in doses of 0.01-0.02 mg/kg IV initially and then increasing to 0.1 mg/kg IV. When this does not work, and ineffective CPR is suspected, alternative resuscitative measures should be considered.

Effect of high-dose sodium bicarbonate on the vasopressor effects of epinephrine during cardiopulmonary resuscitation

We attempted to determine the effect of extreme alkalemia induced by high‐dose sodium bicarbonate on the vasopressor effects of epinephrine during cardiopulmonary resuscitation (CPR). Subjects in this randomized, blinded study performed in a controlled laboratory environment were 12 mongrel dogs that had had a previous episode of CPR. Each dog underwent 3 minutes of ventricular fibrillation (VF) followed by 7 minutes of closed‐chest CPR. Animals were assigned to receive either sodium bicarbonate 3 mEq/kg and epinephrine 0.1 mg/kg, or normal saline 3 ml/kg and epinephrine 0.1 mg/kg. The sodium bicarbonate or normal saline was infused over 2 minutes beginning at 4 minutes of VF (1 min of CPR) followed by bolus epinephrine. Arterial pH in the sodium bicarbonate group was significantly higher at each sampling point (7.7 ± 0.1 vs 7.29 ± 0.06 at 1 min after drug, p<0.001). However, there were no statistically or clinically significant differences in coronary perfusion pressure between the groups at any time: 29 ± 13 versus 32 ± 21 mm Hg 1 minute, and 22 ± 12 versus 26 ± 19 mm Hg 4 minutes after epinephrine for sodium bicarbonate and normal saline, respectively (p>0.7). Increased arterial pH (alkalemia) induced by high‐dose sodium bicarbonate administration did not improve the vasopressor effects of epinephrine during CPR in this canine model. These results suggest the limited value of administering sodium bicarbonate during CPR to improve the responsiveness to epinephrine.

Effect of dose on the nasal absorption of epinephrine during cardiopulmonary resuscitation

Abstract Delay in epinephrine administration during cardiopulmonary resuscitation (CPR) due to technical difficulties in obtaining an access site may be detrimental. To avoid this potential delay, we have previously shown that intranasal administration of phentolamine and epinephrine is a rapidly obtainable and feasible route of administration during CPR. The objective of this study was to determine the optimal dose of phentolamine and epinephrine to be administered during CPR. A randomized blinded dose ranging study was performed in a controlled laboratory environment. Thirty-six mongrel dogs were randomized to one of the following dosage regimens: phentolamine, 0.25 or 2.5 mg/kg/nostril; epinephrine, 0.075, 0.75, or 7.5 mg/kg/nostril. Phentolamine was administered intranasally 1 minute before the intranasal administration of epinephrine to improve absorption. Each dog underwent 3 minutes of ventricular fibrillation followed by 7 minutes of closed chest CPR. Epinephrine was administered at 3 minutes of CPR. Data from 26 dogs were included for analysis. Treatment B (0.25 and 7.5 mg/kg/nostril of phentolamine and epinephrine, respectively) produced the greatest elevation in coronary perfusion pressure (17 ± 11 vs 4 ± 3 mm Hg for the next highest group, P 5 5 ) versus 0% to 50% for the other groups (P

Brain Activation Patterns at Exhaustion in Rats That Differ in Inherent Exercise Capacity

In order to further understand the genetic basis for variation in inherent (untrained) exercise capacity, we examined the brains of 32 male rats selectively bred for high or low running capacity (HCR and LCR, respectively). The aim was to characterize the activation patterns of brain regions potentially involved in differences in inherent running capacity between HCR and LCR. Using quantitative in situ hybridization techniques, we measured messenger ribonuclease (mRNA) levels of c-Fos, a marker of neuronal activation, in the brains of HCR and LCR rats after a single bout of acute treadmill running (7.5–15 minutes, 15° slope, 10 m/min) or after treadmill running to exhaustion (15–51 minutes, 15° slope, initial velocity 10 m/min). During verification of trait differences, HCR rats ran six times farther and three times longer prior to exhaustion than LCR rats. Running to exhaustion significantly increased c-Fos mRNA activation of several brain areas in HCR, but LCR failed to show significant elevations of c-Fos mRNA at exhaustion in the majority of areas examined compared to acutely run controls. Results from these studies suggest that there are differences in central c-Fos mRNA expression, and potential brain activation patterns, between HCR and LCR rats during treadmill running to exhaustion and these differences could be involved in the variation in inherent running capacity between lines.

Effect of vehicle on the nasal absorption of epinephrine during cardiopulmonary resuscitation

Study Objectives. We have shown in previous studies that epinephrine administered intranasally is a feasible route of administration during cardiopulmonary resuscitation (CPR). To promote the absorption of epinephrine we administered phentolamine prior to epinephrine and used a bile salt as a vehicle to dissolve the epinephrine. The purpose of this study was to compare the effect of two different vehicles (bile salt vs surfactant) in promoting the absorption of nasally administered epinephrine during CPR and to determine their effects on the nasal mucosa.

Intrinsic aerobic capacity sets a divide for aging and longevity: Koch & Kemi-Rat models link exercise capacity with mortality

Rationale: Low aerobic exercise capacity is a powerful predictor of premature morbidity and mortality for healthy adults as well as those with cardiovascular disease. For aged populations, poor performance on treadmill or extended walking tests indicates closer proximity to future health declines. Together, these findings suggest a fundamental connection between aerobic capacity and longevity. Objectives: Through artificial selective breeding, we developed an animal model system to prospectively test the association between aerobic exercise capacity and survivability (aerobic hypothesis). Methods and Results: Laboratory rats of widely diverse genetic backgrounds (N:NIH stock) were selectively bred for low or high intrinsic (inborn) treadmill running capacity. Cohorts of male and female rats from generations 14, 15, and 17 of selection were followed for survivability and assessed for age-related declines in cardiovascular fitness including maximal oxygen uptake (VO2max), myocardial function, endurance performance, and change in body mass. Median lifespan for low exercise capacity rats was 28% to 45% shorter than high capacity rats (hazard ratio, 0.06; P<0.001). VO2max, measured across adulthood was a reliable predictor of lifespan (P<0.001). During progression from adult to old age, left ventricular myocardial and cardiomyocyte morphology, contractility, and intracellular Ca2+ handling in both systole and diastole, as well as mean blood pressure, were more compromised in rats bred for low aerobic capacity. Physical activity levels, energy expenditure (VO2), and lean body mass were all better sustained with age in rats bred for high aerobic capacity. Conclusions: These data obtained from a contrasting heterogeneous model system provide strong evidence that genetic segregation for aerobic exercise capacity can be linked with longevity and are useful for deeper mechanistic exploration of aging.

Intrinsic Aerobic Capacity Sets a Divide for Aging and LongevityNovelty and Significance

Rationale: Low aerobic exercise capacity is a powerful predictor of premature morbidity and mortality for healthy adults as well as those with cardiovascular disease. For aged populations, poor performance on treadmill or extended walking tests indicates closer proximity to future health declines. Together, these findings suggest a fundamental connection between aerobic capacity and longevity. Objectives: Through artificial selective breeding, we developed an animal model system to prospectively test the association between aerobic exercise capacity and survivability (aerobic hypothesis). Methods and Results: Laboratory rats of widely diverse genetic backgrounds (N:NIH stock) were selectively bred for low or high intrinsic (inborn) treadmill running capacity. Cohorts of male and female rats from generations 14, 15, and 17 of selection were followed for survivability and assessed for age-related declines in cardiovascular fitness including maximal oxygen uptake (VO2max), myocardial function, endurance performance, and change in body mass. Median lifespan for low exercise capacity rats was 28% to 45% shorter than high capacity rats (hazard ratio, 0.06; P<0.001). VO2max, measured across adulthood was a reliable predictor of lifespan (P<0.001). During progression from adult to old age, left ventricular myocardial and cardiomyocyte morphology, contractility, and intracellular Ca2+ handling in both systole and diastole, as well as mean blood pressure, were more compromised in rats bred for low aerobic capacity. Physical activity levels, energy expenditure (VO2), and lean body mass were all better sustained with age in rats bred for high aerobic capacity. Conclusions: These data obtained from a contrasting heterogeneous model system provide strong evidence that genetic segregation for aerobic exercise capacity can be linked with longevity and are useful for deeper mechanistic exploration of aging.