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Biomedical subjects

Tom L Broderick

Publications and source records attributed to Tom L Broderick.

14 recordsLinked to original sources
PubMed2006

MgSO4 prevents left ventricular dysfunction in an animal model of preeclampsia.

OBJECTIVE: We hypothesized that cardiac function would be reduced in a pregnant rat model of preeclampsia induced by L-NAME, a NOS inhibitor, and be reversed with magnesium sulfate prophylaxis. STUDY DESIGN: Female Sprague-Dawley rats were bred in-house. On gestational day 17, rats were anesthetized and osmotic minipumps were implanted to continuously deliver saline, L-NAME, or L-NAME and MgSO4. On gestational day 21, hearts were isolated and perfused in the working mode using Krebs Henseleit buffer. RESULTS: Pregnant rats treated with L-NAME displayed significant hypertension compared to the saline-treated controls (P < 0.05). Moreover, cardiac output and cardiac work were significantly reduced in the L-NAME-treated rats compared to controls (P < 0.05). In the L-NAME-treated rats given MgSO4, cardiac function remained normal. CONCLUSION: Cardiac function is depressed in an animal model of preeclampsia induced by L-NAME infusion. MgSO4 prevented the reduction in cardiac function and is clearly beneficial in preserving normal heart function in preeclampsia.

Animals↗
PubMed2006

Effect of a novel molybdenum ascorbate complex on ex vivo myocardial performance in chemical diabetes mellitus.

BACKGROUND: The insulin-like action of metal complexes on target tissues, including the heart, has been reported in experimental diabetes mellitus. Since streptozotocin-induced diabetes is associated with insulin deficiency and left ventricular dysfunction, this study was designed to determine whether the novel metal complex molybdenum ascorbate [MoO(2)(aa)(2)] would improve cardiac function in this model of diabetes. METHODS: Diabetes was induced in Sprague-Dawley rats (n = 6) following an intravenous injection of streptozotocin (60 mg/kg). After 8 weeks of diabetes, cardiac function was determined in isolated working hearts perfused with 11 mmol/L glucose, 1.2 mmol/L palmitate and 3% albumin. MoO(2)(aa)(2 )was added directly into the perfusate of working hearts at a concentration of 200 micromol/L for a period of 30 minutes. Age-matched control rats served as controls (n = 6). RESULTS: Cardiac function, expressed as heart rate (HR) and aortic flow, was significantly decreased in diabetic hearts compared with control hearts. The diabetic state was associated with 23% and 60% reductions in HR and aortic flow, respectively. Short-term addition of MoO(2)(aa)(2) was beneficial and partially prevented the attenuation in diabetic rat heart function. MoO(2)(aa)(2 )increased HR by 15%, while aortic flow was increased by 85%. In control hearts, MoO(2)(aa)(2) had no effect on HR and increased aortic flow by 12%. CONCLUSION: This study extends previous observations on the benefit of metal complexes in experimental diabetes. Our results indicate that short-term treatment with MoO(2)(aa)(2) partially reversed the left ventricular dysfunction associated with the streptozotocin model of diabetes.

Animals↗
PubMed2006

Hypocarnitinaemia induced by sodium pivalate in the rat is associated with left ventricular dysfunction and impaired energy metabolism.

Carnitine is a naturally occurring compound that is essential in energy metabolism of the mammalian heart. In addition to its essential role in facilitating beta-oxidation, carnitine eliminates excess toxic acyl residues and regulates the mitochondrial acetyl coenzyme A (CoA)/CoA ratio. Thus, it is not surprising that patients with carnitine deficiency syndromes exhibit defects in energy metabolism and in some cases demonstrate left ventricular dysfunction. Pivalic acid is commonly used to create prodrugs, such as pivampicillin and pivmecillinam, to facilitate enteral absorption and increase oral bioavailability. Pivalic acid released from the drug following absorption readily forms an ester with carnitine, which is then excreted as pivaloylcarnitine. Sustained loss of carnitine in the form of this ester induces a state of carnitine deficiency, exemplified by low plasma and tissue carnitine content. This review examines the effects in the rat of short- and long-term sodium pivalate treatment on: (1) cardiac carnitine content; (2) in vitro mechanical function; (3) markers of glycolytic and fatty acid metabolism; and (4) energy substrate metabolism. Treatment with sodium pivalate induces a gradual loss of cardiac carnitine content for up to 12 weeks. Doubling the duration of treatment is not associated with any further decrease in cardiac carnitine content. While heart function following short-term treatment (2 weeks) is normal under aerobic conditions, impaired recovery of function following ischaemia is seen. In contrast, long-term treatment (11-28 weeks) is associated with impaired heart function, which is dependent on workload and substrate availability. Impaired heart function is also associated with reductions in activity of 3-hydroxyacyl CoA dehydrogenase and rates of fatty acid oxidation. However, to maintain adenosine triphosphate production, glucose metabolism, expressed as hexokinase activity and glucose oxidation, is increased in carnitine-deficient hearts. Hearts from sodium pivalate-treated animals demonstrate a cardiomyopathy that is dependent on duration of treatment, workload and substrate supply. This model of hypocarnitinaemia may thus be useful to study the metabolic and cardiac consequences of carnitine-deficiency syndromes.

Animals↗
PubMed2004

Cardiac dysfunction in the euglycemic diabetic-prone BB Wor rat.

The purpose of this study was to examine cardiac function in the diabetic-prone BB Wor rat. The study involved 2 groups: diabetic resistant control littermates of BB rats and diabetic-prone BB rats that had yet to demonstrate overt signs of diabetes. Hearts from these animals were isolated and cardiac function examined in response to incremental increases in left atrial filling pressure. Hearts were also perfused at an increased aortic afterload resistance with buffer consisting of glucose alone or glucose in the presence of palmitate. Hearts from diabetic-prone rats exhibited depressed contractility and ventricular relaxation at high filling pressures. Ventricular function, expressed as cardiac output, was also depressed in diabetic-prone rats perfused at increased afterload resistance, but only in the presence of palmitate. Our results indicate that hearts from diabetic-prone BB Wor rats demonstrate abnormalities in contractile performance and thus may be a useful model for the study of cardiac function in the prediabetic state.

Animals↗
PubMed2004

Effect of gender and fatty acids on ischemic recovery of contractile and pump function in the rat heart.

BACKGROUND: Clinical studies have shown that the incidence of heart disease is lower in premenopausal women compared with men. However, women are at increased risk of developing cardiac dysfunction after myocardial infarction. During a myocardial infarction, plasma levels of free fatty acids increase and contribute to postischemic left ventricular dysfunction. OBJECTIVE: The purpose of this study was to examine the effect of increasing concentrations of fatty acids on recovery of contractile parameters and pump function after 20 minutes of global ischemia and 30 minutes of reperfusion in male and female rat hearts. METHODS: Hearts were isolated and perfused with 5.5 mM glucose and 50 muU/mL insulin alone or in the presence of 0.4 or 1.2 mM palmitate. To determine whether inhibition of fatty acid metabolism was accompanied by an improvement in recovery of cardiac function after ischemia, the inhibitor of mitochondrial palmitate uptake, oxfenicine (2 mM), was used in female hearts perfused with 1.2 mM palmitate. RESULTS: Twenty-two female and 21 age-matched male rats were used. In hearts perfused under normoxic conditions, 1.2 mM palmitate reduced cardiac output and systolic pressure in female rat hearts. Heart rate, ventricular contraction, and ventricular relaxation were similar between male and female hearts and were not altered by fatty acids. After transient ischemia, all contractile parameters in male hearts returned to preischemic levels, regardless of the level of fatty acids in the perfusate. Recovery of female hearts, however, was inhibited by fatty acids. Aortic flow, ventricular contraction, ventricular relaxation, and systolic pressure were significantly lower in female hearts compared with male hearts in the presence of 1.2 mM palmitate (P < 0.05). In female hearts perfused with oxfenicine, however, recovery of systolic pressure, cardiac output, and ventricular contraction was significantly increased compared with control hearts (P < 0.05). CONCLUSIONS: Our data indicate that the female myocardium is more sensitive to the effects of fatty acids after global ischemia compared with male hearts. This confirms that a gender effect exists in the recovery of heart function after ischemia, which can be accounted for by differences in ventricular contraction and relaxation.

Analysis of Variance↗
PubMed2004

Effects of propionyl-carnitine on mitochondrial respiration and post-ischaemic cardiac function in the ischaemic underperfused diabetic rat heart.

BACKGROUND AND OBJECTIVE: Carnitine and its derivatives, namely propionyl-carnitine (PC), have been shown to protect cardiac metabolism and function in diabetes mellitus and ischaemic heart disease. Since diabetes is associated with abnormalities in mitochondrial metabolism of fuels, we examined the effects of PC on mitochondrial respiration in ischaemic hearts from streptozotocin-diabetic rats. METHODS: Diabetes was induced in Sprague-Dawley rats by an intravenous injection of streptozotocin. Following the diagnosis of diabetes, oral PC treatment was initiated for a period of 6 weeks. After treatment, cardiac function was determined from working hearts perfused under aerobic conditions and in a separate group of hearts subjected to ischaemia and reperfusion. Mitochondrial respiration was determined under aerobic conditions and following low-flow ischaemia. RESULTS: Rates of state 3 mitochondria respiration with pyruvate were significantly lower in diabetic (n = 4) hearts compared with control (n = 6) hearts (80 +/- 5 vs 112 +/- 5 nanoatoms O2/mg protein/min, respectively), but those with palmitoylcarnitine were similar (101 +/- 11 vs 106 +/- 6 nanoatoms O2/mg protein/min). Diabetic rat heart (n = 8) function, expressed as rate pressure product, was also significantly decreased compared with control (n = 8) hearts (21.5 +/- 1.0 vs 29.5 +/- 0.9 beats x mm Hg x 10(-3)/min, respectively). In PC-treated diabetic (n = 6) hearts, state 3 respiration with pyruvate was increased, and a marked improvement in left ventricular function from 21.5 +/- 1.0 to 26.0 +/- 0.6 beats x mm Hg x 10(-3)/min was observed. During low-flow ischaemia, state 3 respiration with pyruvate remained lower in diabetic (n = 5) hearts compared with control (n = 5) hearts (64 +/- 3 vs 46 +/- 5 nanoatoms O2/mg protein/min, respectively). Following treatment with PC (n = 4), however, respiration with this substrate was significantly increased to 57 +/- 4 nanoatoms O2/mg protein/min. PC was also associated with a significant improvement in cardiac function in reperfused diabetic rat (n = 4) hearts (18.4 +/- 0.2 beats x mm Hg x 10(-3)/min). CONCLUSION: Our results showed that PC has a beneficial effect on cardiac function and increases ischaemic tolerance of the diabetic rat heart. This beneficial effect of PC can be explained, in part, as an improvement in mitochondrial metabolism of pyruvate during the actual ischaemic period.

Animals↗
PubMed2003

Prevention of ischemic heart failure by exercise in spontaneously diabetic BB Wor rats subjected to insulin withdrawal.

Poor metabolic control resulting from insulin withdrawal in chronic type 1 diabetic rats results in ischemic heart failure. In the present study, we determined whether heart failure occurs in acute type 1 diabetic rats following insulin withdrawal and if prior exercise training can prevent this dysfunction. Four-week-old diabetic prone BB Wor rats were either sedentary or moderately exercised by daily treadmill running. Training was discontinued at the onset of diabetes. Isolated working rat heart function was then assessed in the following groups: diabetic resistant, uncontrolled sedentary diabetic (USD), controlled sedentary diabetic (CSD), uncontrolled trained diabetic (UTD), and controlled trained diabetic (CTD) rats. To induce an uncontrolled state, insulin treatment was withheld for 24 hours. During increased metabolic demand and reperfusion following ischemia, heart rate, contractility, and cardiac output were depressed in hearts from USD animals. Treatment with insulin prevented the depressions in cardiac performance from occurring. Hearts from UTD rats perfused under these conditions showed comparable cardiac function to that seen in the controlled state. This occurred despite poor metabolic control, reflected by elevated levels of plasma glucose and free fatty acids. Our results indicate that metabolic deteriorations in acute diabetes result in ischemic heart failure. However, this cardiac dysfunction can be prevented with exercise training.

Animals↗
PubMed2003

Depression in mechanical function following ischemia in the female rat heart: role of fatty acids and altered mitochondrial respiration.

BACKGROUND: Clinical studies have shown that the incidence of myocardial infarction is lower in women compared to men. However, following a myocardial infarct, women are at increased risk of developing ventricular dysfunction. OBJECTIVE: High levels of free fatty acids, observed in the clinical setting of ischemia, impair recovery of mechanical function during reperfusion of ischemic hearts. This study was designed to determine whether hearts from female rats are more sensitive to ischemia than male hearts when supplied with relevant levels of fatty acids. METHODS: Hearts from male and female Sprague-Dawley rats were isolated and perfused in the working mode with 5.5 mM glucose and 50 microU/mL insulin alone or in the presence of 1.2 mM palmitate. Cardiac function, expressed as heart rate-pressure product (RPP), was measured under preischemic conditions and during reperfusion following a period of transient global ischemia. RESULTS: Following the ischemic insult, RPP of male hearts returned to preischemic levels regardless of the substrates used. RPP of female hearts perfused with glucose alone also recovered to preischemic function. However, in female hearts perfused with the fatty acid, recovery of RPP was significantly lower compared to the female hearts perfused with glucose alone. In these hearts, recovery during reperfusion was only approximately 60% of preischemic function. CONCLUSION: Our results indicate that the sensitivity of the female myocardium to postischemic dysfunction is enhanced in the presence of fatty acids, suggesting that a gender effect on recovery of cardiac function following ischemia exists.

Animals↗
PubMed2002

Caloric restriction restores the cardioprotective effect of preconditioning in the rat heart.

Preconditioning (PC) describes the observation that brief periods of ischemia paradoxically protect the heart and limit necrosis caused by a subsequent more prolonged period of ischemia. However, the PC response is attenuated in hearts from 9- to 12-month-old Sprague-Dawley rats, as compared to young adults. This study determined whether long-term caloric restriction (CR) could preserve the PC response, since CR increases ischemic tolerance in these hearts. Following 6 months of CR, isolated hearts underwent PC followed by ischemia and reperfusion. In contrast to control hearts in which PC response was attenuated, PC in CR hearts was clearly of benefit. In these hearts, aortic flow was increased resulting in a dramatic improvement of cardiac output. Our study suggests that CR is effective in preserving the PC response.

Animals↗
PubMed2002

Effects of chronic caloric restriction on mitochondrial respiration in the ischemic reperfused rat heart.

Dietary restriction increases life span and delays the development of age-related diseases in rodents. We have recently demonstrated that chronic dietary restriction is beneficial on recovery of heart function following ischemia. We studied whether the metabolic basis of this benefit is associated with alterations in mitochondrial respiration. Male Wistar rats were assigned to an ad libitum-fed (AL) group and a food restricted (FR) group, in which food intake was reduced to 55% of the amount consumed by the AL group. Following an 8-month period of restricted caloric intake, isolated working hearts perfused with glucose and high levels of fatty acids were subjected to global ischemia followed by reperfusion. At the end of reperfusion, total heart mitochondria respiration was assessed in the presence of pyruvate, tricarboxylic acid intermediates, and palmitoylcarnitine. Recovery of heart function following ischemia was greater in FR hearts compared to AL hearts. Paralleling these changes in heart function was an increase in state 3 respiration with pyruvate. The respiratory control ratios in the presence of pyruvate and tricarboxylic acid intermediates were higher in FR hearts compared to AL hearts, indicating well-coupled mitochondria. Overall energy production, expressed as the ADP:O ratio and the oxidative phosphorylation rate, was also improved in FR hearts. Our results indicate that the beneficial effect of FR on recovery of heart function following ischemia is associated with changes in mitochondrial respiration.

Adenosine Diphosphate↗
PubMedDate not supplied

Exercise training restores abnormal myocardial glucose utilization and cardiac function in diabetes.

BACKGROUND: Clinical and experimental studies have shown that a reduction in myocardial glucose utilization is a factor contributing to diabetic cardiomyopathy. This study determined whether exercise training could prevent the depression in glucose utilization observed in the diabetic rat heart. METHODS: Diabetes was induced in Sprague-Dawley rats by an intravenous injection of streptozotocin (60 mg/kg). After 10 weeks of treadmill running, exogenous myocardial glucose utilization and cardiac function were determined in isolated working hearts perfused under aerobic conditions and then subjected to a 60-min period of low-flow ischemia followed by reperfusion. RESULTS: Compared to aerobically perfused sedentary control hearts, rates of myocardial glucose oxidation and glycolysis were lower in diabetic hearts. Diabetes was also characterized by a pronounced decrease in cardiac function. Following exercise training, rates of myocardial glucose oxidation and glycolysis were restored and cardiac performance was improved compared to sedentary diabetic hearts. During low-flow ischemia, the decrease in glycolysis observed in hearts of sedentary diabetic rats was attenuated following exercise training. Following ischemia, glucose oxidation and glycolysis returned to preischemic levels in all groups. However, hearts from trained diabetic animals had higher rates of glucose oxidation compared to their respective sedentary group. This was accompanied by an enhanced recovery of heart function following ischemia. CONCLUSIONS: Our results indicate that exercise training is effective in preventing the depression in myocardial glucose metabolism observed in the diabetic rat. This may explain the benefits of exercise in preventing cardiac dysfunction in diabetes.

Animals↗
PubMedDate not supplied

Whole-body heat shock protects the ischemic rat heart by stimulating mitochondria respiration.

Whole-body heat shock (HS) leads to an enhancement of postischemic mechanical function and an improvement in glucose use by the rat heart. Here, we examine the effect of HS on isolated mitochondrial metabolism during reperfusion in the working rat heart. Rats were anesthetized, and their body temperature was raised to 41-42 degrees C for 15 min. Control rats were treated the same way but were not exposed to hyperthermia. Twenty-four hours after HS or sham treatment, rats were reanesthetized and the hearts were removed for perfusion with Krebs-Henseleit buffer, containing 11 mmol glucose/L and 1.2 mmol palmitate/L prebound to 3% albumin. Hearts were subjected to 25 min of global ischemia followed by 30 min of reperfusion. At the end of reperfusion, heart mitochondria were isolated using differential centrifugation and respiration measured in the presence of pyruvate, glutamate, or palmitoylcarnitine. Hearts subjected to HS showed an enhanced recovery of function, expressed as aortic flow, during the reperfusion period, compared with sham hearts. This improved functional status was associated with a significant increase in state 3 respiration in the presence of pyruvate, glutamate, or palmitoylcarnitine. These results show that HS offers protection against ischemic damage, and that a possible mechanism might be the enhanced myocardial metabolism of fuels.

Animals↗