Short-term carnitine deficiency does not alter aerobic rat heart function but depresses reperfusion recovery after ischemia.

Clinical and experimental studies have shown that long-term carnitine deficiency is often associated with cardiomyopathy and ischemic failure. The present study was designed to determine whether cardiac dysfunction is seen in an experimental model of short-terrm carnitine deficiency. Carnitine deficiency was induced in Sprague-Dawley rats by supplementing the drinking water with sodium pivalate for a period of 2 weeks. This resulted in a 25% depletion of total myocardial carnitine content. When isolated working hearts from these animals were paced and subjected to increments in left atrial filling pressure, there were no differences in mechanical function compared with control hearts. Following no-flow ischemia, however, recovery of cardiac output and relaxation parameters was depressed in hearts from pivalate-treated animals. Under these conditions, L-carnitine prevented the depressions of function from occurring. Our results show that short-term carnitine deficiency is not associated with cardiac dysfunction under normoxic conditions. However, hearts from pivalate-treated animals are more susceptible to ischemic injury and thus may prove to be useful for the study of metabolic and functional aspects of carnitine deficiency.

Q methodology: a new way of assessing employee satisfaction.

As yet another nursing shortage faces the country, the issue of the satisfaction of nurses again becomes of critical concern to nursing managers in the interest of staff retention. The authors describe the use of the statistical technique Q methodology to assess the needs of nurses and other medical staff at a level one, tertiary care emergency department in the United States. Using the Q method, the authors were able to identify different, unique viewpoints concerning employee needs among the study population, as well as commonly shared views. This level of detail, not obtainable using more traditional statistical techniques, can aid in the design of more effective strategies aimed at fulfilling the needs of an organization's staff to increase their satisfaction.

Effects of propionyl-L-carnitine on isolated mitochondrial function in the reperfused diabetic rat heart.

The effects of propionyl-L-carnitine (PLC) on isolated mitochondrial respiration in the ischemic reperfused diabetic heart were studied. Oral PLC treatment of STZ-diabetic rats was initiated for a period of 6 weeks. After treatment, isolated working hearts from diabetic rats were perfused under aerobic conditions then subjected to 25 min of no-flow ischemia followed by 15 min of aerobic reperfusion. At the end of reperfusion, heart mitochondria was isolated using differential centrifugation and respiration measured in the presence of pyruvate, glutamate, and palmitoylcarnitine. Our results indicate that diabetes was characterized by a pronounced decrease in heart function under aerobic conditions as well as during reperfusion following ischemia. Treatment with PLC resulted in a significant improvement in heart function under these conditions. The depressions in state 3 mitochondrial respiration with both pyruvate and glutamate seen in reperfused hearts from diabetic rats were prevented by PLC. State 3 respiration in the presence of palmitoylcarnitine was also improved in the ischemic reperfused diabetic rat heart. Our results show that PLC improves recovery of mechanical function following ischemia in the diabetic rat heart. The beneficial effects of PLC are associated with enhanced mitochondrial oxidation of fuels.

Using Q methodology to assess the needs of emergency medicine support staff employees.

The support staff members of any Department of Emergency Medicine perform a plethora of tasks that are crucial to the productivity of both individual physicians and the department as a whole. It is important to ensure that the personal and professional needs of the support staff are being met. This report describes the use of a relatively new statistical technique, Q methodology, to elucidate the needs of the support staff. This method allowed the investigators to quantitatively reveal the presence of two distinct viewpoints on employee needs among the support staff. Additionally, opinions that were held by the employees concerning their needs were identified. These results allowed for strategies to be tailored to both the individual and the group. The results indicate that Q methodology can have widespread application in the relatively new area of health care quality research.

Propionyl-L-carnitine effects on postischemic recovery of heart function and substrate oxidation in the diabetic rat.

Previous studies have shown that propionyl-L-carnitine (PLC) can exert cardiac antiischemic effects in models of diabetes. In the nonischemic diabetic rat heart, PLC improves ventricular function secondary to stimulation in the oxidation of glucose and palmitate. Whether this increase in the oxidation of these substrates can explain the beneficial effects of PLC in the ischemic reperfused diabetic rat heart has yet to be determined. Diabetes was induced in male Sprague-Dawley rats by an intravenous injection of streptozotocin (60 mg/kg). Treatment was initiated by supplementing the drinking water with propionyl-L-carnitine at the concentration of 1 g/L. After a 6-week treatment period, exogenous substrate oxidation and recovery of mechanical function following ischemia were determined in isolated working hearts. In aerobically perfused diabetic hearts, compared with those of controls, rates of glucose oxidation were lower, but those of palmitate oxidation were similar. Diabetes was also characterized by a pronounced decrease in heart function. Following treatment with by propionyl-L-carnitine, however, there was a marked increase in rates at which glucose and palmitate were oxidized by diabetic hearts and a significant improvement in heart performance. Postischemic recovery of function in diabetic hearts was also improved with PLC. This improvement in contractile function was accompanied by an increase in both glucose and palmitate oxidation. Our findings show that postischemic diabetic rat heart function can be improved following chronic PLC treatment. This beneficial effect of propionyl-L-carnitine can be explained, in part, by an improvement in the oxidation of glucose and palmitate.

Effect of palmitate on carbohydrate utilization and Na/K-ATPase activity in aortic vascular smooth muscle from diabetic rats.

Several investigators have reported that carbohydrate metabolism is suppressed in blood vessels from diabetic (Db) rats. However, it is not known if metabolites from the reciprocal increase in oxidation of long-chain fatty acids that accompanies insulin-deficiency exacerbates the suppression of this pathway in the Db blood vessels. Such inhibition may have particularly deleterious consequences in vascular smooth muscle since aerobic glycolysis is believed to preferentially fuel the sarcolemmal Na/K ATPase in this tissue. Therefore, this study evaluated the effect of physiological (0.4 mM) and elevated (1.2 mM) concentrations of the long-chain fatty acid palmitate on both carbohydrate utilization and Na/K-ATPase activity in aorta from insulin-deficient Db rat. Thoracic aorta were removed from 10 week Db (streptozotocin 60 mg/Kg , i.v.) or control (C) rats and intima-media aortic preparations were incubated in the absence or presence of palmitate. Glycolysis (microM/g dry wt/h) and glucose oxidation (microM/g dry wt/h) were quantified using 3H-glucose and 14C-glucose, respectively. Na/K-ATPase activity was estimated by the measurement of 86rubidium uptake in the absence and presence of 2 mM ouabain. In the absence of exogenous palmitate, glycolysis (p < 0.05), glucose oxidation (p < 0.01) and the estimated ATP production from exogenous glucose were decreased in aorta from Db rat. However, despite this diminished rate of glycolysis, Na/K ATPase activity was similar in Db and C aorta. Palmitate (0.4 mM) inhibited Na/K ATPase activity and glucose oxidation to a similar extent in both Db and C but had no effect on glycolysis in either group. Elevation of palmitate to 1.2 mM had no additional inhibitory effect on glucose oxidation, Na/K ATPase activity or glycolysis in either the Db or C aorta. The metabolism of exogenous palmitate restored the ATP production in Db to control values. These data demonstrate that, despite the diminished glycolysis and glucose oxidation demonstrated in the Db tissue, Na/K ATPase activity was comparable in the C and Db aorta, in the absence or presence of exogenous long-chain fatty acid. Therefore, the accelerated oxidation of palmitate in diabetic vascular smooth muscle had no additional inhibitory effect on glycolysis or Na/K ATPase activity. These data suggest that Na/K ATPase activity in vascular smooth muscle is not impaired by the altered pattern of substrate utilization that occurs in insulin-deficient Db rats.

Carnitine deficiency-induced cardiomyopathy.

The results of clinical and animal studies suggest that a short term period of moderate secondary carnitine deficiency, in and of itself, does not have a major effect on the cardiac contractile function, although substrate oxidation may be altered. However, with longer durations of carnitine deficiency, alterations occur within the heart that may result in impaired contractile performance, particularly at high workloads. At this point, the mechanisms responsible for the cardiac depression are uncertain. We hypothesize that the alterations in substrate metabolism produced by the carnitine deficient state results in inadequate ATP production under high workload conditions which result in impaired cardiac contractile performance. Carnitine deficiency may also induce a number of changes in gene expression of key enzymes required for normal cardiac contractile function and metabolism.

Effects of oral vanadyl treatment on diabetes-induced alterations in the heart GLUT-4 transporter.

Vanadyl sulfate was administered orally during a 10-week trial period to streptozotocin-diabetic and control male rats to test the hypothesis that chronic vanadyl supplementation would prevent the decline in cardiac muscle cell glucose transporter protein (GLUT-4) that otherwise manifests in conjunction with insulin deficiency. Isolated cardiac myocytes and cardiac sarcolemmal vesicles were prepared from heart tissue of rats that had been maintained on the following regimens: untreated control, oral vanadyl-supplemented control (0.6 mg/ml), untreated diabetic (streptozotocin-induced; 60 mg/kg), and vanadyl-supplemented diabetic. Myocytes isolated from untreated diabetic rat hearts had decreased rates of glucose oxidation. Chronic, oral administration of vanadyl to diabetic rats maintained glucose oxidation rates of cardiac myocytes at control levels. Immunoblot analyses revealed that total cardiac myocyte and sarcolemmal GLUT-4 glucose transporter protein levels were significantly lower in the diabetic group relative to control. Vanadyl treatment of diabetic rats produced a normalization of both sarcolemmal GLUT-4 and total cardiac myocyte levels towards control levels. The reduction of GLUT-4 mRNA levels seen with untreated diabetes was also completely prevented with vanadyl treatment. These results demonstrate that chronic-oral vanadyl sulfate supplementation limits the decline in glucose oxidative capacity of cardiac myocytes that otherwise manifests in the untreated diabetic state. This action of vanadyl may occur via a mechanism that is linked to the preservation of sarcolemmal GLUT-4 protein levels.

Inhibition of nitric oxide synthase by L-NAME improves ventricular performance in streptozotocin-diabetic rats.

The overall goal of this study was to determine if activation of the nitric oxide synthetic pathway suppressed basal ventricular performance and the responsiveness to beta-adrenergic stimulation characteristic of cardiac function in the 8-week streptozotocin (60 mg/kg, i.v.) diabetic (STZ-Db) rat. Left ventricular performance was measured in isolated working hearts, before and at the peak response to 0.8 microM dobutamine, in the absence or presence of NG-nitro-L-arginine methyl ester (L-NAME, 1 mM), a non-selective inhibitor of nitric oxide synthase (NOS). Ventricular performance was suppressed in the STZ-Db heart under basal (decreased heart rate, cardiac output, aortic flow -dP/dt) and dobutamine-stimulated (diminished rise in +dP/dt and maximum systolic pressure) conditions. L-NAME had minimal effects on basal or dobutamine-stimulated ventricular performance in control hearts. In contrast, L-NAME infusion in hearts from STZ-Db returned the depressed heart rate to control values, which was correlated with an increase in aortic flow. In addition, the dobutamine-stimulated rise in maximum systolic pressure and +dP/dt were similar in the control and STZ-Db rats in the presence of l-NAME. Western blot analysis detected the presence of inducible nitric oxide synthase (NOS) and a significant (P<0.001) increase in the constitutive NOS in ventricular myocytes from STZ-Db rats. These data suggest that an increased production of nitric oxide by NOS in ventricular myocytes from STZ-Db animals suppressed basal ventricular performance and the responsiveness to beta-adrenergic stimulation in diabetic hearts.

The diabetic heart is more sensitive to ischemic injury.

Clinical studies have suggested that the diabetic heart is more sensitive to ischemic injury than the non-diabetic heart. However, results from a number of experimental studies using animal models of diabetes reported no change, increased or decreased sensitivity to ischemia. The purpose of this review is to discuss the possible explanations for this apparent discrepancy. Analysis of the conflicting literature on this subject reveals a pattern which suggests that the disparity of experimental findings stems from differences in the duration and severity of the diabetic state, the ischemic flow rate and whether fatty acids are provided as an exogenous substrate. It appears that short-term or mild diabetes is associated with decreased sensitivity to zero-flow ischemic injury. However, as the duration or severity of diabetes increases, this beneficial effect disappears. The diabetic heart also appears to be more vulnerable to injury during low-flow ischemia and when elevated fatty acids are present.

Na+/K(+)-ATPase activity in vascular smooth muscle from streptozotocin diabetic rat.

OBJECTIVES: Insulin-deficient diabetes impairs carbohydrate metabolism in a variety of tissues. Vascular smooth muscle may be susceptible to the diabetes-induced disturbance in glycolysis since Na+/K(+)-ATPase in this tissue preferentially utilizes ATP generated by glycolysis. The purpose of this study was to determine if chronic exposure to the metabolic alterations associated with insulin-deficient diabetes directly inhibited Na+/K(+)-ATPase activity, or its regulation, in vascular smooth muscle. METHODS: Diabetes was induced by intravenous administration of streptozotocin (60 mg/kg). After 12 weeks, Na+/K(+)-ATPase activity in aorta and superior mesenteric artery was evaluated under a variety of conditions. Na+/K(+)-ATPase was estimated by measuring the influx of rubidium-86 (86Rb) in the presence or absence of the Na+/K(+)-ATPase inhibitor, ouabain. The metabolism of [3H]glucose and [14C]glucose was used to estimate glycolysis or glucose oxidation, respectively. RESULTS: Glycolysis and glucose oxidation were decreased in aortic smooth muscle (27 and 34%, respectively). An intact endothelium was associated with a marked decrease in ouabain-sensitive (pump-mediated) 86Rb uptake in diabetic aorta. However, ouabain-sensitive 86Rb uptake was similar in de-endothelialized aorta and superior mesenteric artery from diabetic and non-diabetic rats under both unstimulated conditions and during maximal stimulation. Removal of glucose or oxygen reduced ouabain-sensitive 86Rb uptake to a similar extent in both groups. In contrast, the receptor-mediated stimulation of ouabain-sensitive 86Rb uptake by insulin was decreased. CONCLUSIONS: These results suggest that intrinsic Na+/K(+)-ATPase activity is not diminished in diabetic vascular smooth muscle under physiological conditions and that the impairment of cellular metabolism in diabetic blood vessels does not limit stimulation of Na+/K(+)-ATPase activity. However, modulation of Na+/K(+)-ATPase activity by endothelial factors or insulin appears to be altered in aorta from diabetic rats.

Exercise training increases sarcolemmal GLUT-4 protein and mRNA content in diabetic heart.

This study determined whether dynamic exercise training of diabetic rats would increase the expression of the GLUT-4 glucose transport protein in prepared cardiac sarcolemmal membranes. Four groups were compared: sedentary control, sedentary diabetic, trained control, and trained diabetic. Diabetes was induced by intravenous streptozotocin (60 mg/kg). Trained control and diabetic rats were run on a treadmill for 60 min, 27 m/min, 10% grade, 6 days/wk for 10 wk. Sarcolemmal membranes were isolated by using differential centrifugation, and the activity of sarcolemmal K(-)-p-nitrophenylphosphatase (pNPPase; an indicator of Na(+)-K(+)-adenosinetriphosphatase activity) was quantified. Hearts from the sedentary diabetic group exhibited a significant depression of sarcolemmal pNPPase activity. Exercise training did not significantly alter pNPPase activity. Sedentary diabetic rats exhibited an 84 and 58% decrease in GLUT-4 protein and mRNA, respectively, relative to control rats. In the trained diabetic animals, sarcolemmal GLUT-4 protein levels were only reduced by 50% relative to control values, whereas GLUT-4 mRNA were returned to control levels. The increase in myocardial sarcolemmal GLUT-4 may be beneficial to the diabetic heart by enhancing myocardial glucose oxidation and cardiac performance.

Heat stress induces rapid recovery of mechanical function of ischemic fatty acid perfused hearts by stimulating glucose oxidation during reperfusion.

Whole-body heat stress (HS) in rats leads to the accumulation of myocardial heat shock proteins and subsequent protection against ischemic injury in glucose-perfused hearts. We determined whether HS treatment would confer protection against ischemia in hearts perfused with high levels of fatty acids. In addition, since fatty acids can potentiate ischemic injury by inhibiting glucose metabolism, the effects of HS on glucose utilization were also determined. Anesthetized rats were subjected to whole-body hyperthermia by raising body temperature to 41-42 degrees C 15 min. Twenty four hours later, their hearts were perfused with buffer containing either 11 mM glucose alone or 11 mM glucose and 1.2 mM palmitate, and then subjected to ischemic conditions followed by reperfusion. In hearts perfused with glucose only, HS improved aortic flow (expressed as percent change from preischemic aortic flow) late into the reperfusion period. Rates of overall glucose utilization under these conditions were similar between control and HS hearts. When hearts were perfused with 1.2 mM palmitate, the benefits of HS on aortic flow occurred at the onset of the reperfusion period. This beneficial effect was associated with a significant increase in glucose oxidation. Our results show that HS induces a faster rate of recovery in fatty acid perfused hearts but does not offer more protection against ischemic damage when compared with hearts perfused with glucose as a sole substrate.

L-propionylcarnitine enhancement of substrate oxidation and mitochondrial respiration in the diabetic rat heart.

This study was designed to determine whether L-propionylcarnitine (LPC) treatment is beneficial in preventing the depression in cardiac function from occurring in chronic diabetes. Diabetes was induced by tail vein injection of streptozotocin (60 mg/kg). Two weeks later, treatment was initiated by supplementing the drinking water with LPC at the concentration of 1 mg/ml. Following a 6-week treatment period, myocardial substrate utilization and cardiac function were determined in isolated working hearts. In a separate group of hearts, the effects of LPC treatment on mitochondrial respiration were also determined. The results showed that diabetic hearts, compared with those of controls, oxidized glucose at a much lower rate, but oxidized palmitate at a similar rate. The effect of diabetes compared a controls was also characterized by a pronounced decrease in cardiac pump function. Following treatment with LPC, however, there was a marked increase in the rates at which glucose and palmitate were oxidized by diabetic hearts, and a significant improvement in cardiac pump performance. In addition, the depression of cardiac mitochondrial respiration seen in diabetes was prevented with LPC treatment. Our findings show that the depression of cardiac pump function by diabetes can be prevented with chronic LPC treatment. Possible mechanisms for this beneficial effect include an energetically favorable shift in glucose and fatty acid metabolism.

L-carnitine improvement of cardiac function is associated with a stimulation in glucose but not fatty acid metabolism in carnitine-deficient hearts.

OBJECTIVES: Increasing myocardial carnitine content can improve heart function in patients with carnitine deficiency. We were interested in determining the effects of L-carnitine on cardiac function and substrate metabolism in a rat model of carnitine deficiency. METHODS: Carnitine deficiency was induced in male Sprague-Dawley rats by supplementing the drinking water with 20 mM sodium pivalate. Control animals received an equimolar concentration of sodium bicarbonate. Following treatment, cardiac function and myocardial substrate utilization were determined in isolated working hearts perfused with glucose and relevant levels of fatty acids. To increase tissue levels of carnitine, hearts were perfused with 5 mM L-carnitine for a period of 60 min. RESULTS: Hearts from sodium pivalate-treated animals demonstrated a 60% reduction in total heart carnitine content, depressions in cardiac function and rates of palmitate oxidation, and elevated rates of glycolysis compared to control hearts. Treatment with L-carnitine increased total carnitine content and reversed the depression in cardiac function seen in carnitine-deficient hearts. However, this was not associated with any improvement in palmitate oxidation. Rates of glycolysis and glucose oxidation, on the other hand, were increased with L-carnitine. CONCLUSIONS: Our findings indicate that acute L-carnitine treatment is of benefit to cardiac function in this model of secondary carnitine deficiency by increasing overall glucose utilization rather than normalizing fatty acid metabolism.

The emergency department log as a simple injury-surveillance tool.

STUDY OBJECTIVE: To describe the development of an injury-surveillance system based on the emergency department log. SETTING: An ED with 40,000 visits annually, tertiary care center. PARTICIPANTS: All patients to our ED during a 6-month period. ED logs are used to collect basic information such as demographics, chief complaint, mode of arrival, and disposition. Our log was modified for collection of injury-related information such as whether the ED visit was because of an injury and, if so, the mechanism of injury. A list of 16 mechanism-of-injury codes was developed on the basis of review of existing literature and on a 1-month review of injuries in our population. The ED log data were entered into a database, and descriptive analysis was performed. RESULTS: A list of mechanisms of injury was developed that, when implemented, was successful in coding 93% of injured patients in our ED population. The expansion of the ED log for collection of injury data required minimal training and cost. An example of the data obtained is presented to demonstrate the type of information available. Of the 18,742 patients, the ED log identified 5,067 patients (27%) as having been injured. Most were male (2,972 of 5,067 [59%]), and most were between 15 and 40 years of age (2,857 of 5,067 [61%]). Common mechanisms of injury included falls (907 of 5,067 [19%]), transportation (706 of 5,067 [15%]), cuts or punctures (332 of 5,067 [7%]), sports (323 of 5,067 [7%]), and assaults (245 of 5,067 [5%]). CONCLUSION: With minimal training and cost, the ED log can be adapted for collection of injury data on all patients seen in the ED.

Fatty acid oxidation and cardiac function in the sodium pivalate model of secondary carnitine deficiency.

Carnitine-deficiency syndromes are often associated with alterations in lipid metabolism and cardiac function. The present study was designed to determine whether this is also seen in an experimental model of carnitine deficiency. Carnitine deficiency was induced in male Sprague-Dawley rats supplemented with sodium pivalate for 26 to 28 weeks. This treatment resulted in nearly a 60% depletion of myocardial total carnitine content as compared with control hearts. When isolated working hearts from these animals were perfused with 5.5 mmol/L glucose and 1.2 mmol/L palmitate and subjected to incremental increases in left-atrial filling pressures, cardiac function remained dramatically depressed. The effects of carnitine deficiency on glucose and palmitate utilization were also assessed in hearts perfused at increased workload conditions. At this workload, function was depressed in carnitine-deficient hearts, as were rates of 1.2-mmol/L [U-14C]-palmitate oxidation, when compared with control hearts (544 +/- 37 vs 882 +/- 87 nmol/g dry weight.min, P < .05). However, glucose oxidation rates from 5.5 mmol/L [U-14C]-glucose were slightly increased in carnitine-deficient hearts. To determine whether the depressed fatty acid oxidation rates were a result of reduced mechanical function in carnitine-deficient hearts, the workload of hearts was reduced. Under these conditions, mechanical function was similar among control and carnitine-deficient hearts. Palmitate oxidation rates were also similar in these hearts (526 +/- 69 v 404 +/- 47 nmol/g dry weight.min for control and carnitine-deficient hearts, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

L-propionylcarnitine effects on cardiac carnitine content and function in secondary carnitine deficiency.

Long-term treatment with sodium pivalate, a compound conjugated to carnitine and excreted in the urine, results in carnitine deficiency and cardiac dysfunction. Since L-propionylcarnitine (LPC) is generally of benefit to cardiac function, it was of interest to determine whether it is effective in preventing the reductions in both heart carnitine content and function from occurring in carnitine deficiency. Secondary carnitine deficiency was induced in male Sprague-Dawley rats by supplementing the drinking water with 20 mM sodium pivalate for 26 weeks. Control animals received an equimolar concentration of sodium bicarbonate. At 13 weeks into treatment, a subgroup of control and sodium pivalate animals were given 80 mg/kg of LPC in their drinking water. Following treatment, isolated working hearts were perfused with buffer containing 11 mM glucose and 0.4 mM palmitate. Hearts from sodium pivalate treated animals demonstrated a severe reduction in tissue carnitine. When mechanical function was measured in these hearts, heart rate, rate-pressure product, and aortic flow were significantly depressed. Treatment with LPC, however, prevented the depletion in cardiac carnitine content and improved these cardiac parameters. Our results demonstrate that LPC treatment is beneficial in preventing the depression in cardiac function from occurring in this model of secondary carnitine deficiency.