Intramuscular fatty acid metabolism evaluated with stable isotopic tracers

We evaluated the applicability of stable isotopic tracers to the study of intramuscular fatty acid metabolism by infusing both [U-13C]palmitate and [1-13C]oleate intravenously for 4 h into fasted conscious rats. Skeletal muscles were sequentially biopsied, and the concentration and 13C enrichment of fatty acids were measured by gas chromatography/combustion/isotope ratio mass spectrometry. Throughout the study, the 13C enrichment of plasma palmitate and oleate remained substantially greater than intramuscular nonesterified palmitate and oleate enrichment, which in turn was greater than intramuscular triglyceride palmitate and oleate enrichment. Fractional synthesis rates of intramuscular triglycerides in gastrocnemius and soleus were 0.267 +/- 0.075 and 0. 100 +/- 0.030/h (P = 0.04), respectively, as determined by using [U-13C]palmitate, and were 0.278 +/- 0.049 and 0.075 +/- 0.013/h (P = 0.02), respectively, by using [1-13C]oleate. We conclude that plasma free fatty acids are a source for intramuscular triglycerides and nonesterified fatty acids; the latter are likely the synthetic precursors of the former. Uniformly and singly labeled [13C]fatty acid tracers will provide an important tool to study intramuscular fatty acid and triglyceride metabolism.     

Uptake of seven myocardial tracers during increased myocardial blood flow by dobutamine infusion

RATIONALE AND OBJECTIVES: Direct comparison of myocardial perfusion tracers has been made difficult by variability in experimental models, and by a virtual absence of data comparing tracer uptake to myocardial blood flow under conditions of increased myocardial oxygen consumption, similar to what occurs with dynamic exercise. METHODS: Tracer uptake versus myocardial blood flow was evaluated for thallium-201 (201TI) and six technetium-99m (99mTc) myocardial-imaging agents in 24 open-chest canines with an occluded left-anterior descending coronary artery during dobutamine infusion. Data were fitted to the exponential model y = ax(1 - exp[-PSc/x]), where y is the tissue tracer/g normalized to normal (activity at 1 mL/minute/g) and x is the blood flow measured by the radioactive microsphere method. RESULTS: With dobutamine, myocardial tracer uptake was linear across a wide range of ischemic and hyperemic flows for each tracer. Based on the permeability surface area product, 201TI and 99mTc Q3 provided the best tracer estimate of myocardial blood flow (5.30+/-0.86 mL/minute/g, r = 0.91; 5.46+/-0.58 mL/minute/g, r = 0.94, respectively). Correlation coefficient (r) values for other tracers studied were 99mTc Q4 (r =0.93), 99mTc Q12 (r = 0.93), 99mTc sestamibi (r = 0.90), 99mTc tetrofosmin (r = 0.96), and 99mTc-N-Noet (r = 0.82). CONCLUSIONS: Of the 99mTc tracers examined under conditions of dobutamine-altered myocardial contractility, the myocardial uptake properties of 99mTc Q3 were most similar to those of 201TI.     

Relationship between fatty acid delivery and fatty acid oxidation during strenuous exercise

To evaluate the extent to which decreased plasma free fatty acid (FFA) concentration contributes to the relatively low rates of fat oxidation during high-intensity exercise, we studied FFA metabolism in six endurance-trained cyclists during 20-30 min of exercise [85% of maximal O2 uptake (VO2max)]. They were studied on two occasions: once during a control trial when plasma FFA concentration is normally low and again when plasma FFA concentration was maintained between 1 and 2 mM by intravenous infusion of lipid (Intralipid) and heparin. During the 20-30 min of exercise, fat and carbohydrate oxidation were measured by indirect calorimetry, and the rates of appearance (Ra) of plasma FFA and glucose were determined by the constant infusion of [6,6-2H2]glucose and [2H2]palmitate. Lipid-heparin infusion did not influence the Ra or rate of disappearance of glucose. During exercise in the control trial, Ra FFA failed to increase above resting levels (11.0 +/- 1.2 and 12.4 +/- 1.7 mumol.kg-1.min-1 for rest and exercise, respectively) and plasma FFA concentration dropped from a resting value of 0.53 +/- 0.08 to 0.29 +/- 0.02 mM. The restoration of plasma FFA concentration resulted in a 27% increase in total fat oxidation (26.7 +/- 2.6 vs. 34.0 +/- 4.4 mumol.kg-1.min-1, P < 0.05) with a concomitant reduction in carbohydrate oxidation, apparently due to a 15% (P < 0.05) reduction in muscle glycogen utilization. However, the elevation of plasma FFA concentration during exercise at 85% VO2max only partially restored fat oxidation compared with the levels observed during exercise at 65% VO2max. These findings indicate that fat oxidation is normally impaired during exercise at 85% VO2max because of the failure of FFA mobilization to increase above resting levels, but this explains only part of the decline in fat oxidation when exercise intensity is increased from 65 to 85% VO2max.     

Activation of beta-adrenergic receptor kinase during myocardial ischemia

During myocardial ischemia, a local release of noradrenaline coincides with an increased density of beta-adrenergic receptors. The functional activity of these receptors, however, is mainly determined by their state of phosphorylation. The beta-adrenergic receptor kinase (beta ARK) specifically phosphorylates and thereby inactivates beta-adrenergic receptors after stimulation by receptor agonists, facilitating the binding of the inhibitor protein beta-arrestin to the receptors. beta ARK activation involves a translocation of the enzyme to the membrane. In the present study, we investigated the density and the functional activity of beta-adrenergic receptors, the enzymatic activity of beta ARK in membranes and cytosol, the mRNA levels of beta ARK-1, and the expression of beta-arrestin during stop-flow and low-flow ischemia in the isolated perfused rat heart. After 60 minutes of stop-flow ischemia, beta-adrenergic receptor density was upregulated, but beta-agonist-mediated adenylate cyclase activity was blunted. Simultaneously, beta ARK activity in the particulate fraction was significantly induced. The increase in beta ARK activity was reversible after inhibition of ischemia-evoked noradrenaline release by desipramine. Also, exposure to externally given noradrenaline increased beta ARK activity in the particulate fraction. Cytosolic beta ARK activity remained largely unchanged during stop-flow or low-flow ischemia. The steady state concentration of beta ARK-1 mRNA increased after 20 minutes of stop-flow ischemia and then returned to baseline values after another 20 minutes. Cardiac ischemia did not alter beta-arrestin levels. During myocardial ischemia, an increase in the number of beta-adrenergic receptors is paralleled by increased membrane activity of the receptor kinase beta ARK. This increased membrane activity may contribute to enhanced receptor phosphorylation and inactivation.     

Prediction of functional outcome after myocardial infarction using BMIPP and sestamibi scintigraphy

We determined the predictive value of combined beta-methyl iodophenyl pentadecanoic acid (BMIPP) and sestamibi scintigraphy for the functional outcome after myocardial infarction and compared the value of this approach with dobutamine echocardiography. METHODS: Rest BMIPP, rest sestamibi and low-dose dobutamine echocardiographic studies were obtained in 18 patients 4 to 10 days after infarction (mean 6.7 +/- 2.0 days). Six months later, a rest echocardiographic study was performed to assess functional outcome. RESULTS: Wall motion improved in 27/33 segments (82%) which showed mismatching but not in 19/21 segments (90%) with matched defects (p < 0.001). The accuracy of combined BMIPP and sestamibi SPECT in predicting segmental functional outcome was higher (85%) than that of sestamibi uptake alone (77%). Wall motion improved in 16/20 segments (80%) showing contractile reserve and not in 21/34 segments (63%) with the negative dobutamine test, giving an accuracy of 69% for dobutamine echocardiography. Combination of the two techniques resulted in higher positive (94%) and negative predictive values (94%). CONCLUSION: Mismatching of BMIPP and sestamibi uptake is predictive for long-term functional recovery after acute myocardial infarction. In contrast, segments with matched defects contain only scar tissue. Combined BMIPP and sestamibi scintigraphy offers increased accuracy compared to dobutamine echocardiography.     

Effects of hypoxia and hypercapnia on non-esterified free fatty acid and cortisol levels

In the dog, FFA (free fatty acid) and cortisol levels in arterial blood plasma are lowered by anesthesia. Induced hypercapnia does not alter the cortisol levels but increases FFA levels. Hypoxia tends to raise the FFA levels. Possible causes of modifications in the FFA and cortisol levels are briefly discussed.     

Effect of ischemic preconditioning on myocardial oxygen consumption during ischemia

Ischemic preconditioning (IPC) in the heart may reduce myocardial energy demand. The present study was undertaken to examine changes in myocardial oxygen consumption (MVO2) during ischemia by IPC in Langendorff perfused rat hearts. We assessed MVO2 during ischemia from the measurement of mitochondrial cyt. aa3 redox state by a two-wavelength reflectance spectrophotometry where T(1/2), the time from the onset of ischemia to the point for half reduction of cyt. aa3, was assumed to represent MVO2. The heart was preconditioned by three cycles of 5 min ischemia plus 5 min reperfusion and then subjected to 30 min global ischemia followed by reperfusion for 30 min. The T(1/2) was significantly longer in the preconditioned heart (30 +/- 6 s, n = 10) than the control heart (14 +/- 5 s, n = 9, P<0.001), indicating a reduction of MVO2 during ischemic period by IPC. The prolongation of T(1/2) was evident after only one IPC episode. When the heart was perfused with high K+ solution to abolish MVO2 for contractions, we still found the prolongation of T1(1/2) in the preconditioned heart (116 +/- 12 s, n = 6) compared to the control heart (86 +/- 10 s, n = 6, P<0.01), suggesting that decrease in contractile activity may be, in part but not completely, responsible for the reduction of MVO2. In contrast, the prolongation of T(1/2) was completely abolished by administration of a NO synthase inhibitor N omega-nitro-L-arginine in the high K+ arrested heart, demonstrating involvement of NO in the reduction of MVO2, presumably by suppression of mitochondrial respiratory chain. In conclusion, IPC reduces MVO2 during ischemia. The reduction of MVO2 in the preconditioned heart may be accounted for by decreased contractile activity and by depression of respiratory chain by NO.     

Assessment of 123I-beta-methyl iodophenyl pentadecanoic acid (BMIPP) myocardial scintigraphy in patients of chronic right ventricular overload--fatty acid metabolism in right ventricular myocardium

An investigation on the right ventricular pressure level and the abnormalities in the fatty acid metabolism of myocardium was made using 123I-beta-methyl-iodophenyl pentadecanoic acid (BMIPP) myocardial SPECT in patients with chronic right ventricular overloading. Twenty patients who presented with right ventricular systolic pressure (RVSP) of 35 mmHg or more were used as the subjects. Dual myocardial SPECT with 201TlCl (Tl) and BMIPP was carried out for the subjects and RVc/LVc, a ratio of radioactivity count incorporated in the right ventricular free wall to the left one was determined for Tl and BMIPP. And the correlations between RVc/LVc and RVSP, and RVc/LVc and RVSP/LVSP were examined. The subjects were classified into 3 groups based on the RVSP levels and the count ratio, BMIPP/Tl was compared among the three groups. With respect of Tl uptake, there were significant, positive correlations between RVc/LVc and RVSP (correlation coefficient r = 0.51, p < 0.05) and between RVc/LVc and RVSP/LVSP (correlation coefficient r = 0.59, p < 0.01). On the other hand, no significant correlation was found between them with respect of the uptake of BMIPP. The BMIPP/Tl ratio in the group with higher than 80 mmHg of RVSP was 0.82 +/- 0.06, which was significantly lower than the ratio's for two groups of less than 80 mmHg; 0.91 +/- 0.07 and 0.98 +/- 0.04 in the group with 35-49 and 50-79 mmHg of RVSP, respectively. These results show that when compared with BMIPP, Tl is superior for the estimation of right ventricular pressure. For the patients with right ventricular overloading, it was suggested that when RVSP reaches 80 mmHg or more, there appear some disorders in the fatty acid metabolism in the right ventricular myocardium.     

Flow versus uptake comparisons of thallium-201 with technetium-99m perfusion tracers in a canine model of myocardial ischemia

We investigated the myocardial flow kinetics of six putative radioperfusion agents (99mTc-Q3, 99mTc-Q4, 99mTc-Q12, 99mTc-sestamibi, 99mTc-tetrofosmin and 99mTcN-NOET) and 201Tl in a canine model of myocardial ischemia with pharmacologic coronary artery vasodilation. METHODS: In 31 open-chest dogs with acute coronary occlusion, dipyridamole (approximately 0.56 mg/kg) was infused intravenously, followed by a perfusion tracer injection and radioactive microspheres for myocardial blood flow (MBF) measurement. The paired data were normalized using three techniques; average, normal or maximum myocardial tracer activity and MBF. RESULTS: The upper limit of MBF obtained for the group of tracers ranged from 4.2 ml/min/g to 8.2 ml/min/g. There was a statistically significant (p < 0.0001) linear correlation (r = 0.87-0.98) between the normalized myocardial activity and the normalized MBF values of each of the tracers. The slope of the curve normalized by average for 201Tl (0.83) was greater than those for the 99mTc tracers, and the intercept (0.07) was lower than those for the 99mTc tracers. Slopes and intercepts for the 99mTc agents were as follows: 99mTc-Q3, 0.81 and 0.18; 99mTc-Q4, 0.61 and 0.41; 99mTc-Q12, 0.63 and 0.39; 99mTc-sestamibi, 0.62 and 0.34; 99mTc-tetrofosmin, 0.68 and 0.32; and 99mTcN-NOET, 0.71 and 0.29, respectively. CONCLUSION: In an anesthetized open-chest canine model of regional myocardial ischemia with dipyridamole induced hyperemia, 201Tl shows a more ideal relationship between tracer uptake and MBF than do the 99mTc-based agents. Of the various 99mTc-based imaging agents studied, the myocardial flow kinetics of 99mTc-Q3 appear to be closest to ideal. This relationship is maintained regardless of the normalization technique used. This may, in theory, imply a higher sensitivity in discerning ischemic from normal myocardium and a role in diagnostic nuclear imaging for 99mTc-Q3.     

Aminosulfonic acid buffer preserves myocardium during prolonged ischemia

Prevention of myocardial acidosis during global ischemia in operative cardiopreservation was explored in two series of dogs where acid-base control was the only variable. A specifically designed aminosulfonic acid buffer composition, 3:1 molar equivalents NaMOPS to HEPES, 0.2 mol/L, was compared with NaHCO3 (pH 8). Dissolved in standard cardioplegic solution it was given every 30 minutes by coronary infusion at 20 degrees C during 3 hours of global ischemia. Glass electrode intramyocardial pH, adenosine triphosphate (ATP) level, left ventricular contractility (Dp/Dt) and compliance (-Dp/Dt), and other cardiovascular parameters were measured frequently throughout ischemia and for 75 minutes thereafter. In the buffer group (n = 6) myocardial pH remained above entry levels throughout the study period, adenosine triphosphate level remained normal during ischemia, and Dp/Dt and -Dp/Dt at 75 minutes of reperfusion were above entry levels. In the NaHCO3 group (n = 6) pH declined and remained depressed throughout ischemia, adenosine triphosphate level fell steadily and significantly throughout the experiment, and Dp/Dt and -Dp/Dt never regained entry levels. The difference in each parameter between the two groups was statistically significant (p < 0.05). We conclude that control of myocardial acid-base equilibrium alone during global ischemia will preserve myocardial function and minimize reperfusion injury.     

Determinants of left ventricular diastolic function during myocardial ischemia: influence of myocardial structure and pericardial constraint

The genotoxic activities of 8-methoxypsoralen (8-MOP) and 4,4',5'-trimethylazapsoralen (4,4',5'-TMAP) on plasmid DNA have been compared. In a previous work, 4,4',5'-TMAP, a methyl derivative of a psoralen isoster, had shown potential photochemotherapeutic activity. The mutagenic activity of mono- and bifunctional lesions caused by these compounds was evaluated both after UVA irradiation, which causes the formation of both kinds of lesions, and after a two-step irradiation procedure of the psoralen-plasmid DNA complex, which allowed monoadducts and interstrand crosslinks to be studied separately. Furthermore, we used a procedure that allowed us to evaluate both the mutagenic and recombinogenic activity of the two compounds. Results indicate that the most important difference between 8-MOP and 4,4',5'-TMAP consists in their mode of photoreaction with DNA rather than in their mutagenic potential. In fact, in all of the experimental procedures, 4,4',5'-TMAP shows a lower ability than 8-MOP to generate interstrand crosslinks. However, when comparable toxicity levels are reached, the two compounds show the same mutagenic potentiality.     

Effects of hyperthermic stress on myocardial function during experimental coronary ischemia

We evaluated hyperthermic influences on ischemic hearts by comparing two groups of intact working swine hearts (n = 20) made globally ischemic. Heart muscle temperature was selectively increased from 37.5 +/- 0.3 degrees C to 39.7 +/- 0.3 degrees C in one group (n = 11) by warming the coronary perfusate. Ischemia in normothermic hearts significantly (P less than 0.05) decreased mechanical function (as reflected by increases in left ventricular end-diastolic pressure [LVEDP]), myocardial oxygen consumption (MVO2), glucose uptake, glycolytic flux, free fatty acid (FFA) uptake and oxidation, and tissue stores of high energy phosphates. Hearing in ischemic hearts further depressed mechanical function at similar reductions in coronary flow and MVO2. Glucose uptake was terminally increased over normothermic values (329 vs. 221 mumol/hr per g) as was glycolytic metabolism, FFA uptake (26 vs. 17 mumol/hr per g), and FFA oxidation (21 vs. 11 mumol/hr per g). However, these changes were not translated into increased energy stores of tissue creatine phosphate and ATP. Thus, in ischemic hearts, hyperthermia neither prevented the development of mechanical deterioration nor improved oxidative phosphorylation despite increases in metabolic substrate utilization. These data suggest that in experimental global ischemia heat is an added energy drain in already burdened myocardium.     

Silent myocardial ischemia and nitrates

Silent ischaemia (SI), generally identifiable as a transient abnormality of ECG, not accompanied by angina or equivalent clinical symptoms, is a common finding in patients suffering from coronary heart disease before and after myocardial infarction, or after surgical coronary revascularization or angioplasty. SI per se is considered to be a serious independent cardiovascular risk factor. From a pathophysiological point of view, SI is intimately related to myocardial oxygen imbalance, in which the demand, both at rest and during effort, exceeds the supply, essentially due to coronary arteriosclerosis or arterial spasm, or both, alongside other neuroendocrine and clotting factors which contribute to the final clinical picture. The absence of large-scale prospective studies prevents a rigorous assessment of whether the currently available anti-ischaemic treatments modify the cardiovascular prognosis related to the presence of SI. Long-acting nitrates, as well as beta-blockers and type L calcium channel blockers exert a beneficial effect on the total ischaemic load, improving not only the clinical profile of angina patients and their exercise tolerance, but also, in most published series, considerably decreasing the number of silent ischaemic events. Today's medical challenge therefore consists of determining whether the reduction of SI by means of anti-ischaemic drugs is accompanied by a proportional reduction of overall morbidity and mortality attributable to this process. As the asymptomatic nature of this type of ischaemia prevents evaluation on the basis of clinical data, it specialized analyses are necessary, such as stress ECG, Holter monitor, TEP, or Thallium 201 myocardial scan, and especially prognostic follow-up, in order to establish the real efficacy of drugs therapy. Coronary videoangiography and the various myocardial revascularization techniques can be applied when the ischaemia cannot be controlled clinically, and when a significant reduction of total ischaemic load is not obtained. In situations of pre-infarction ischaemia, some studies show that the use of nitrate vasodilators reduces the total ischaemic load, improving the clinical course of the disease and significantly reducing the total number of silent ischaemic episodes, although their secondary preventive action remains to be demonstrated. The anti-ischaemic action is more obvious for events triggered by physical effort (ergometry) than for those observed during Holter monitoring, which confirms that multiple mechanisms are responsible for inducing ischaemia and that circadian variability also depends on many factors, which is why the choice of an anti-ischaemic drug must be based on a thorough knowledge of the pathophysiological mechanisms which induce ischaemia and the anatomical and functional setting in which it develops. It has been clearly shown that nitrate vasodilators not only exert a beneficial action in terms of the control of painful or silent ischaemic events, but that they are also useful as coadjuvant therapy in the presence of signs of ischaemic ventricular dysfunction.     

Electrophysiologic effects of quinaprilat in dogs during acute myocardial ischemia and following reperfusion

BACKGROUND: There have been few studies concerning the electrophysiologic changes associated with the use of angiotensin-converting enzyme inhibitors in patients with acute myocardial infarction. We examined the electrophysiologic effects of quinaprilat in dogs during acute myocardial ischemia and following reperfusion. METHODS: The left anterior descending coronary artery was occluded for 10 min and reperfused for 10 min. Animals received intravenous quinaprilat (3 micrograms/kg per min, quinaprilat group) or saline (control group). We measured the ventricular effective refractory period and intra-myocardial conduction time within the left anterior descending coronary artery region (ischemic region) during myocardial ischemia and following reperfusion, and determined the frequency of ventricular fibrillation. RESULTS: The effective refractory period in the ischemic region decreased during myocardial ischemia and decreased further immediately after reperfusion in the control group. The intra-myocardial conduction time in the ischemic region increased during myocardial ischemia but rapidly shortened after reperfusion in the control group. In the quinaprilat group, however, no significant differences were evident between the ischemic and non-ischemic regions in either the effective refractory period or the intra-myocardial conduction time during myocardial ischemia or following reperfusion. The percentage shortening of the effective refractory period and the percentage prolongation of the intra-myocardial conduction time in the ischemic region were significantly lower in the quinaprilat group than in the control group during myocardial ischemia and following reperfusion. The frequency of ventricular fibrillation during myocardial ischemia and following reperfusion was significantly lower in the quinaprilat group (21%) than in the control group (74%; P < 0.01). CONCLUSIONS: Quinaprilat protects against electrophysiologic abnormalities, and may decrease arrhythmias during acute myocardial ischemia and following reperfusion.     

Changes in fatty acid compositions of myocardial lipids in rats with heart failure following myocardial infarction

Changes in fatty acid composition of myocardial lipids were examined in rats with heart failure following myocardial infarction. Left ventricular systolic pressure (LVSP) was decreased and left ventricular end-diastolic pressure (LVEDP) was elevated 24 h, 1 and 12 weeks after left coronary artery ligation (CAL), suggesting the development of heart failure at these periods in this model. Hearts were isolated 24 h, 1 week and 12 weeks after the operation. Myocardial lipids in the infarcted scar tissue, non-infarcted remaining left ventricle including interseptum and right ventricle were separated into phospholipid (PL), triacylglycerol (TG), diacylglycerol (DAG) and free fatty acid (FFA) fractions. In the scar tissue PL content markedly decreased whereas TG, DAG and FFA contents increased 24 h after CAL. Despite a marked decrease in constituted fatty acids of PL fraction in the scar tissue the percentage of arachidonic acid in PL was elevated 12 weeks after CAL, suggesting that release of arachidonic acid during PL degradation was suppressed. In the non-infarcted viable left ventricle PL content remained unchanged throughout the experiment whereas TG, DAG and FFA contents were elevated 24 h after CAL. Despite no changes in PL and other lipid contents in the non-infarcted tissue the percentage of linoleic acid in PL was reduced and that of docosahexaenoic acid in PL was elevated 12 weeks after CAL. Our findings showed that myocardial lipid composition of the non-infarcted left ventricle was altered only in an early stage of the development of heart failure and fatty acid compositions of PL was exchanged in a late stage of the development of heart failure. The exchange may be related to cardiac dysfunction or myocardial remodelling in the rat with heart failure.     

Comparison of the fatty acid compositions in intraepithelial and infiltrating lesions of the cervix: part II, free fatty acid profiles

Clinical studies report a low incidence of intestinal side effects with transdermally administered fentanyl (TTS-fentanyl) in comparison with oral morphine. To support these clinical data, analgesic and intestinal effects of both opioids were compared in rats. After subcutaneous injection, analgesia in the tail withdrawal reaction test was obtained at a peak effect dose of 0.032 mg/kg with fentanyl and 8.0 mg/kg with morphine. This analgesic dose exceeded the ED50 for inhibition of castor oil-induced diarrhea only slightly (1.1 x) in the case of fentanyl (0.028 mg/kg) but markedly (36 x) in the case of morphine (0.22 mg/kg). To reverse completely the antidiarrheal effect of equivalent analgesic doses of the opioids (their ED50S for analgesia lasting 2 hours), much more naloxone was required in the case of morphine (5.4 mg/kg) than in the case of fentanyl (0.19 mg/kg). After oral administration, the difference between both opioids was less pronounced. Analgesia was obtained at 0.85 mg/kg with fentanyl and 32 mg/kg with morphine. This analgesic dose only slightly (1.7 x) exceeded the antidiarrheal dose in the case of fentanyl (0.49 mg/kg) but significantly (6.2 x) in the case of morphine (5.2 mg/ kg). To reverse completely the antidiarrheal effect of equivalent analgesic oral doses of the opioids (their ED50S for analgesia lasting 2 hours), more naloxone was required in the case of morphine (11 mg/kg) than in the case of fentanyl (2.0 mg/kg). Rapid penetration of fentanyl into the brain is thought to be responsible for small dissociation between the analgesic and intestinal effect of this lipophilic opioid. The present data provide preclinical evidence to support the relatively low incidence of intestinal side effects observed clinically with the use of TTS-fentanyl in comparison with orally administered morphine.     

Treatment of myocardial ischemia and myocardial infarction in the elderly

The diagnosis of coronary artery disease in the elderly is problematic because older patients often present atypical symptoms or are asymptomatic. Once coronary disease is diagnosed, the proper course of treatment is not always clear, since few studies have focused on patients older than 65 years. Moreover, older patients often have medical conditions that may aggravate coexisting cardiovascular problems or interfere with conventional pharmacotherapy. For these reasons many physicians who treat cardiovascular problems aggressively in younger patients are reluctant to do so in older individuals. There is considerable evidence, however, that older patients could benefit as much or more from aggressive therapy because of their greater risk of mortality from myocardial ischemia and infarction.     

Identification of fatty acid ethyl esters as products of rabbit myocardial ethanol metabolism

To characterize metabolic factors potentially associated with alcohol-induced heart disease, myocardial ethanol intermediary metabolism was studied in isolated, perfused rabbit hearts and whole heart homogenates. Results showed that intact rabbit hearts and homogenates of rabbit left ventricle incorporate carbon-14-labeled ethanol at 20 and 59 nmol/g/h, respectively, into a neutral lipid species that co-migrates with triacylglycerides in standard chromatographic solvent systems. After isolation and purification by thin layer chromatography in an apolar solvent system, the labeled species were identified by gas chromatographic-mass spectral analysis to be a family of fatty acid ethyl esters. Heat inactivation of incorporation and the kinetics of formation of products suggest that the process is enzymatic. Gas chromatography identified the fatty acid components as predominantly unsaturated moieties, especially oleic, linoleic, and arachidonic acids. These results provide insight into potential biochemical mechanisms contributing to the triacylglyceride accumulation, decreased beta oxidation of fatty acids, and other lipid abnormalities typical of effects of ethanol on the heart.     

Renal ischemia/reperfusion remotely improves myocardial energy metabolism during myocardial ischemia via adenosine receptors in rabbits: effects of "remote preconditioning"

OBJECTIVES: This study examined the changes in myocardial energy metabolism during myocardial ischemia after "remote preconditioning" and investigated the involvement of adenosine receptors in the mechanisms of this effect. BACKGROUND: Recent studies have indicated that a brief period of ischemia and reperfusion (ischemic preconditioning, PC) in a remote organ reduces myocardial infarct size (IS) protecting against subsequent sustained myocardial ischemia. However, the mechanisms of "remote PC" remain unclear. We assessed myocardial energy metabolism during sustained myocardial ischemia and reperfusion after renal PC (RPC), in comparison with that after myocardial PC (MPC) in open-chest rabbits. It has been established that adenosine receptors are involved in the mechanisms of MPC. METHODS: Rabbits that had been anesthetized with halothane were divided into six groups. The control (CNT) group underwent 40-min coronary occlusion followed by 120 min reperfusion. Before the procedure, the MPC group underwent an additional protocol of 5 min coronary artery occlusion and 20 min reperfusion, and the RPC group received a 10 min episode of renal artery occlusion and 20 min reperfusion. In additional experimental groups, 8 sulfophenyl-theophylline (SPT, 10 mg/kg), an adenosine receptor inhibitor, was intravenously injected before the 40 min myocardial ischemia (SPT, MPC + SPT and RPC + SPT groups, respectively). Myocardial levels of phosphocreatine (PCr), ATP and intracellular pH (pHi) were measured by 31P-NMR spectroscopy. RESULTS: RPC and MPC delayed the decreases in ATP levels, preserved pHi during 40-min myocardial ischemia and resulted in better recovery of ATP and PCr during 120 min reperfusion compared with the controls. SPT abolished the improvement in myocardial energy metabolism and the reduction in myocardial IS caused by MPC or RPC. Myocardial IS in the CNT (n = 8), MPC (n = 9), RPC (n = 9), SPT (n = 6), MPC + SPT (n = 8) and RPC + SPT (n = 8) groups averaged 42.8+/-3.5%, 18.2+/-1.8%*, 19.6+/-1.3%*, 44.9+/-5.0%, 35.6+/-2.7% and 34.8+/-3.6% of the area at risk (*p < 0.05 vs. CNT), respectively. CONCLUSIONS: PC in a remote organ, similar to MPC, improved myocardial energy metabolism during ischemia and reperfusion and reduced IS in vivo by an adenosine-dependent mechanism in rabbits.