Assessment of transmyocardial perfusion in alligator hearts

BACKGROUND: Techniques for achieving myocardial perfusion directly from the left ventricular chamber are currently under investigation. Although originally based on the anatomy of reptilian hearts, which are rich in transmural channels and reported to have a poorly developed coronary vasculature, the blood flow capacity of a transmyocardial blood supply has not been studied in these hearts. With the ultimate goal of providing insight into the potential for achieving transmyocardial perfusion in human hearts, we studied the relative contribution of transmyocardial and coronary perfusion in alligator hearts. METHODS AND RESULTS: After explanation from six American alligators, the left ventricle was instrumented, and coronary arteries were perfused with oxygenated physiological solution. Using microspheres to estimate regional myocardial perfusion in the beating hearts, we show that although the epicardium was well perfused by the coronary arteries (0.20 +/- 0.08 versus 0.07 +/- 0.01 mL.min-1.g-1 owing to flow from the ventricular chamber), a significant proportion of endocardial perfusion was from the ventricular chamber (0.21 +/- 0.07 mL.min-1.g-1 from the left ventricle versus 0.13 +/- 0.04 mL.min-1.g-1 from coronary arteries). CONCLUSIONS: A significant amount of direct transmyocardial perfusion is present in alligator hearts. The conditions that apparently permit this situation in reptilian hearts are reviewed, and their implications for aiding in the optimization of techniques for achieving transmyocardial flow in humans are discussed.     

Altered hypoxia-induced coronary vasodilatation in diabetic rabbit heart

The effect of type 1 diabetes mellitus on hypoxia-induced coronary vasodilation was studied in isolated perfused rabbit hearts. Four groups of hearts were compared: control hearts from normal rabbits perfused with physiological buffer (5 mM glucose and 2 mM pyruvate added), hearts from alloxan-induced diabetic rabbits (same perfusion as control), hyperglycemic hearts from normal rabbits perfused with 22 mM glucose and 2 mM pyruvate, and hyperosmotic hearts from normal rabbits perfused with 5 mM glucose, 2 mM pyruvate, and 8.5 mM choline chloride. Hypoxia was produced by perfusion with a mixture of N2- and O2- saturated solutions. Endothelium-dependent and -independent dilators were also tested. Papaverine-induced coronary vasodilatation was unaltered, whereas that of serotonin and adenosine was significantly reduced in hyperglycemic and hyperosmotic hearts but not in diabetic hearts perfused with normoglycemic buffer. Hypoxia (PO2 from 515 +/- 86 to 131 +/- 24 mmHg; 1 mmHg = 133.3 Pa) caused a significant coronary vasodilatation in normal hearts (-66 +/- 3%). This vasodilatation was reduced slightly in diabetic (-45 +/- 7%, p < 0.05) and severely in hyperglycemic (-21 +/- 5%, p < 0.05) and hyperosmotic (-24 +/- 5%, p < 0.05) hearts. The adenosine-receptor antagonist 8-phenyltheophylline (10 microM) reduced hypoxia-induced vasodilatation in normal and diabetic hearts. However, inhibition of prostaglandin synthesis with diclofenac (1 microM), which reduces hypoxia-induced vasodilatation in normal hearts, had no effect in diabetic hearts. In conclusion, alloxan-induced type 1 diabetes mellitus in rabbits is accompanied by a reduced coronary vasodilator response to hypoxia. The contribution of adenosine in this response is unaffected. However, the abated contribution of cyclooxygenase products may account for the reduced vasodilatation during hypoxia in this particular model.     

Medical options for early pregnancy termination

OBJECTIVES: We sought to assess the relation between glucose metabolism, myocardial perfusion and cardiac work after orthotopic heart transplantation. BACKGROUND: The metabolic profile of the transplanted cardiac muscle is affected by the lack of sympathetic innervation, impaired inotropic function, chronic vasculopathy, allograft rejection and immunosuppressive therapy. In relation to myocardial perfusion and cardiac work, glucose metabolism has not previously been studied in heart transplant recipients. METHODS: Regional myocardial blood flow (ml.min-1.g-1) and 18F-2-fluoro-2-deoxyglucose (18FDG) uptake rate (ml.s-1.g-1) were measured after an overnight fast in 9 healthy male volunteers (mean age +/- SD 32 +/- 7 years) and in 10 male patients (mean age 50 +/- 10 years) who had a nonrejecting heart transplant, normal left ventricular function and no angiographic evidence of epicardial coronary sclerosis. Measurements were made by using dynamic positron emission tomography (PET) with 15O-labeled water and 18FDG, respectively. Heart rate and blood pressure were also measured for calculation of rate-pressure product. RESULTS: 18FDG uptake was similar in all heart regions in the patients and volunteers (intrasubject regional variably 12 +/- 8% and 16 +/- 12%, respectively, p = 0.51). Regional myocardial blood flow was similarly evenly distributed (intrasubject regional variability 14 +/- 10% and 12 +/- 8%, respectively, p = 0.67). Mean 18FDG uptake and myocardial blood flow values for the whole heart are given because no regional differences were identified. 18FDG uptake was on average 196% higher in the patients than in the volunteers (2.90 +/- 1.79 x 10(-4) vs. 0.98 +/- 0.38 x 10(-4) ml.s-1.g-1, p = 0.006). Regional myocardial blood flow and rate-pressure product were similarly increased in the patient group, but by only 41% (1.14 +/- 0.3 vs. 0.81 +/- 0.13 ml.min-1.g-1, p = 0.008) and 53% (11,740 +/- 2,830 vs. 7,689 +/- 1,488, p = 0.001), respectively. CONCLUSIONS: 18FDG uptake is homogeneously increased in normally functioning nonrejecting heart transplants. This finding suggests that glucose may be a preferred substrate in the transplanted heart. The magnitude of this observed increase is significantly greater than that observed for myocardial blood flow or cardiac work. In the patient group, the latter two variables were increased to a similar degree over values in control hearts, indicating a coupling between cardiac work load and myocardial blood flow. The disproportionate rise in 18FDG uptake may be accounted for by inefficient metabolic utilization of glucose by the transplanted myocardium or by the influence of circulating catecholamines, which may stimulate glucose uptake independently of changes in cardiac work load.     

Pyruvate reverses fatty-acid-induced depression of ventricular function and calcium overload after hypothermia in guinea pig hearts

OBJECTIVE: High levels of free fatty acids have been shown to impair mechanical recovery and calcium homeostasis of isolated rat hearts following hypothermic perfusion. The objective of the present study was to investigate whether inhibition of fatty acid oxidation through activation of pyruvate dehydrogenase by millimolar concentrations of pyruvate could influence functional recovery and Ca2+ homeostasis after a hypothermic insult. METHODS: Ventricular function and myocardial calcium ([Ca]total) were measured in 3 different groups of Langendorff-perfused guinea pig hearts exposed to 40 min hypothermic (15 degrees C) perfusion, followed by 30 min rewarming at 37 degrees C. The hearts were perfused with either 11.1 mM glucose (G), glucose and 1.2 mM palmitate (GP), or glucose, palmitate and 5 mM pyruvate (GPP) as energy substrates. RESULTS: All groups showed marked elevations in [Ca]total during hypothermia (from 0.6-0.7 mumol.g dry wt-1 to 9.3-12.2 mumol.g dry wt-1 at 40 min hypothermia, P < 0.05), associated with a pronounced increase in left ventricular end-diastolic pressure (LVEDP from 0-2 to 50-60 mmHg). Following rewarming, GP-perfused hearts showed significantly lower recovery of mechanical function compared to both G- and GPP-perfused hearts (% recovery of left ventricular developed pressure: 27 +/- 8 vs. 62 +/- 3 and 62 +/- 8%, respectively, P < 0.05). The reduced mechanical recovery of GP-perfused hearts was associated with elevated [Ca]total. In separate experiments we found that addition of 1.2 mM palmitate reduced glucose oxidation ([14C]glucose) from 1.77 +/- 0.28 mumol.min-1.g dry wt-1 (G-perfused hearts) to 0.15 +/- 0.04 mumol.min-1.g dry wt-1 (GP-perfused hearts, P < 0.05), implying that fatty acids had become the major substrate for oxidative phosphorylation. Fatty acid oxidation was, however, less pronounced after further addition of 5 mM pyruvate. Thus, palmitate oxidation ([3H]palmitate) was more than 40% lower in GPP-perfused than in GP-perfused hearts (0.83 +/- 0.22 vs. 1.41 +/- 0.12 mumol.min-1.g dry wt-1, P < 0.05). CONCLUSIONS: The present results demonstrate impaired ventricular function and calcium homeostasis after hypothermia in guinea pig hearts perfused with fatty acids in addition to glucose, as compared to hearts perfused with glucose alone. Furthermore, we show that these unfavourable effects of fatty acids can be overcome by an exogenous supply of pyruvate.     

Measurement of kinetic perfusion parameters of gadoteridol in intact myocardium: effects of ischemia/reperfusion and coronary vasodilation

Quantitation of myocardial perfusion is feasible using contrast enhanced magnetic resonance imaging. A method to quantitate myocardial blood flow is provided by the Kety model modified to account for a diffusable tracer such as gadoteridol. In the present study, perfusion parameters of the modified Kety model (partition coefficient and extraction efficiency) were determined for gadoteridol in intact myocardium using a constant flow, isolated, perfused heart model. Perfusion conditions included hearts with normal perfusion, hearts made globally ischemic for 20 min then perfused normally, and hearts whose coronary flow was more than doubled with 9 microM adenosine. T1 relaxation times were rapidly measured at 0.5 T following step increases in perfusate gadoteridol concentration and at steady state. Both the partition coefficient and extraction efficiency were found to be significantly increased in ischemic/reperfused hearts compared to normal. While flow rates in adenosine hearts were too high for accurate extraction efficiency determination using this technique, the partition coefficient was no different between adenosine and normally perfused hearts. The method described in this article allowed the kinetic parameters of the modified Kety model to be determined in intact heart using NMR relaxation time measurements as the basis of the calculation.     

An improved isolated, left ventricular ejecting, murine heart model. Functional and metabolic evaluation

An improved, isolated, left ventricular-ejecting, murine heart model is described and evaluated. Special attention was paid to the design and impedance characteristics of the artificial aortic outflow tract and perfusate composition, which contained glucose (10 mM plus insulin) and pyruvate (1.5 mM) as substrates. Temperature of the isolated perfused hearts was maintained at 38.5 degrees C. During antegrade perfusion (preload 10 mm Hg, afterload 50 mm Hg, 2.5 mM Ca2+) proper design of the aortic outflow tract provided baseline values for cardiac output (CO), left ventricular developed pressure (LVDP) and the maximum first derivative of left ventricular pressure (LV dP/dtmax) of 11.1+/-1.7 ml min-1, 83+/-5 mm Hg and 6283+/-552 mm Hg s-1, respectively, resembling findings in the intact mouse. During 100 min normoxic antegrade perfusion CO declined non-significantly by less than 10%. Varying pre- and afterloads resulted in typical Frank-Starling relationships with maximal CO values of 18.6+/-1.8 ml min-1 at pre- and afterload pressures of 25 and 50 mm Hg, respectively. Left ventricular function curves were constructed at free [Ca2+] of 1.5 and 2.5 mM in the perfusion medium. Significantly higher values for CO, LVDP and LV dP/dtmax and LV dP/dtmin were obtained at 2.5 mM Ca2+ at all loading conditions investigated. Phosphocreatine and creatine levels remained stable throughout the perfusion period. Despite a small but significant decline in tissue ATP content, the sum of adenine nucleotides did not change during the normoxic perfusion period. The tissue content of glycogen increased significantly.     

Blood flow distribution in working in situ canine muscle during blood flow reduction

The purpose of this study was to determine whether reduction in apparent muscle O2 diffusing capacity (Dmo2) calculated during reduced blood flow conditions in maximally working muscle is a reflection of alterations in blood flow distribution. Isolated dog gastrocnemius muscle (n = 6) was stimulated for 3 min to achieve peak O2 uptake (VO2) at two levels of blood flow (controlled by pump perfusion): control (C) conditions at normal perfusion pressure (blood flow = 111 +/- 10 ml.100 g-1.min-1) and reduced blood flow treatment [ischemia (I); 52 +/- 6 ml.100 g-1.min-1]. In addition, maximal vasodilation was achieved by adenosine (A) infusion (10(-2)M) at both levels of blood flow, so that each muscle was subjected randomly to a total of four conditions (C, CA, I, and IA; each separated by 45 min of rest). Muscle blood flow distribution was measured with 15-microns-diameter colored microspheres. A numerical integration technique was used to calculate Dmo2 for each treatment with use of a model that calculates O2 loss along a capillary on the basis of Fick's law of diffusion. Peak VO2 was reduced significantly (P < 0.01) with ischemia and was unchanged by adenosine infusion at either flow rate (10.6 +/- 0.9, 9.7 +/- 1.0, 6.7 +/- 0.2, and 5.9 +/- 0.8 ml.100 g-1.min-1 for C, CA, I, and IA, respectively). Dmo2 was significantly lower by 30-35% (P < 0.01) when flow was reduced (except for CA vs. I; 0.23 +/- 0.03, 0.20 +/- 0.02, 0.16 +/- 0.01, and 0.13 +/- 0.01 ml.100 g-1.min-1.Torr-1 for C, CA, I, and IA, respectively). As expressed by the coefficient of variation (0.45 +/- 0.04, 0.47 +/- 0.04, 0.55 +/- 0.03, and 0.53 +/- 0.04 for C, CA, I, and IA, respectively), blood flow heterogeneity per se was not significantly different among the four conditions when examined by analysis of variance. However, there was a strong negative correlation (r = 0.89, P < 0.05) between Dmo2 and blood flow heterogeneity among the four conditions, suggesting that blood flow redistribution (likely a result of a decrease in the number of perfused capillaries) becomes an increasingly important factor in the determination of Dmo2 as blood flow is diminished.     

Influence of an early adrenergic blockade on thrombotic infarct size and myocardial metabolism

To evaluate the extent to which the protective effect of metoprolol was accompanied by changes in myocardial oxygen consumption and metabolism, thrombotic occlusion of coronary artery followed by infusion of metoprolol or placebo was performed in twenty four German Shepherds. To restore a coronary blood flow rt-PA was administered. Plasma levels of oxygen, glucose, lactic acid, non esterified fatty acids, triacylglyceride and adenosine breakdown products were measured before and at the end of the occlusion and in the early and late reperfusion periods. Regional myocardial blood flow was measured by means of radioactive tracer microspheres. Infarct size was estimated after perfusion and staining of excised hearts with Evans blue. Plasma levels of metoprolol were determinated before the end of occlusion and during reperfusion and therapeutic concentrations were confirmed. The infarct size was smaller in dogs receiving metoprolol (21.6 +/- 20.7 vs 43.0 +/- 17.3% p. < 0.02). Coronary collateral blood flow was greater in metoprolol than in placebo dogs (18.68 +/- 7.58 vs 11.05 +/- 6.10 ml/min/100g, p. < 0.01). As a consequence of myocardial ischemia a shift toward carbohydrate utilization, the myocardial lactate release and the accompanying symptoms of diminished myocardial lipid uptake were observed. A washout of adenosine degradation products during early reperfusion was also noticed. In beta 1 blocked animals the reduction of myocardial oxygen consumption and preserved myocardial uptake of lactate and non esterified fatty acids were documented.     

Lactate release and uptake in hepatoma 7288CTC perfused in situ with L-[(U)-14C]lactate or D-[(U)-14C]glucose

Arteriovenous differences (AVD) for glucose and lactic acid measured across tissue-isolated rat tumors in vivo have shown that individual tumors with similar rates of glucose consumption may either release or utilize lactic acid. The experiments described here investigated the relationships among arterial blood lactate concentrations and tumor lactate and glucose balances. AVDs for lactate, pyruvate, glucose, 14CO2, PO2, PCO2, pH, and lactate specific activities were measured across 17 tissue-isolated 7288CTC hepatomas perfused in situ with arterial blood containing 2.5 to 14.4 mmol/L lactate and either L-[(U)-14C]lactic acid or D-[(U)-14C]glucose. Measurements were made over a range of blood flow rates from 60% to 200% of the mean in vivo rate, 0.11 mL/min. Data collected during steady states were compared by regression analysis. Tumor lactate balance and the arterial blood lactate concentration were directly related (r = .895, n = 22, P < .01). Net negative and positive balances occurred below and above approximately 6.5 mmol/L arterial blood lactate, respectively. The mean intratumor lactate concentration for all tumors was 6.9 +/- 1.0 mmol/L (mean +/- SD, n = 13). Rates of 14C-lactate oxidation to 14CO2 (r = .716, n = 18, P < .01) and tumor venous/arterial blood 14C-lactate specific activity ratios (r = .845, n = 19, P < .01) were low during lactate release and were increased during lactate uptake. Total arterial blood lactate removal estimated from chemical and isotopic analyses was 23.1% +/- 11% and 43.0% +/- 16% (P < .05), respectively, for six lactate-utilizing tumors. Perfusions performed with 14C-glucose showed that approximately 50% of the glucose consumed during net negative lactate balance was released as 14C-lactate to the tumor venous blood, whereas only 5% was released as 14C-lactate during net positive lactate balance. The data support the following conclusions: Arterial blood lactate controls net lactate balance in solid tumors; high concentrations increase uptake. Lactate uptake inhibits lactate formation from glucose without changing the glucose balance. Lactate is release during net lactate uptake. Since lactate uptake may exceed glucose uptake, arterial blood lactate can be a substrate for tumor energy metabolism and growth.     

Contraction-induced increase in Vmax of palmitate uptake and oxidation in perfused skeletal muscle

To evaluate the effects of contractions on the kinetics of uptake and oxidation of palmitate in a physiological muscle preparation, rat hindquarters were perfused with glucose (6 mmol/l), albumin-bound [1-14C]palmitate, and varying amounts of albumin-bound palmitate (200-2,200 micro mol/l) at rest and during muscle contractions. When plotted against the unbound palmitate concentration, palmitate uptake and oxidation displayed simple Michaelis-Menten kinetics with estimated maximal velocity (Vmax) and Michaelis-Menten constant (Km) values of 42.8 +/- 3.8 (SE) nmol . min-1 . g-1 and 13.4 +/- 3.4 nmol/l for palmitate uptake and 3.8 +/- 0.4 nmol . min-1 . g-1 and 8.1 +/- 2.9 nmol/l for palmitate oxidation, respectively, at rest. Whereas muscle contractions increased the Vmax for both palmitate uptake and oxidation to 91.6 +/- 10.1 and 16.5 +/- 2.3 nmol . min-1 . g-1, respectively, the Km remained unchanged. Vmax and Km estimates obtained from Hanes-Woolf plots (substrate concentration/velocity vs. substrate concentration) were not significantly different. In the resting perfused hindquarter, an increase in palmitate delivery from 31.9 +/- 0.9 to 48.7 +/- 1.2 micro mol . g-1 . h-1 by increasing perfusate flow was associated with a decrease in the fractional uptake of palmitate so that the rates of uptake and oxidation of palmitate remained unchanged. It is concluded that the rates of uptake and oxidation of long-chain fatty acids (LCFA) saturate with an increase in the concentration of unbound LCFA in perfused skeletal muscle and that muscle contractions, but not an increase in plasma flow, increase the Vmax for LCFA uptake and oxidation. The data are consistent with the notion that uptake of LCFA in muscle may be mediated in part by a transport system.     

Effects of short-term treatment of hyperlipidemia on coronary vasodilator function and myocardial perfusion in regions having substantial impairment of baseline dilator reverse

BACKGROUND: We tested the hypothesis that correction of hyperlipidemia improves coronary vasodilator response and maximal perfusion in myocardial regions having substantial impairment of pretreatment vasodilator capacity. METHODS AND RESULTS: Measurements of myocardial blood flow were made with PET [13N]ammonia in 12 patients with ischemic heart disease (11 men; age, 65+/-8 years [mean+/-SD]) at rest and during adenosine at 70 and then 140 microg . kg-1 . min-1 for 5 minutes each before and approximately 4 months after simvastatin treatment (40 mg daily). Simvastatin reduced LDL (171+/-13 before versus 99+/-18 mg/dL after simvastatin, P<0.001) and increased HDL (39+/-8 versus 45+/-9 mg/dL, P<0.05). Myocardial segments were classified on the basis of pretreatment blood flow response to 140 microg . kg-1 . min-1 adenosine as normal (flow >/=2 mL . min-1 . g-1) or abnormal (flow <2 mL . min-1 . g-1). In normal segments, baseline myocardial blood flow (0.95+/-0.32) increased (P<0.001) at both low- (1.62+/-0.81) and high- (2.63+/-0.41) dose adenosine and was unchanged both at rest and with adenosine after simvastatin. In abnormal segments, myocardial blood flow at rest (0. 73+/-0.19) increased at low- (1.06+/-0.59, P<0.02) and high- (1. 29+/-0.33, P<0.01) dose adenosine. After simvastatin, myocardial blood flow increased more compared with pretreatment at both low- (1. 37+/-0.66, P<0.05 versus pretreatment) and high- (1.89+/-0.79, P<0. 01 versus pretreatment) dose adenosine. CONCLUSIONS: Short-term lipid-lowering therapy increases stenotic segment maximal myocardial blood flow by approximately 45%. The mechanism involves enhanced, flow-mediated dilation of stenotic epicardial conduit vessels and may account at least in part for the efficacy of lipid lowering in secondary prevention trials and in reducing ischemic episodes in ambulatory patients.     

Effect of systemic corticoid and antihistamine alone or in combination on elements of the response to a two dose nasal allergen challenge

Adenosine, an endogenous vasodilator, induces a cerebral vasodilation at hypotensive infusion rates in anaesthetized humans. At lower doses (< 100 micrograms kg-1 min-1), adenosine has shown to have an analgesic effect. This study was undertaken to investigate whether a low dose, causing tolerable symptoms of peripheral vasodilation affects the global cerebral blood flow (CBF). In nine healthy volunteers CBF measurements were made using axial magnetic resonance (MR) phase images of the internal carotid and vertebral arteries at the level of C2-3. Quantitative assessment of CBF was also obtained with positron emission tomography (PET) technique, using intravenous bolus [15O]butanol as tracer in four of the subject at another occasion. During normoventilation (5.4 +/- 0.2 kPa, mean +/- s.e.m.), the cerebral blood flow measured by magnetic resonance imaging technique, as the sum of the flows in both carotid and vertebral arteries, was 863 +/- 66 mL min-1, equivalent to about 64 +/- 5 mL 100 g-1 min-1. The cerebral blood flow measured by positron emission tomography technique, was 59 +/- 4 mL 100 g-1 min-1. All subjects had a normal CO2 reactivity. When adenosine was infused (84 +/- 7 micrograms kg-1 min-1.) the cerebral blood flow, measured by magnetic resonance imaging was 60 +/- 5 mL 100 g-1 min-1. The end tidal CO2 level was slightly lower (0.2 +/- 0.1 kPa) during adenosine infusion than during normoventilation. In the subgroup there was no difference in cerebral blood flow as measured by magnetic resonance imaging or positron emission tomography. In conclusion, adenosine infusion at tolerable doses in healthy volunteers does not affect global cerebral blood flow in unanaesthetized humans.     

The deleterious effects of exogenous angiotensin I and angiotensin II on myocardial ischemia-reperfusion injury

Angiotensin II is well known to have a cardiotoxic effects. However, it is still unclear whether exogenous angiotensin I or angiotensin II has a deleterious effect on myocardial ischemia-reperfusion injury. To examine this deleterious effects, we administered angiotensin I and angiotensin II to perfused hearts before ischemia, and measured creatine kinase (CK) release and cardiac function during subsequent reperfusion. Wistar Kyoto rats were used and the hearts were perfused by the Langendorff technique at a constant flow (10 ml/min). Seven hearts were perfused for 20 min and then subjected to 15 min of global ischemia (Control). In the experimental groups, during the 5 min before ischemia, we administered 100 ng/ml angiotensin I (Ang I; n = 9), 1 microgram/ml enalaprilat (ACEI; n = 5), both agents (ACEI + Ang I) (n = 6), or 10 ng/ml angiotensin II (Ang II; n = 6). The perfusates were then sampled to measure angiotensin II. After 15 min of ischemia, the hearts were reperfused with control perfusate. Throughout the 20 min of reperfusion, the effluent was collected to measure cumulative CK release. Angiotensin I increased coronary perfusion pressure (CPP) by 32 +/- 4 mmHg, however, the angiotension converting enzyme inhibitor inhibited the increase of CPP by angiotension I (11 +/- 1 mmHg) (p < 0.01). The contents of angiotensin II in the effluent in Ang I and Ang I + ACEI were 11.5 +/- 1.9 ng/ml and 4.0 +/- 0.5 ng/ml (p < 0.01). After 20 min of reperfusion, the left ventricular developed pressure was unchanged in all of the groups. CPP was also unchanged by ischemia in all of the groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Novel approach for enhancing atrioventricular nodal conduction delay mediated by endogenous adenosine

The 2-amino-3-benzoylthiophene derivative PD 81,723 potentiates the A1 receptor-mediated negative dromotropic effect of exogenous adenosine and adenosine receptor agonists in guinea pig isolated perfused and in situ hearts. The objective of this study was to determine whether PD 81,723 could amplify the cardiac actions of endogenous adenosine. Two approaches known to increase the myocardial interstitial concentration of adenosine--hypoxia, which increases the production of adenosine and the inhibition of adenosine kinase, which decreases its metabolism--were used to test this hypothesis. In guinea pig hearts in situ, PD 81,723 (2 mg/kg i.v.) potentiated the atrioventricular (AV) nodal conduction delay caused by hypoxemia (PaO2, 14 to 19 mm Hg). In guinea pig isolated hearts, PD 81,723 (5 mumol/L) increased by twofold the stimulus-to-His bundle (S-H) interval prolongations induced by both a 5-minute period of hypoxia (25% O2/70% N2/5% CO2) and the administration of the adenosine kinase inhibitor iodotubercidin (40 to 70 nmol/L) but had no effect on coronary conductance. Hypoxia and hypoxia plus PD 81,723 (5 mumol/L) caused equivalent increases in the concentration of adenosine in epicardial transudate, from 0.13 +/- 0.15 to 0.48 +/- 0.1 and 0.45 +/- 0.4 mumol/L, respectively. Similar to the allosteric enhancer, the nucleoside uptake blocker draflazine (0.1 mumol/L) also increased by twofold the S-H interval prolongation caused by hypoxia. In contrast to the allosteric enhancer, draflazine increased the concentration of adenosine in epicardial transudate during hypoxia from 0.48 +/- 0.15 to 1.5 +/- 0.4 mumol/L. Draflazine also increased coronary conductance by approximately twofold in guinea pig normoxic constant-fold perfused hearts.(ABSTRACT TRUNCATED AT 250 WORDS)     

Microvascular permeability of the isolated rat heart to various solutes in well-oxygenated and hypoxic conditions

The aim of this study was to investigate the effect of a moderate degree of hypoxia on coronary vascular permeability to various lipophobic solutes. Using the multiple indicator dilution method the permeability-surface area (PS) products were determined for 125I-albumin, 125I-insulin and 57Co-cyanocobalamin in perfused rat hearts (flow approximately 10 ml.min-1.g-1) either with well-oxygenated (pO2 approximately 96 kPa) or hypoxic (pO2 approximately 45 kPa) solutions. The PS products for albumin, insulin and cyanocobalamin during the well-oxygenated equilibration period were 0.20 +/- 0.03, 0.29 +/- 0.06 and 2.0 +/- 0.3 ml.min-1.g-1 (mean +/- SE), respectively, relative to 131I-gamma-globulin. The PS products for these solutes 15 min after the induction of hypoxia were 1.3 +/- 0.3, 0.8 +/- 0.1 (p < 0.05) and 2.1 +/- 0.2 (p < 0.05), respectively. In hearts perfused with well-oxygenated solution for 75 min, the PS products for these solutes remained stable throughout the period of the study. Electron-microscopic examination of hypoxic tissues showed the presence of endothelial gaps of approximately 1 micron which were underlined by an intact basal lamina. We conclude that a moderate degree of hypoxia produces a large increase in permeability of albumin and insulin but has no effect on the PS products for cyanocobalamin and that the endothelial gaps are the likely mechanism of the observed increase in permeability.     

18F-2-deoxyglucose deposition and regional flow in pigs with chronically dysfunctional myocardium. Evidence for transmural variations in chronic hibernating myocardium

BACKGROUND: Hibernating myocardium in patients with collateral-dependent myocardium is characterized by relative reductions in resting flow and increases in the uptake of 18F-2-deoxyglucose (FDG) in the fasting state. We performed the present study to examine whether these key physiological alterations could be produced in a porcine model of chronic coronary occlusion and to assess whether the adaptations consistent with hibernation varied across the myocardial wall. METHODS AND RESULTS: We chronically instrumented pigs (n = 18) with a fixed occluder on the proximal left anterior descending coronary artery (LAD). Three months later, ventricular function, regional myocardial perfusion, and FDG deposition (by excised tissue counting or positron emission tomography) were assessed in pigs after an over-night fast in the closed-chest anesthetized state. Total LAD occlusion with angiographic collaterals was present in the majority of animals. Left ventriculography showed severe anterior hypokinesis, and resting perfusion was significantly reduced in the hibernating LAD region in comparison with the normal remote regions (subendocardium: 0.80 +/- 0.06 versus 1.07 +/- 0.06 mL.min-1.g-1, P < .001; full-thickness: 0.87 +/- 0.04 versus 0.99 +/- 0.06 mL.min-1.g-1, P < .01). There was a twofold increase in full-thickness fasting FDG uptake in the dysfunctional LAD region (1.8 +/- 0.2 by positron emission tomography versus 1.9 +/- 0.1 by ex vivo counting). Ex vivo tissue counting revealed a pronounced transmural variation in FDG uptake in the hibernating region (LAD/normal), which averaged 2.5 +/- 0.2 in the subendocardium, 1.9 +/- 0.2 in the midmyocardium, and 1.4 +/- 0.1 in the subepicardium. CONCLUSIONS: These results demonstrate that pigs instrumented with a proximal LAD stenosis develop hibernating myocardium characterized by relative reductions in resting function and perfusion in association with increased uptake of FDG in the fasting state. The transmural variations in relative resting flow and FDG uptake suggest that myocardial adaptations consistent with hibernation are most pronounced in the subendocardial layers and vary in relation to local coronary flow reserve.     

Experience with the Cryosurgical treatment of the prostatic diseases in 100 patients (author''s transl)]

The semitendinosus muscle of the dog is supplied by two separate arteries and drained by two corresponding veins. In the muscles used in this study no blood entering via the distal artery was found to leave via the proximal vein during perfusion through both arteries (orthograde perfusion). Therefore, collateral flow (CF) could be determined as proximal venous outflow during occlusion of the proximal artery. During orthograde perfusion total blood flow averaged 12 ml x min-1 x 100 g-1 at rest and 58.4 ml x min-1 x 100 g-1 during exercise. CF was found to average 6.2 ml x min-1 x 100 g-1 at rest and increased to 9.2 ml x min-1 x 100 g-1 during exercise. CF was sufficient to cover the metabolic demand of resting muscle. During exercise the O2-uptake (VO2) of the distal muscle portion was increased 13.4 fold in comparison to a 3.1 fold increase in the proximal muscle portion. The average contractile power decreased by 46%. Additional infusion of adenosine into the distal artery resulted in an increase of CF to 11.4 ml x min-1 x 100 g-1 and of orthograde flow to 71 ml x min-1 x 100 g-1. The average contractile power of the muscle increased by 13%. Both orthograde flow and CF were found to decrease with increasing muscle load. But this decrease was significantly more pronounced in the case of CF especially at a lower range of loads. It is concluded that after acute occlusion of orthograde flow, CF is limited by the number, the size and the dilatory capacity of precapillary network vessels. Furthermore, CF is influenced considerably by changes of extravascular support.     

Effects of rho-chloroamphetamine on locomotor activity and brain 5-hydroxyindoles

The conversion of 14C-maltose into glucose, lactate and 14 CO2 was studied in perfused livers from fed and fasted rats and in isolated hepatocytes. Maximal glucose production was 30 mM x g-1 x h-1; half-maximal rates were found with 3 mM maltose. About 0.01 % of the radioactivity infused was recovered as 14CO2. The addition of maltose had no effect on rates of oxygen consumption, lactate production or ketogenesis. The data suggest that maltose did not serve as a major substrate for biosynthetic or energy producing processes under the conditions of the perfused rat liver.     

Increase in incidence of insulin-dependent diabetes mellitus among children in Finland

It has been proposed that NO may function as an endogenous cardioprotectant. We have investigated whether modulation of NO levels (detected in coronary effluent by chemiluminescence) by a blocker of its synthesis, by supplementation of its precursor, and by administration of an NO donor can influence reperfusion arrhythmias in the isolated rat heart. Rat hearts were perfused with modified Krebs' solution and subjected to 5, 35, or 60 minutes of left regional ischemia followed by 10 minutes of reperfusion. NG-Nitro-L-arginine methyl ester (L-NAME), which blocks NO synthase, increased the incidence of reperfusion-induced ventricular fibrillation (VF) from 5% in the control condition to 35% after 60 minutes of ischemia (n = 20, P < .05). The profibrillatory effect of L-NAME was prevented in hearts coperfused with 1 or 10 mmol/L L-arginine (an NO precursor) but persisted in hearts coperfused with D-arginine (1 mmol/L). L-NAME did not increase VF susceptibility in hearts reperfused after 5 or 35 minutes of ischemia. L-NAME caused sinus bradycardia (264 +/- 10 versus 309 +/- 5 bpm in control groups, P < .05) and reduced coronary flow before ischemia (6.2 +/- 0.6 versus 9.2 +/- 0.6 mL.min-1.g-1 tissue in controls, P < .05). L-NAME reduced coronary effluent NO levels after 60 minutes of ischemia; during the first minute of reperfusion, values were reduced from 1457 +/- 422 to 812 +/- 228 pmol.min-1.g-1 (P < .05). This effect was prevented by coperfusion with L-arginine (10,344 +/- 1730 pmol.min-1.g-1, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Detection of subclinical sensory nerve dysfunction in amyotrophic lateral sclerosis--a microneurographic study

AIM: To study the effects of panaxadiol saponins (PDS) on burn rat heart functions and try to find its mechanisms. METHODS: A 35% skin-full-thickness burn was produced by using napalm in Wistar rats. PDS 30 mg kg-1 was injected i.p. to rats immediately after burn and repeated 2 h before examination. Using the isolated perfused working heart and biochemistry methods, heart rate (HR), cardiac output (CO), coronary flow (CF), left ventricular pressure (LVP), aortic pressure (AP), +/- dp/dtmax, and content of malondialdehyde (MDA), activity of superoxide dismutase (SOD) in ventricular myocardium homogenate were examined 8 h after burn. RESULTS: After burn, HR, CO, CF, LVP, AP, +dp/dtmax, -dp/dtmax, and SOD activity decreased from 206 bpm, 92 mL min-1 g-1, 26 mL min-1 g-1, 7 kPa, 5.9 kPa, 149 kPa s-1, 73 kPa s-1, 2.9 NU/mg protein to 162 bpm, 72 mL min-1 g-1, 14 mL min-1 g-1, 4 kPa, 2.2 kPa, 77 kPa s-1, 44 kPa s-1, 1.7 NU/mg protein, respectively, and MDA content raised from 0.77 nmol/mg protein to 1.35 nmol/mg protein (P all < 0.05). But in PDS-treated group, above decreased or increased dates restored to 202 bpm, 91 mL min-1 g-1, 25 mL min-1 g-1, 6 kPa, 4.1 kPa, 112 kPa s-1, 62 kPa s-1, 2.8 NU/mg protein, 0.91 nmol/mg protein, respectively (P all < 0.05 vs burn). CONCLUSION: PDS exerts definite protective effects on the cardiac functions after burn injury possibly through its enhancement of SOD activity and the reduction of both the levels of free radicals and lipid peroxides (LPO) of the myocardium.