Biomedical subjects
P Owen
Publications and source records attributed to P Owen.
Detecting congenital heart disease prenatally.
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The gram-negative outer membrane: structure, biochemistry and vaccine potential.
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Decreased rates of release of atrial natriuretic peptide from isolated hearts from aging hypertensive rats.
We tested the hypothesis that in genetically hypertensive New Zealand rats left ventricular hypertrophy predisposes to left atrial disease and should be associated with a decreased release of atrial natriuretic peptide (ANP) in response to acute left atrial stretch. Abrupt distention of the left atrium was achieved by the acute onset of left atrial distention in Langendorff-perfused isolated rat hearts, which resulted in a rapid release of ANP in all groups of hearts. Comparisons were made between normotensive and hypertensive hearts using rats aged 2 months, 8 months, 12 months, and 16 months. Rates of release of ANP from normotensive and hypertensive hearts were similar at 2 months. Thereafter, there was a progressive impairment of ANP release, until in rats aged 16 months, rates of release achieved in hypertensive hearts 2 min after the onset of left atrial distention were only about half of those of normotensive hearts (55%, P < .005). At all ages above 2 months, hypertensive hearts failed to increase the concentration of ANP in the coronary effluent at the onset of increased heart work. Therefore, in rats with genetic hypertension, there is an impairment of release of ANP from the isolated heart in response to left atrial distention.
Set menus and clinical freedom.
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Effect of pH shifts induced by oxygenating crystalloid cardioplegic solutions.
Oxygenation of a bicarbonate-containing crystalloid cardioplegic solution alters the partial pressure of both oxygen (O2) and carbon dioxide (CO2). Therefore, oxygenating St. Thomas' Hospital II plus glucose (11 mmol/L) cardioplegic solution with 95% O2 + 5% CO2 induces a pH shift to 7.0 (10 degrees C) as opposed to pH 9.3 with 100% O2. In an isolated working rat heart model, we show that pH 7.0 (10 degrees C) improves mechanical postischemic recovery in the absence or presence of O2. However, in the absence of O2, pH 7.0 appears to inhibit glycolysis and diminish the stability of cellular membranes. The provision of O2 independently improved mechanical recovery and at pH 7.0, improved the preservation of the sarcolemma. Increasing the O2 content by including a perfluorocarbon (FC-43) in the oxygenated St. Thomas' plus glucose cardioplegia is not additionally beneficial. St. Thomas' Hospital plus glucose cardioplegic solution should be oxygenated, but with 95% O2 + 5% CO2 and not 100% O2.
Adenosine cardioplegia: reducing reperfusion injury of the ischaemic myocardium?
Hyperkalaemia-induced hypopolarization of the sarcolemnal membrane during standard crystalloid cardioplegic arrest potentiates calcium influx during reperfusion and is associated with depletion of high-energy phosphate reserves. Adenosine has been shown to induce fast cardiac arrest whilst preserving membrane hyperpolarization in an isolated rat heart model. In this study we compared the efficacy of adenosine, both as an arresting agent and as an ultrastructural, haemodynamic and high-energy phosphate preserving agent, in an in situ global ischemia model in the baboon with St. Thomas' Hospital solution No. 2 (ST2; n = 8) and with Krebs-Henseleit buffer (KHB; n = 7). The addition of 10 mM adenosine to the non-cardioplegic KHB (ADO; n = 8) improved haemodynamic recovery significantly in terms of cardiac index (91.6% +/- 7.2 vs 59.9% +/- 9.9) and stroke volume index (101.6% +/- 8.9 vs 55.6 +/- 10.0) and was not statistically distinguishable from the ST2 with regard to cardiac index (91.6% +/- 7.2 vs 94.8% +/- 5.8), stroke volume index (101.6% +/- 8.9 vs 114.0% +/- 8.3) or left ventricular dP/dt (73.1% +/- 9.9 vs 87.0% +/- 12.4). Adenosine triphosphate was best preserved with ADO (103.5% +/- 21.1 vs 67.9% +/- 9.3 and 48.5% +/- 8.7) although this was not statistically significant. This suggests therefore that the mechanism of cardioprotection by adenosine occurs by means other than its role as high-energy phosphate precursor.
Idiopathic thrombocytopenic purpura in pregnancy: a randomized trial on the effect of antenatal low dose corticosteroids on neonatal platelet count.
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St. Thomas' Hospital cardioplegic solution. Beneficial effect of glucose and multidose reinfusions of cardioplegic solution.
The intention of this study was to determine whether glucose is beneficial in a cardioplegic solution when the end products of metabolism produced during the ischemic period are intermittently removed. The experimental model used was the isolated working rat heart, with a 3-hour hypothermic 10 degrees C cardioplegic arrest period. Cardioplegic solutions tested were the St. Thomas' Hospital No. 2 and a modified Krebs-Henseleit cardioplegic solution. Glucose (11 mmol/L) was beneficial when multidose cardioplegia was administered every 30 minutes. Including glucose in Krebs-Henseleit cardioplegic solution improved postischemic recovery of aortic output from 57.0% +/- 1.8% to 65.8% +/- 2.2%; p less than 0.025. The addition of glucose to St. Thomas' Hospital No. 2 cardioplegic solution improved aortic output from 74.6% +/- 1.9% to 87.4% +/- 1.9%; p less than 0.005. Furthermore, a dose-response curve showed that a glucose concentration of 20 mmol/L gave no better recovery than 0 mmol/L, and glucose in St. Thomas Hospital No. 2 cardioplegic solution was beneficial only in the range of 7 to 11 mmol/L. In addition, we showed that multidose cardioplegia was beneficial independent of glucose. Multidose St. Thomas' Hospital No. 2 cardioplegia, as opposed to single-dose cardioplegia, improved aortic output recovery from 57.4% +/- 5.2% to 74.6% +/- 1.9%; p less than 0.025, and with St. Thomas' Hospital No. 2 cardioplegic solution plus glucose (11 mmol/L) aortic output recovery improved from 65.9% +/- 2.9% to 87.4% +/- 1.9%; p less than 0.005. Hence, at least in this screening model, the St. Thomas' Hospital cardioplegic solution should contain glucose in the range of 7 mmol/L to 11 mmol/L, provided multidose cardioplegia is given. We cautiously suggest extrapolation to the human heart, on the basis of supporting clinical arguments that appear general enough to apply to both rat and human metabolisms.
Effect of oxygenation and consequent pH changes on the efficacy of St. Thomas' Hospital cardioplegic solution.
The hypothesis tested is that shifts in pH, induced when a cardioplegic solution is oxygenated, can be detrimental. We added either 100% nitrogen, 95% nitrogen and 5% carbon dioxide, 100% oxygen, or 95% oxygen and 5% carbon dioxide to the cardioplegic solution (St. Thomas' Hospital No. 2 plus glucose 11 mmol/L), and determined postischemic recovery of isolated rat hearts after 3 hours of 10 degrees C cardioplegic protected ischemia. Hearts were arrested and reinfused every 30 minutes throughout the ischemic period with cardioplegic solution. When 5% carbon dioxide was added to nitrogen, the pH of the cardioplegic solution decreased from 9.1 (100% nitrogen) to 7.0 (95% nitrogen: 5% carbon dioxide), a change associated with improved postischemic functional recovery. Aortic output improved from 52.3% +/- 2.7% to 63.9% +/- 2.8%, p less than 0.05, and cardiac output from 60.8% +/- 3.6% to 75.4% +/- 3.3%, p less than 0.01. This improvement was associated with diminished efflux of lactate during ischemia but increased postischemic release of lactate dehydrogenase. When nitrogen was replaced with oxygen, the addition of 5% carbon dioxide resulted in a similar decrease of pH, which again was associated with improved postischemic functional recovery. Aortic output improved from 66.3% +/- 2.8% (100% oxygen) to 88.9% +/- 3.7% (95% oxygen: 5% carbon dioxide), p less than 0.005, and cardiac output from 75.3% +/- 4.1% to 88.9% +/- 2.4%, p less than 0.01. The efflux of lactate during ischemia and the postischemic release of lactate dehydrogenase were similar in both groups. Furthermore, provision of additional oxygen with perfluorocarbons in an electrolyte solution identical to the St. Thomas' Hospital plus glucose solution and oxygenated with 95% oxygen: 5% carbon dioxide conferred no extra protection. In conclusion, the St. Thomas' Hospital No. 2 plus glucose cardioplegic solution should be oxygenated but with 95% oxygen: 5% carbon dioxide and not 100% oxygen because of the additive effect of a relatively "acidotic" pH.
Effect of a general practitioner's consulting style.
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Reperfusion damage: free radicals mediate delayed membrane changes rather than early ventricular arrhythmias.
STUDY OBJECTIVE - The aim of the study was to reassess the role of reactive oxygen species in causing reperfusion arrhythmias, which they might do either by directly generating free oxygen radicals or by using scavengers of free oxygen radicals. DESIGN - Ventricular arrhythmias were studied in isolated rat hearts (n = 8-15 per experiment) subjected to regional ischaemia and treated with various free radical scavengers and spin trap agents. Reoxygenation automaticity was similarly studied in isolated guinea pig papillary muscles (n = 6-13 per experiment). MEASUREMENTS and RESULTS - In isolated rat hearts early reperfusion ventricular arrhythmias were unaltered by superoxide dismutase (1 X 10(5) IU.litre-1), catalase (1 X 10(6) IU.litre-1), N-tert-butyl-alpha-phenylnitrone (30 mumols.litre-1), 5,5-dimethyl-1-pyrroline-N-oxide (1 mmol.litre-1), or the combination of superoxide dismutase 1 X 10(5) IU.litre-1, catalase 1 X 10(6) IU.litre-1, and mannitol 10 mol.litre-1, or by the generation of the free radical .OH (Fe:ADP plus dihydroxyfumerate). In the isolated reoxygenated guinea pig papillary muscle, the incidence of reoxygenation automaticity was significantly reduced by verapamil 5 mumols.litre-1 but not by the following free oxygen radical scavengers: reduced glutathione (0.5 mmol.litre-1), N-acetyl cysteine (1 mmol.litre-1), the combination of superoxide dismutase (3 X 10(4) IU.litre-1) and catalase (5 X 10(3) IU.litre-1), or by pretreatment with allopurinol (30 mg.kg-1). Generating systems of .O2- or .OH induced relatively slow electrophysiological changes, including a decreased action potential duration. Reperfusion ventricular fibrillation in the rat heart was increased by increasing the extracellular calcium concentration from 1.25 to 1.9 or 2.5 mmol.litre-1, or by prolongation of the ischaemic time. CONCLUSIONS - Because of (a) the lack of an arrhythmogenic effect of free radical generating systems or of scavengers of free radicals, (b) the calcium sensitivity of reperfusion arrhythmias, and (c) the relatively slow time course of electrophysiological changes induced by free radical generating systems, we propose that free radicals are unlikely to be the prime cause of early ventricular arrhythmias in the systems that we tested. The mechanism of such arrhythmias is more likely to be a calcium sensitive process. The relatively slow electrophysiological changes mediated by free radicals suggest that these agents can cause delayed membrane change.
Characterization of envelope proteins from Pasteurella haemolytica and Pasteurella multocida.
A method was devised for the reproducible isolation of envelopes from Pasteurella haemolytica serotype A2. It was also possible to prepare envelopes from other serotypes of P. haemolytica and Pasteurella multocida using this methodology. Examination of these preparations by SDS-PAGE showed major differences between strains of P. haemolytica and strains of P. multocida which allowed the clear distinction of isolates of these species. Amongst the P. haemolytica serotypes it was possible to distinguish envelope preparations made from A biotype and T biotype organisms easily, but it was not possible to identify individual serotypes from each other. Envelope profiles were sufficiently different between the individual P. multocida serotypes examined to allow each to be identified by its polypeptide profile. Experiments using radiolabelling, antibody absorption, and susceptibility to protease digestion, together with heat modifiability and detergent solubility characteristics indicated that 13 of the envelope proteins were probably surface-located. A high molecular mass immunogenic envelope protein was shown, by immunoblotting, to be present in all strains of P. haemolytica and P. multocida examined.
Glucose flux rate regulates onset of ischemic contracture in globally underperfused rat hearts.
This study analyzes the importance of the source and rate of ATP production (glucose flux, glycogenolysis, and oxidative phosphorylation) in the prevention of ischemic contracture in isolated rat hearts. Ischemic contracture was initiated at about 10 minutes by buffer perfusion with nonglycolytic substrates whereas the addition of 11 mM glucose prevented contracture for 2 hours. Tissue values of ATP, phosphocreatine, and lactate could be dissociated from onset of ischemic contracture. In hearts perfused with acetate or free fatty acid, with 11 mM glucose, glycolytic ATP production was 2.3-2.8 mumol/g fresh wt/min; as initial rates of glycogenolysis fell, glycolysis was maintained by a steady increase of glucose flux to values in excess of 2 mumol ATP/g fresh wt/min. Decreasing the glucose flux by lowering the perfusate glucose or by the addition of 2-deoxyglucose precipitated ischemic contracture. When oxidative phosphorylation was further reduced by hypoxia, glucose still prevented ischemic contracture; however, when oxidative phosphorylation dropped to near zero (near-anoxic) rates, glycolysis was inhibited, and glucose could only delay ischemic contracture to about 45 minutes. Combined ATP production rates could be dissociated from contracture. The metabolic parameter that correlated best with prevention or delay of ischemic contracture was the rate of glycolytic flux from glucose, which in this model of global low-flow ischemia had to accelerate to provide a rate of ATP production from glucose in excess of 2 mumol/g fresh wt/min within 30 minutes of the start of ischemia to prevent ischemic contracture.
Adenosine and its role in cardioplegia: effects on postischemic recovery in the baboon.
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Ultrastructural correlates of ischaemic contracture during global subtotal ischaemia in the rat heart.
The development of left ventricular ischaemic contracture and its correlation with ultrastructural and sarcolemmal permeability defects were studied in isolated rat hearts during global subtotal ischaemia. With acetate as substrate the hearts exhibited a rise in diastolic tension after 8-10 min at which time small foci of contracted myocytes were scattered throughout the myocardium. In hearts with 5% of the maximum diastolic tension (termed 5% contracture), the foci were situated predominantly in the subendocardium and papillary muscle. Contracted myocytes in these foci were capable of excluding ionic lanthanum thus demonstrating retention of normal sarcolemmal permeability properties. With 30% contracture ultrastructural damage had spread to the subepicardium and with further contracture there was an associated increase in the number and size of foci in all regions. In these foci, swelling of the tubular sarcolemmal system and occasionally of the sarcoplasmic reticulum appeared to precede myofibrillar contraction. At 50% contracture lanthanum influx into contracted cells became more frequent. Hearts developed full contracture by 15-18 min at which time most myocytes were contracted and retained lanthanum intracellularly. The heterogeneity of the response at a cellular level may offer a possible explanation for the lack of correlation between contracture and tissue ATP. A possible sequence of structural injury leading to impaired calcium homeostasis is also suggested.
Adenosine as adjunct to potassium cardioplegia: effect on function, energy metabolism, and electrophysiology.
Adenosine is known to induce rapid cardioplegic arrest and to improve postischemic recovery in the isolated rat heart. Long exposures to high doses of adenosine impair postischemic recovery, however. In this paper we tested the combination of low-dose adenosine (1 mmol/L) with potassium (26 mmol/L), with the aim of achieving rapid arrest (as with high-dose adenosine) but eliminating the need for postarrest washout of adenosine. Cardioplegic solutions studied were (1) Krebs-Henseleit potassium (26 mmol/L) (K); (2) K plus adenosine (1 mmol/L) (KA); (3) K plus an adenosine deaminase inhibitor [erythro-9-(2-hydroxy-3-nonyl)adenine] (0.1 mmol/L) (KE); and as control (4) Krebs-Henseleit potassium (6 mmol/L) (C). We induced cardiac arrest in Langendorff-perfused rat hearts by infusing the cardioplegic solution for 3 minutes at 3 ml/min. Total ischemia lasted 20 minutes at 37 degrees C, followed by reperfusion for 30 minutes. High potassium decreased the arrest time from 260 +/- 16 seconds (group C, mean values +/- standard error of the mean) to 22 +/- 4 seconds (group K). A further decrease to 10 +/- 2 seconds was observed with KA (p = 0.016 versus K). KE, which increased endogenous adenosine, gave intermediate effects. All hearts recovered during reperfusion; the product of developed tension and heart rate (grams per minute) was superior in KA hearts (6250 +/- 740 versus K hearts 4380 +/- 390; p = 0.050). KE gave an intermediate result (5290 +/- 900), while C showed the worst recovery (3180 +/- 830). Our electrophysiologic studies with sinus node and atrial tissue suggest that adenosine induced hyperpolarization and an increase in potassium permeability, thereby arresting the sinus node before depolarization of the membrane by potassium (26 mmol/L). We conclude that low-dose adenosine as an adjunct to potassium shortens the arrest time in this model and improves postischemic recovery.