Energy turnover in the normoxic and anoxic turtle heart

We examined the possibility that the heart of the turtle Chrysemys scripta is an exceptional anaerobic performer, by measuring myocardial power output, lactate output, and estimated ATP turnover in perfused heart preparations. Over a range of myocardial power outputs at 5 and 15 degrees C we find that turtle hearts perfused with anoxic saline do not show a particularly outstanding ability to produce ATP anaerobically. Furthermore, at 15 degrees C anoxia reduced the ATP turnover rate to 50% of the normoxic rate. At 5 degrees C the anoxia-induced depression of ATP turnover was even more pronounced, being 4-fold lower than the normoxic rate. In addition, anoxia at 5 degrees C reduced the basal metabolic rate of the turtle heart. We conclude that long-term cardiac tolerance of hypoxia in this species is more likely related to metabolic depression rather than to an exceptional anaerobic performance. (C) 1997 Elsevier Science Inc.

Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonary hypertension

Pulmonary vascular remodeling is an important pathological feature of pulmonary hypertension, leading to increased pulmonary vascular resistance and reduced compliance. It involves thickening of all three layers of the blood vessel wall (due to hypertrophy and/or hyperplasia of the predominant cell type within each layer), as well as extracellular matrix deposition. Neomuscularisation of non-muscular arteries and formation of plexiform and neointimal lesions also occur. Stimuli responsible for remodeling involve transmural pressure, stretch, shear stress, hypoxia, various mediators [angiotensin II, endothelin (ET)-1, 5-hydroxytryptamine, growth factors, and inflammatory cytokines], increased serine elastase activity, and tenascin-C. In addition, there are reductions in the endothelium-derived antimitogenic substances, nitric oxide, and prostacyclin. Intracellular signalling mechanisms involved in pulmonary vascular remodeling include elevations in intracellular Ca2+ and activation of the phosphatidylinositol pathway, protein kinase C, and mitogen-activated protein kinase. In animal models of pulmonary hypertension, various drugs have been shown to attenuate pulmonary vascular remodeling. These include angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, ET receptor antagonists, ET-converting enzyme inhibitors, nitric oxide, phosphodiesterase 5 inhibitors, prostacyclin, Ca2+-channel antagonists, heparin, and serine elastase inhibitors. Inhibition of remodeling is generally accompanied by reductions in pulmonary artery pressure. The efficacy of some of the drugs varies, depending on the animal model of the disease. In view of the complexity of the remodeling process and the diverse aetiology of pulmonary hypertension in humans, it is to be anticipated that successful anti-remodeling therapy in the clinic will require a range of different drug options. (C) 2001 Elsevier Science Inc. All rights reserved.

Comparison of pulmonary vascular function and structure in early and established hypoxic pulmonary hypertension in rats

In pulmonary hypertension, changes in pulmonary vascular structure and function contribute to the elevation in pulmonary artery pressure. The time-courses for changes in function, unlike structure, are not well characterised. Medial hypertrophy and neomuscularisation and reactivity to vasoactive agents were examined in parallel in main and intralobar pulmonary arteries and salt-perfused lungs from rats exposed to hypoxia (10% O-2) for 1 and 4 weeks (early and established pulmonary hypertension, respectively). After 1 week of hypoxia, in isolated main and intralobar arteries, contractions to 5-hydroxytryptamine and U46619 (thromboxane-mimetic) were increased whereas contractions to angiotensins I and II and relaxations to acetylcholine were reduced. These alterations varied quantitatively between main and intralobar arteries and, in many instances, regressed between 1 and 4 weeks. The alterations in reactivity did not necessarily link chronologically with alterations in structure. In perfused lungs, constrictor responses to acute alveolar hypoxia were unchanged after 1 week but were increased after 4 weeks, in conjunction with the neomuscularisation of distal alveolar arteries. The data suggest that in hypoxic pulmonary hypertension, the contribution of altered pulmonary vascular reactivity to the increase in pulmonary artery pressure may be particularly important in the early stages of the disease.

Pulmonary Vascular remodelling in hypoxic rats: effects of amlodipine, alone and with perindopril

This study investigated whether pulmonary Vascular remodelling in hypoxic pulmonary hypertensive rats (10% oxygen; 4 weeks) could be prevented by treatment, during hypoxia, with amlodipine (IO mg/kg/day, p.o.), either alone or in combination with the angiotensin converting enzyme inhibitor, perindopril (30 mg/kg/day, p.o.). Medial thickening of pulmonary arteries (30-500 mum o.d.) was attenuated by amlodipine whereas it was totally prevented by the combination treatment (amlodipine plus perindopril); neomuscularisation of small alveolar arteries (assessed from critical closing pressure in isolated perfused lungs) was not affected. Pulmonary vascular resistance (isolated perfused lungs) was reduced by both treatment regimes but only combination treatment reduced right ventricular hypertrophy. Taus, amlodipine has anti-remodelling properties in pulmonary hypertensive rats. The finding that combining amlodipine with another anti-remodelling drug produced effects on vascular structure that were additive raises the question of whether combination therapy with two different anti-remodelling drugs may be of value in the treatment of patients with hypoxic (and possibly other forms of) pulmonary hypertension. (C) 2001 Elsevier Science B.V. All rights reserved.

Acquired central diabetes insipidus in children: A 12 year Brisbane experience

Objective: To study the clinical, endocrine and radiological features and progress of children presenting with acquired diabetes insipidus (CDI). Methodology: Chart review of children presenting because of CDI to Brisbane paediatric endocrine clinics between 1987 and 1999. Results: Thirty-nine children (female/male ratio 21/18) aged 0.1-15.4 years (mean age 6.7 years) were identified. Aetiologies were head trauma or familial in eight cases (20.5%) each, central nervous system (CNS) tumours in five cases (12.8%), CNS malformations in four cases (10.2%), histiocytosis in three cases (7%) and hypoxia and infection in two cases (5.1%) each. Seven cases (17.9%) remain undiagnosed. Of the 32 (82%) cases with isolated anti-diuretic hormone deficiency at presentation, 24 cases (61.5%) experienced no further endocrine deficit. Additional endocrine deficits occurred mainly in the tumour or undiagnosed groups. On follow-up brain magnetic resonance imaging (MRI) scans in the seven undiagnosed cases, six patients bad mild or no change and one patient had marked improvement of MRI findings. These changes occurred 10-48 months (mean 18 months) after presentation. Conclusions: Children without an aetiological diagnosis for the uncommon condition of acquired CDI require careful follow-up. More intensive investigation at presentation (e.g. estimation of cerebrospinal fluid human chorionic gonadotrophin) promises to lessen the number of such cases. Pituitary stalk biopsies should be reserved for those patients with progressive MRI changes. If these changes do not occur early, our experience suggests that follow-up MRI scans may need to be performed only yearly.

Development of the pulmonary surfactant system in the green sea turtle, Chelonia mydas

This study describes the developmental changes in pulmonary surfactant (PS) lipids throughout incubation in the sea turtle, Chelonia mydas. Total phospholipid (PL), disaturated phospholipid (DSP) and cholesterol (Chol) harvested from lung washings increased with advancing incubation, where secretion was maximal at pipping, coincident with the onset of pulmonary ventilation. The DSP/PL ratio increased, whereas the Chol/PL and the Chol/DSP ratio declined throughout development. The phospholipids, therefore, are independently regulated from Chol and their development matches that of mammals. To explore whether hypoxia could elicit an effect on the development of the PS system, embryos were exposed to a chronic dose of 17% O-2 for the final similar to 40% of incubation. Hypoxia did not affect incubation time, absolute, nor relative abundance of the surfactant lipids, demonstrating that the development of the system is robust and that embryonic development continues unabated under mild hypoxia. Hypoxia-incubated hatchlings had lighter wet lung weights than those from normoxia, inferring that mild hypoxia facilitates lung clearance in this species. (C) 2001 Elsevier Science B.V. All rights reserved.

Assessment of regional long-axis function during dobutamine echocardiography

Echocardiographic analysis of regional left ventricular function is based upon the assessment of radial motion. Long-axis motion is an important contributor to overall function. but has been difficult to evaluate clinically until the recent development of tissue Doppler techniques. We sought to compare the standard visual assessment of radial motion with quantitative tissue Doppler measurement of peak systolic velocity. timing and strain rate (SRI) in 104 patients with known or suspected coronary artery disease undergoing dobutamine stress echocardiography (DbE). A standard DbE protocol was used with colour tissue Doppler images acquired in digital cine-loop format. peak systolic velocity (PSV), time to peak velocity (TPV) and SRI were assessed off-line by an independent operator. Wall motion was assessed by an experienced reader. Mean PSV, TPV and SRI values were compared with wall motion and the presence of coronary artery disease by angiography. A further analysis included assessing the extent of jeopardized myocardium by comparing average values of PSV, TPV and SRI against the previously validated angiographic score. Segments identified as having normal and abnormal radial wall motion showed significant differences in mean PSV (7.9 +/- 3.8 and 5.9 +/- 3.3 cm/s respectively; P < 0.001), TPV (84 40 and 95 +/- 48 ms respectively; P = 0.005) and SRI (- 1.45 +/- 0.5 and - 1.1 +/- 0.9 s(-1) respectively; P < 0.001). The presence of a stenosed subtending coronary artery was also associated with significant differences from normally perfused segments for mean PSV (8.1 3.4 compared with 5.7 +/- 3.7 cm/s; P < 0.001), TPV (78 50 compared with 92 +/- 45 ms; P < 0.001) and SRI (- 1.35 0.5 compared with - 1.20 +/- 0.4 s(-1); P = 0.05). PSV, TPV and SRI also varied significantly according to the extent of jeopardized myocardium within a vascular territory. These results suggest that peak systolic velocity, timing of contraction and SRI reflect the underlying physiological characteristics of the regional myocardium during DbE, and may potentially allow objective analysis of wall motion.

Diurnal changes in the photochemical efficiency of the symbiotic dinoflagellates (Dinophyceae) of corals: photoprotection, photoinactivation and the relationship to coral bleaching

The photochemical efficiency of symbiotic dinoflagellates within the tissues of two reef-building corals in response to normal and excess irradiance at wafer temperatures < 30 C were investigated using pulse amplitude modulated (PAM) chlorophyll fluorescence techniques, Dark-adapted F-v/F-m showed clear diurnal changes, decreasing to a low at solar noon and increasing in the afternoon. However, F-v/F-m also drifted downwards at night or in prolonged darkness, and increased rapidly during the early morning twilight. This parameter also increased when the oxygen concentration of the wafer holding the corals was increased. Such changes have not been described previously, and most probably reflect state transition's associated with PQ pool reduction via chlororespiration. These unusual characteristics may be a feature of an endosymbiotic environment, reflective of the well-documented night-time tissue hypoxia that occurs in corals. F-v/F-m decreased to 0.25 in response to full sunlight in shade-acclimated (shade) colonies of Stylophora pistillata, which is considerably lower than in light-acclimated (sun) colonies. In sun colonies, the reversible decrease in F-v/F-m was caused by a lowering of F-m and F-o suggesting photoprotection and no lasting damage. The decrease in F-v/F-m, however, was caused by a decrease in F-m and an increase in F-o in shade colonies suggesting photoinactivation and long-term cumulative photoinhibition. Shade colonies rapidly lost their symbiotic algae (bleached) during exposure to full sunlight. This study is consistent with the hypothesis that excess light leads to chronic damage of symbiotic dinoflagellates and their eventual removal from reef-building corals. It is significant that this can occur with high light conditions alone.

Transient mesenteric ischaemic episodes tracked by continuous jejunal PCO2 monitoring during liquid feeding

Objective: To test the effect of liquid feeds on the responses to splanchnic ischaemia of a continuous rapid response PCO2 sensor inserted in the jejunum. Design: Prospective experimental animal study in a university research laboratory. Subjects: Adult male Wistar rats. Interventions: Adult male Wistar rats (285-425 g) were anaethetised with sodium pentobarbitone 60 mg/ kg i.p. and ventilated with 100 % oxygen and isoflurane via tracheostomy to a PaCO2 of 30-40 mmHg. A sensor was inserted into the mid-jejunum to record PCO2 every second. Distal aortic pressure was transduced. Four control rats received no feeds whilst in another four rats liquid feed was infused into the proximal jejunum at 3 ml/h. In each rat five episodes of splanchnic ischaemia were induced by 2-min elevations of an aortic sling to a mean distal aortic pressure of 30 mmHg. Measurements and main results: PCO2 elevations were always detectable, usually less than a minute from the onset of splanchnic ischaemia in both fed and unfed rats, with no difference in mean times to detectable response. In the fed rats there was a small but significant increase in the time to peak sensor response (196 +/- 16 vs. 180 +/- 12 s) and a trend towards an elevated mean baseline luminal PCO2 (67 +/- 9 vs. 55 +/- 4 mmHg). Conclusions: Brief episodes of splanchnic ischaemia were tracked successfully by a rapid response jejunal continuous PCO2 sensor during the infusion of a proprietary liquid feed preparation despite minor changes in PCO2 response characteristics and a possible elevation in baseline luminal PCO2.

Alteplase: descendancy in myocardial infarction, ascendancy in stroke

Tissue type plasminogen activator is available, through recombinant technology, for thrombolytic use as alteplase. Alteplase is relatively clot specific and should cause less bleeding side effects than the non-specific agents such as streptokinase. Alteplase has been used successfully in evolving myocardial infarction (MI) to reopen occluded coronary arteries. It is probably equally effective or superior to streptokinase in opening arteries and reducing mortality in Mi. Alteplase is most effective when given early in Mi and is probably ineffective when given 12 h after the onset of symptoms. The effectiveness of alteplase in Mi can be increased by front loading with a bolus of 15 mg, followed by an infusion of 50 mg over 30 min and 35 mg over 60 min. Percutaneous transluminal coronary angioplasty or stenting is associated with a greater patency and lower rates of serious bleeding, recurrent ischaemia and death than alteplase in MI and is likely to take over from alteplase as the standard Mi treatment. A reduced dose of alteplase to increase coronary artery patency prior to angioplasty may be useful in Mi. An exciting new indication for the use of alteplase is in stroke, where it has become the first beneficial intervention. Alteplase is used to reopen occluded cerebral vessels but is associated with an increased risk of intracerebral haemorrhage. Alteplase is beneficial if given within 3 h of the onset of stroke but not after this time period. Therefore, the next challenge is to increase the percentage of people being diagnosed and treated within this period. Clinical trials have not established a role for alteplase in the treatment of acute coronary syndromes or deep vein thrombosis. However, alteplase is useful in treating pulmonary thromboembolism and peripheral vascular disease.

Vascular endothelial growth factor-B-deficient mice show impaired development of hypoxic pulmonary hypertension

To test the hypothesis that Vegf-B contributes to the pulmonary vascular remodelling, and the associated pulmonary hypertension, induced by exposure of mice to chronic hypoxia. Methods: Right ventricular systolic pressure, the ratio of right ventricle/[left ventricle+septum] (RV/[LV+S]) and the thickness of the media (relative to vessel diameter) of intralobar pulmonary arteries (o.d. 50-150 and 151-420 mum) were determined in Vegfb knockout mice (Vegfb(-/-); n=17) and corresponding wild-type mice (Vegfb(+/+); n=17) exposed to chronic hypoxia (10% oxygen) or housed in room air (normoxia) for 4 weeks. Results: In Vegfb(+/+) mice hypoxia caused (i) pulmonary hypertension (a 70% increase in right ventricular systolic pressure compared with normoxic Vegfb(+/+) mice; P

Effect of water temperature and oxygen levels on the diving behavior of two freshwater turtles: Rheodytes leukops and Emydura macquarii

Rheodytes leukops is a bimodally respiring turtle that extracts oxygen from the water chiefly via two enlarged cloacal bursae that are lined with multi-branching papillae. The diving performance of R. leukops was compared to that of Emydura macquarii, a turtle with a limited ability to acquire aquatic oxygen. The diving performance of the turtles was compared under aquatic anoxia (0 mmHg), hypoxia (80 mmHg) and normoxia (155 mmHg) at 15, 23, and 30degreesC. When averaged across all temperatures the dive duration of R. leukops more than doubled from 22.4 +/- 7.65 min under anoxia to 49.8 +/- 19.29 min under normoxic conditions. In contrast, aquatic oxygen level had no effect on the dive duration of E. macquarii. Dive times for both species were significantly longer at the cooler temperature, and the longest dive recorded for each species was 538 min and 166 min for R. leukops and E. macquarii, respectively. Both species displayed a pattern of many short dives punctuated by occasional long dives irrespective of temperature or oxygen regime. Rheodytes leukops, on average, spent significantly less time (42 +/- 2 sec) at the surface per surfacing event than did E. macquarii (106 +/- 20 sec); however, surface times for both species were not related to either water temperature or oxygen level.

Myocardial abnormalities in hypertensive patients with normal and abnormal left ventricular filling: a study of ultrasound tissue characterization and strain

Abnormal left ventricular (LV) filling is common, but not universal, in hypertensive LV hypertrophy (LVH). We sought to elucidate the relative contributions of myocardial structural changes, loading and hypertrophy to LV dysfunction in 113 patients: 85 with hypertensive LVH and 28 controls without LVH and with normal filling. Patients with normal dobutamine stress echocardiography and no history of coronary artery disease were selected, in order to exclude a contribution from ischaemia or scar. Abnormal LV filling was identified in 65 LVH patients, based on Doppler measurement of transmitral filling and annular velocities. All patients underwent grey-scale and colour tissue Doppler imaging from three apical views, which were stored and analysed off line. Integrated backscatter (113) and strain rate imaging were used to detect changes in structure and function; average cyclic variation of 113, strain rate and peak systolic strain were calculated by averaging each segment. Calibrated 113 intensity, corrected for pericardial 113 intensity, was measured in the septum and posterior wall from the parasternal long-axis view. Patients with LVH differed significantly from controls with respect to all backscatter and strain parameters, irrespective of the presence or absence of abnormal LV filling. LVH patients with and without abnormal LV filling differed with regard to age, LV mass and incidence of diabetes mellitus, but also showed significant differences in cyclic variation (P < 0.01), calibrated 113 in the posterior wall (P < 0.05) and strain rate (P < 0.01), although blood pressure, heart rate and LV systolic function were similar. Multivariate logistic regression analysis demonstrated that age, LV mass index and calibrated IB in the posterior wall were independent determinants of abnormal LV filling in patients with LVH. Thus structural and functional abnormalities can be detected in hypertensive patients with LVH with and without abnormal LV filling. In addition to age and LVH, structural (not functional) abnormalities are likely to contribute to abnormal LV filling, and may be an early sign of LV damage. 113 is useful for the detection of myocardial abnormalities in patients with hypertensive LVH.

Cold Storage Preservation and Warm Ischaemic Injury to Isolated Arterial Segments: Endothelial Cell Injury

Injury to endothelial calls is thought to be important to the development of the vascular lesion of chronic rejection. It was the aim of this study to develop a semiquantitative method to assess endothelial injury in arterial grafts and to document the injury produced by cold storage preservation and additional warm ischaemia. Twelve- and 24-h cold preservation of rat aortic segments, together with an additional 1 h of warm ischaemia, were assessed. Electron micrographs of representative endothelial cells were scored for cytoplasmic, nuclear and mitochondrial injury. The overall injury score was obtained by addition of the individual scores. Storage for up to 24 h in University of Wisconsin (UW) and Terasaki did not produce any injury. Twenty-four hours of storage in Euro-Collins resulted in endothelial cell death. Injury occurred after 12 h of storage in Ross, Collins and normal saline, and the injury increased following 24 h of storage. One hour of warm ischaemia did not increase the injury. Injury to endothelial cells varies with the preservation solution used and the time of cold storage, so that both the type of solution and the storage time should be taken into account in clinical studies looking at the influence of cold ischaemia time and graft outcome.

Neural control of the heart: developmental changes in ionic conductances in mammalian intrinsic cardiac neurons

The expression and properties of ionic channels were investigated in dissociated neurons from neonatal and adult rat intracardiac ganglia. Changes in the hyperpolarization-activated and ATP-sensitive K+ conductances during postnatal development and their role in neuronal excitability were examined. The hyperpolarization-activated nonselective cation current, I-h, was observed in all neurons studied and displayed slow time-dependent rectification. An inwardly rectifying K+ current, I-K(I), was present in a population of neurons from adult but not neonatal rats and was sensitive to block by extracellular Ba2+. Using the perforated-patch recording configuration, an ATP-sensitive K+ (K-ATP) conductance was identified in greater than or equal to 50% of intracardiac neurons from adult rats. Levcromakalim evoked membrane hyperpolarization, which was inhibited by the sulphonylurea drugs. glibenclamide and tolbutamide. Exposure to hypoxic conditions also activated a membrane current similar to that induced by levcromakalim and was inhibited by glibenclamide. Changes in the complement of ion channels during postnatal development may underlie observed differences in the function of intracardiac ganglion neurons during maturation. Furthermore, activation of hyperpolarization-activated and KATP channels in mammalian intracardiac neurons may play a role in neural regulation of the mature heart and cardiac function during ischaemia-reperfusion. (C) 2002 Elsevier Science B.V All rights reserved.