Intracellular angiotensin-(1-12) changes the electrical properties of intact cardiac muscle.

In the present work, the influence of intracellular injection of angiotensin-(1-12) [Ang-(1-12)] on the electrical properties of the intact left ventricle of Wistar Kyoto rats was investigated with electrophysiological methods. Particular attention was given to the role of chymostatin on the effect of the peptide. The results indicated that intracellular administration of the peptide elicited a depolarization of the surface cell membrane and an increase of duration of the action potential followed by the generation of early afterdepolarizations. The increment of action potential duration caused by Ang-(1-12) (100 nM) was due to a decrease of total potassium current recorded from single cardiomyocytes using the whole cell configuration of pCAMP. The decrease of potassium current was related to the activation of protein kinase C (PKC) because the specific inhibitor of kinase C, Bis-1 (10-9 M), abolished Ang-(1-12) effects on the potassium current. The question of whether the effect of Ang-(1-12) was related to the formation of Ang II by chymase was investigated.The results revealed that the intracellular administration of chymostatin, a chymase inhibitor (10-9 M) abolished the effect of intracellular Ang-(1-12) on the potassium current. Moreover, intracellular Ang II (100 nM), by itself, reduced the potassium current, an effect decreased by intracellular valsartan (100 nM). Valsartan (10-9 M) dialyzed into the cell abolished the effect of Ang-(1-12) (100 nM). These observations demonstrate that the effect of Ang-(1-12) on potassium current was related to the formation of Ang II and that the peptide has arrhythmogenic properties.

The incidence of pelvic fractures with traumatic lower limb amputation in modern warfare due to improvised explosive devices.

AIMS: A frequently-seen injury pattern in current military experience is traumatic lower limb amputation as a result of improvised explosive devices (IEDs). This injury can coexist with fractures involving the pelvic ring. This study aims to assess the frequency of concomitant pelvic fracture in IED-related lower limb amputation. METHODS: A retrospective analysis of the trauma charts, medical notes, and digital imaging was undertaken for all patients arriving at the Emergency Department at the UK military field hospital in Camp Bastion, Afghanistan, with a traumatic lower limb amputation in the six months between September 2009 and April 2010, in order to determine the incidence of associated pelvic ring fractures. RESULTS: Of 77 consecutive patients with traumatic lower limb amputations, 17 (22%) had an associated pelvic fracture (eleven with displaced pelvic ring fractures, five undisplaced fractures and one acetabular fracture). Unilateral amputees (n = 31) had a 10% incidence of associated pelvic fracture, whilst 30 % of bilateral amputees (n = 46) had a concurrent pelvic fracture. However, in bilateral, trans-femoral amputations (n = 28) the incidence of pelvic fracture was 39%. CONCLUSIONS: The study demonstrates a high incidence of pelvic fractures in patients with traumatic lower limb amputations, supporting the routine pre-hospital application of pelvic binders in this patient group.

Further studies on the effects of intracrine and extracellular angiotensin II on the regulation of heart cell volume. On the influence of aldosterone and spironolactone.

The influence of extracellular and intracellular angiotensin II (Ang II) on the cell volume in the failing heart of cardiomyopathic hamsters (TO2) was further investigated as well as the influence of aldosterone and spironolactone on the Ang II action on cell volume. Measurements of cell width and area of quiescent ventricular cardiomyocytes were performed using a video camera and computer analysis and the relative cell volume was calculated. All measurements of cell volume were performed in the same cell before and after the administration of Ang II (10⁻8M). The results indicated that: a) the increase in cell volume caused by extracellular Ang II(10⁻8 M) was enhanced in cells incubated with aldosterone (100 nM) for 48 h; b) the effect of aldosterone was abolished by spironolactone (10⁻8 M); c) the decline in cell volume elicited by intracellular administration of Ang II (10⁻8 M) was increased by aldosterone and inhibited by spironolactone; d) the effects of aldosterone and spironolactone were related, in part, to a change in expression of AT1 receptors; and e) the intracellular administration of Ang II reduced the swelling-dependent chloride current (I(Clswell)). The implications of these findings to the failing heart and myocardial ischemia are discussed.

The early detection and management of neuropathic pain following combat injury.

The mechanism of injury on the modern battlefield results in a pattern of wounding which is associated with both nociceptive and neuropathic pain. Nociceptive pain is managed using the WHO Analgesic Ladder but neuropathic pain requires the use of co-analgesic drugs, e.g. antidepressants and anticonvulsants. This study was designed to determine the incidence of neuropathic pain within military casualties with limb injuries. From May to November 2007, 50 casualties were interviewed and assessed using the Leeds Assessment of Neuropathic Symptoms and Signs Scale (LANSS) over consecutive weeks. During the first week post injury, 30% of casualties had a LANSS pain score > 12, suggesting a neuropathic element to their pain. The early detection (using LANSS) and management of neuropathic pain using robust protocols represent the most effective strategy to address this significant problem.

Electrical activity of the heart and angiotensin-converting enzyme inhibitors on the hyperpolarising action of enalapril.

This paper describes the effect of angiotensin- converting enzyme (ACE) inhibitors on the electrical properties of the heart, particularly the effect of these drugs on heart cell coupling and impulse propagation and the possible implications for the generation of malignant ventricular arrhythmias. The hyperpolarising action of enalapril is described and evidence is presented that the activation of the sodium-potassium pump is involved in the increment in membrane potential elicited by the ACE inhibitor.

Precipitation chemistry in the coast of the Metropolitan Region of Rio de Janeiro, Brazil.

Precipitation chemistry was studied in the Metropolitan Region of Rio de Janeiro (MRRJ). This study reveals that rainwater in the MRRJ is affected by emissions of air pollutants and provides essential data for future estimates of regional biogeochemical cycles and the impacts of acid deposition on tropical ecosystems. The volume-weighted mean (VWM) pH was 4.77, varying from 3.50 to 6.85. Sea-salt aerosols were the dominant sources of the Na+, Cl- and Mg2+. Excess SO4(2-), Ca2+ and K+ comprised 82, 91, and 87% of their total VWM concentrations, respectively. There were very strong correlations (r > 0.75, P > 0.01) for NO3- and H+, NO3- and excess(exc-)SO4(2-), NH4+ and exc-K+, and exc-SO4(2-) and exc-Ca2+, suggesting causal relationships between these ion pairs. The VWM concentrations of all major ions, except H+, were higher in the dry season, with dry to wet VWM concentration ratios varying from 1.1 (NH4+) to 4.7 (for total K+).

Chronic administration of losartan plus hydrochlorothiazide improves vascular status in young cardiomyopathic hamsters.

The combination of an angiotensin II receptor antagonist and a thiazide has been used extensively in the treatment of patients with overt heart failure. The effect of this combination on the vascular wall early in the disease, however, has not been investigated. To evaluate this effect, the vascular status of 3-month-old cardiomyopathic hamsters was assessed after daily administration of a combination of losartan (25 mg/kg, p.o.) and hydrochlorothiazide (6.5 mg/kg, p.o.) over an 8-week period. Age-matched golden hamsters were used as healthy controls. The contractile response of aortic rings to endothelin-1 was significantly higher in cardiomyopathic hamsters than in control animals. Concentration-response curves for the endothelin-1-induced contraction were displaced to the right after hydrochlorothiazide+losartan treatment (toward the curves for healthy controls); however, E(max) from treated hamsters was significantly reduced when compared to E(max) from untreated cardiomyopathic animals (1.016+/-0.073 vs. 1.346+/-0.153 g, P<0.05, n=6). No significant differences in the EC50 values from these curves were observed between hydrochlorothiazide+losartan treated and untreated cardiomyopathic animals (2.90+/-0.95 vs. 1.10+/-0.85 nM, P>0.05). The acetylcholine-induced relaxation observed in cardiomyopathic animals was not improved after treatment with hydrochlorothiazide+losartan or hydrochlorothiazide alone, but the combination of these drugs increased significantly the basal production of nitric oxide (NO). Angiotensin-converting enzyme activity increased in plasma (from 29.9+/-1.23 to 41.16+/-1.82 nmol x mg(-1) x min(-1), n=8, P<0.05) but decreased in the aorta (from 0.33+/-0.02 to 0.25+/-0.017 nmol x mg(-1) x min(-1), n=6, P<0.05) after treatment with hydrochlorothiazide+losartan. In addition, the combination of these drugs reduced the heart-to-body mass ratio (3.96+/-0.07 for treated vs. 5.01+/-0.20 mg/g for untreated animals, n=7, P<0.05), and the thickness of the aortic media (0.076+/-0.003 for treated vs. 0.149+/-0.009 mm for untreated animals, n=8, P<0.05). Although hydrochlorothiazide alone lowered systolic blood pressure to the same level achieved with both drugs in combination (from 166+/-10 for untreated cardiomyopathic animals to 84+/-1 mm Hg for hydrochlorothiazide+losartan, and 80+/-5 mm Hg for hydrochlorothiazide alone, P<0.05), no significant reduction in heart-to-body mass ratio was observed in animals treated with the diuretic alone (P>0.05). In conclusion, in this model of heart failure, chronic hydrochlorothiazide+losartan administration normalizes the vascular responses to endothelin-1, improves basal vascular tone, and prevents the development of cardiac and vascular hypertrophy.

Cardiac arrhythmias: the possible role of the renin-angiotensin system.

Activation of the renin-angiotensin system during the process of heart failure may predispose the heart to reentrant malignant arrhythmias by reducing the cell coupling and conduction velocity. Here I discuss the possible role of the renin-angiotensin system on the modulation of cell coupling and impulse propagation with consequent generation of reentrant rhythms. Particular emphasis is given to the effects of angiotensin II on the electrical properties of the failing heart and the beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin II AT1 receptor blockade.

Angiotensin II and the heart : on the intracrine renin-angiotensin system.

-The active end product of the renin-angiotensin system, angiotensin II (Ang II), through the activation of specific Ang II receptors, regulates cardiac contractility, cell coupling, and impulse propagation and is involved in cardiac remodeling, growth, and apoptosis. We review these subjects, as well as the second messengers that are involved, and the synthesis of Ang II in the heart under normal and pathological conditions. Finally, we discuss the possibility that there is an intracrine renin-angiotensin system in the heart that plays a role in the control of cell communication and inward Ca(2+) current.

Battlefield analgesia: an advanced approach.

We present an advanced battlefield analgesia protocol that is designed to provide the maximum benefit for the greatest number of patients using the minimum of resources. During the development we considered logistics, drug pharmacology and safety, aetiology of the pain and the experience of the expected administrator. Analgesia is only considered after the "ABCD" criteria of the Primary Survey have been satisfied. The analgesics administered range from enteral nonopioids through to intravenous opioids based dynamically upon the Visual Analogue Score (VAS). We suggest this protocol could be used by healthcare workers who may not have been trained in acute pain management but are called to administer analgesia to the serviceman in pain.

Cell coupling and impulse propagation in the failing heart.

Cell coupling and impulse propagation were investigated in the ventricle of cardiomyopathic hamsters at an advanced stage of heart failure. An appreciable decline in junctional conductance was found, a phenomenon in part related to activation of the plasma and cardiac renin-angiotensin systems. Decreased expression of connexin43 or an alteration of junctional proteins also might be implicated in the decreased cell coupling. Morphologic abnormalities such as fibrosis, necrosis, and rupture of cell contacts contribute to the decline of conduction velocity or to the blockade of impulse propagation in some areas of the ventricle, creating the conditions for anisotropic conduction and cardiac arrhythmias. The decrease in membrane potential found in myopathic cells is related in part to depression of Na-KATPase activity, and the lack of action of beta-adrenergic agonists on junctional conductance is explained by down-regulation of beta receptors and an abnormality of adenyl cyclase.

Correlation between changes in morphology, electrical properties, and angiotensin-converting enzyme activity in the failing heart.

Evidence is available that morphologic and electrophysiologic abnormalities are present in the failing heart. In the present work, the progressive changes in electrical properties and morphology of the failing heart of Syrian cardiomyopathic hamsters (TO2) were investigated at different stages of the pathological process, and the possible role of the renin-angiotensin system was studied. Cardiomyopathic hamsters 2 and 11 months of age were used. Age-matched normal hamsters (F1B) were utilized as controls. Measurements of membrane potential, conduction velocity and refractoriness were made with conventional intracellular electrodes connected to a high impedance DC amplifier. Serum and cardiac angiotensin-converting enzyme (ACE) activities were measured in controls and cardiomyopathic animals. The results indicated that interstitial fibrosis and calcification were present in the heart of 2-month old Syrian cardiomyopathic hamsters. Measurements of the resting potential performed in the isolated right ventricle of 2-month old Syrian cardiomyopathic hamsters indicated an average value of -66.7 +/- 0.96 mV (n = 25); in the controls of the same age was -78.5 +/- 1 mV (n = 25, P < 0.05); and in 11-month old cardiomyopathic hamsters was -67.8 +/- 0.83 mV (n = 10). The duration of the action potential measured at 50 and 90% of repolarization in 2-month old hamsters was well above the controls. The conduction velocity measured in the isolated right ventricle of 2-month old Syrian cardiomyopathic hamsters (44.2 +/- 1.6 cm/s, n = 12) was not different from the control (43.7 +/- 1.1 cm/s, n = 7, P > 0.05) but was significantly larger than that recorded from the ventricle of 11-month old animals (37.8 +/- 2.9 cm/s, n = 11, P < 0.05). ACE activity was 0.26 +/- 0.01 nmol/mg x min in the heart of controls at 2 months of age and did not change with age. Although in the 2-month old cardiomyopathic hamsters the enzyme activity (0.28 +/- 0.04 nmol/mg x min) was not different from the controls (P > 0.05), in myopathic animals at 11 months of age, the enzyme activity (0.56 +/- 0.027 nmol/mg x min) was greater than controls (P < 0.05). The ACE activity in plasma followed the same pattern. The conclusion from these experiments is, that some parameters like resting potential, action potential duration, and morphological abnormalities appeared quite early in the failing process. The decline in conduction velocity, however, appeared later on, concurrently with the activation of plasma and cardiac renin-angiotensin systems.

Genome type analysis of Brazilian adenovirus strains of serotypes 1,2,3,5, and 7 collected between 1976 and 1995.

A collection of 92 epidemiologically unrelated isolates of Ad1 (n = 14), Ad2 (n = 29), Ad3 (n = 19), Ad5 (n = 16), and Ad7 (n = 14) collected in the cities of Belem do Pará (1 degree S 48 degrees W) and Rio de Janeiro (23 degrees S 43 degrees W) between 1976 and 1995 from patients with respiratory disease and conjunctivitis were characterized by restriction enzyme analysis of genomic DNA. Among the strains of subgenus B, two different genome types of serotype 7, 7b and 7e, were identified. The analysis of their temporal distribution throughout the study period suggested an alternating appearance of these two DNA variants. Only one genome type of Ad3, 3p, was detected during the sampling period. Further analysis with Xba I, Bcl I, and Hpa I indicated that it is a p1-like genome type. Both previously described and new genomic variants were identified among subgenus C strains. Genome types D1, D7, D10, and one not previously described were identified among the 14 Ad1 strains analyzed. Genome types D2, D5, D25, and 13 new DNA variants were identified among the 29 Ad2 isolates. Genome type D38 and 5 new variants were found among the 16 strains of Ad5. In spite of the relatively small size of the sample analyzed, the results of this study confirm the important genetic variability previously observed for members of subgenus C by other authors.