Magnitude Of Hemorrhage Research Articles

Cardiac and Renal Nitric Oxide in the Adaptation to Hypovolemic Shock

Evidence is mounting that NO plays a role in the cardiovascular and renal adaptation to the hemorrhagic shock secondary to major blood loss. Recently, we reported cardiac and renal NO-dependent protective mechanisms activated by the hypovolemic state that include stimulation of NO synthase (NOS) expression and activity. In the heart, an increase in endothelial NOS is an early response to regulate cardiac function after blood loss. Meanwhile, inducible NOS increases heart dysfunction in later stages of sustained hemorrhagic shock. Additionally, the hypovolemic state induced changes in water homeostasis associated with alterations in inner medullary aquaporin water channel type 2 (AQP2) protein expressions and subcellular localization. NO production is one of the causes of the age-associated response that modulates AQP2 expression/trafficking in the inner collecting duct principal cells in response to hemorrhage. The complex regulation of NOS in cardiovascular and renal physiology depends on the magnitude of hemorrhage and age. The adaptive enhancement of NO synthesis and availability activates or increases expression of other protective factors, including heat shock proteins, antioxidants and prostaglandins, making the protection more robust and sustained. The work with laboratory animals and experimental hemorrhagic shock identified mitochondria as a sensitive subcellular compartment involved in the NO-mediated response to hypovolemic state. In a separate line of research, mtNOS was probed as a likely pacemaker of mammalian aging. Finally, further research based on the participation of mtNOS and the relationships between NO and other modulators of heart and kidney function, as well as the impact of aging in tissue adaptation to hypovolemia, are new research lines and hypothetical therapeutic strategies for the prevention and early treatment of tissue dysfunction. Keywords: Nitric oxide synthase, mitochondrial nitric oxide synthase, hypovolemia, heart, kidney

Effects of Haemorrhage on Thermoregulation, Heart Rate and Blood Constituents in Goats (Capra hircus)

The effects of two levels of bleeding (15 and 30%) on physiological responses were evaluated in adult goats. The magnitude of haemorrhage was expressed as percentage of initial total blood volume after plasma volume determination by dye dilution. The groups subjected to haemorrhage had higher rectal temperature, respiration rate and heart rate compared to the control; the responses were more marked with the higher level of bleeding. The treated groups had lower Packed Cell Volume (PCV), haemoglobin concentration (Hb) and Total Leucocyte Count (TLC) compared to the control; they were significantly lower with high level of bleeding compared to the control. The ratio of lymphocytes decreased, whereas the neutrophil ratio increased in treated groups compared to the control. The treated groups had lower serum total protein and albumin concentrations compared to the control. The plasma glucose level was higher in treated groups compared to the control and it increased with the increase of bleeding level. The treated groups had lower serum Na, Ca and Mg concentrations compared to the control. The levels of these minerals decreased with increase of bleeding level. The 15% bleeding group returned to normal values within 2 weeks, whereas the 30% bleeding group recovered within 5 weeks.

Pak2a Mutations Cause Cerebral Hemorrhage in Redhead Zebrafish.

Zebrafish are a powerful vertebrate model system for the study of human disease as they share many molecular pathways with mammals. Of note, nearly all of the mammalian coagulation factors are also highly conserved in fish. As part of a whole genome ENU mutagenesis screen, we identified a mutant zebrafish which displayed intraventricular hemorrhage between 2–3 days post fertilization (dpf), which we named redhead. Using an F2 intercross strategy, we mapped this recessive mutant to a 100 kilobase interval on chromosome 2 and identified a splice site mutation in the gene for an ortholog of the p21-activated kinase Pak2. This IVS9 T+2A mutation renders greater than 90% of transcripts nonfunctional, resulting in a hypomorphic allele. Surveying zebrafish expressed sequence tag databases, we identified two Pak2 orthologs in zebrafish, designated Pak2a and Pak2b, with the redhead mutation in pak2a. Central nervous system (CNS) hemorrhage in redhead embryos was rescued by injection of wild type pak2a mRNA. Morpholino knockdown of pak2a in wild type fish phenocopies the redhead mutant, but with an increase in penetrance and severity, including hydrocephalus and pericardial edema secondary to severe hemorrhage. Injection of either pak2a or pak2b mRNA was able to rescue this phenotype. In addition, pak2b knockdown worsened the bleeding phenotype in redhead embryos, with no effect on wild type fish. These results suggest a partial overlap in function between Pak2a and Pak2b. Confocal microscopy was performed at 2.5 dpf in pak2a knockdown embryos transgenic for Gata1-dsRED and Flk1-eGFP, distinctively labeling erythrocytes and endothelial cells, respectively. The sites and magnitude of hemorrhage were variable between individual embryos, but there were no obvious abnormalities in vessel patterning. In summary, we have identified a critical role for Pak2 in maintaining CNS vessel integrity in zebrafish, without apparent effects on other vascular beds. Further analysis of this signaling pathway in the vessel wall may provide novel insight into the mechanisms underlying vascular heterogeneity in mammals, and the tissue specific function of Pak2 in the CNS vasculature.

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Cardiovascular and catecholamine responses to acute haemorrhage in anaesthetized potassium-adapted rats.

The experiments were designed to determine whether potassium-loaded rats have a deficient recovery of blood pressure after a rapid arterial haemorrhage. Potassium loading was achieved by providing a 0.75% KCl solution as drinking fluid for 14 days, while control rats had either distilled water or tapwater. MAP, HR, Hct, and plasma electrolytes were determined before and after 1 and 2% body weight haemorrhage in anaesthetized Sprague-Dawley rats. Potassium-loaded rats had significantly reduced blood pressure recovery within 20 min after haemorrhage. HR was significantly reduced within 5 min only after 2% haemorrhage in potassium-adapted rats. Haemorrhage induced significant hyperkalaemia which was greater and significantly prolonged after 2% haemorrhage. The significant fall in Hct after haemorrhage was not affected by the magnitude of haemorrhage. In an additional group of rats, the pressor response to intravenous infusion of vasopressin was unaffected by potassium loading, whereas that to noradrenaline and angiotensin II was significantly reduced throughout the 20 min of infusion. The peak increase in blood pressure after phenylephrine injection was, however, unaffected by potassium loading. Basal plasma catecholamines concentration as well as concentrations after 1% haemorrhage were unaffected by potassium loading. It is concluded that the reduced vascular response to noradrenaline and angiotensin contributed to the reduced recovery of blood pressure after haemorrhage in potassium-loaded rats. Furthermore, the result with phenylephrine suggest a mechanism that is unrelated to direct vascular effects of noradrenaline and angiotensin II.

Locus coeruleus monoaminergic activity and plasma corticotropin after hemorrhage in cats.

Temporal changes in monoaminergic activity in the locus coeruleus (LC) in response to hemorrhage of 10 or 20% of blood volume were assessed using normal pulse voltammetry in alpha-chloralose-urethan-anesthetized cats. Oxidation current was measured with a carbon microelectrode, and changes at 230 and 450 mV were used as estimates of catecholaminergic and indolaminergic activity, respectively. Plasma adrenocorticotropin (ACTH) was measured by radioimmunoassay. Hemorrhage of 20% blood volume caused a transient increase in the catecholaminergic activity in a compact area in the ventral LC (vLC) that preceded increases in the plasma ACTH. The increase in oxidation current at 450 mV was similar to that at 230 mV, suggesting no significant contribution from indolamines. Dorsal rostral pontine sites outside this area exhibited either sustained decreases in oxidation current or no change in response to hemorrhage. The proportion of sites that exhibited transient increases in oxidation current in the vLC after the 10% blood loss was less than that after the 20% blood loss, suggesting that this response was dependent on the magnitude of hemorrhage. Since the LC was implicated previously in the control of ACTH release, we suggest that hemodynamic signals traversing the LC activate catecholaminergic mechanisms that, in turn, participate in the regulation of ACTH release after hemorrhage.

Impaired restitution of blood volume after large hemorrhage.

Previous studies have suggested that increases in extracellular osmolality mediate a shift of intracellular fluid into the interstitium following 10% hemorrhage. This unidirectional fluid movement is required for full restitution of blood volume (BV) and for cardiovascular stabilization. The extent to which this mechanisms acts in larger hemorrhages was examined in these studies. Forty-two dogs were studies 3 weeks after splenectomy. Twenty were anesthetized with pentobarbital, the others were studied awake. Hemorrhages of 10% (7.5 ml/kg, 15 dogs), 20% (15 ml/kg, 13 dogs), and 30% (22.5 ml/kg, 15 dogs) were carried out over 3 minutes. Patterns of changes in osmolality, total plasma protein content, and blood volume were identical in the two groups, although osmolality was significantly greater during the first 2 hours in anesthetized dogs. Osmolality increased with increasing degrees of hemorrhage, providing an increasing driving force for fluid shifts. Restitution of BV was significantly greater after 20% hemorrhage than after 10% hemorrhage. However, restitution of BV after 30% hemorrhage was no greater than after 10% hemorrhage. Patterns of protein restitution paralleled changes in BV. Cunningham, Shires, and Wagner (7) reported fluid shifts into cells after a 30% hemorrhage associated with a fall in membrane potential. It thus appears likely that a fluid shift out of cells in response to increased osmolality is offset by shifts into cells as the magnitude of hemorrhage becomes large. This failure of homeostatic restoration of BV with consequent failure of cardiovascular stabilization may represent an early event in the development of hemorrhagic shock.

Transplacental passage of red cells in man.

THE purpose of this communication is to report the results of an investigation into the frequency and magnitude of haemorrhage from the fœtal to the maternal circulation in a random series of deliveries. The total separation of the maternal and fœtal circulations was a long-held biological belief, and was only first seriously questioned in 1941, when the mechanism of haemolytic disease of the newborn was elucidated and Levine1 showed that Rh iso-immunization occurred less often than expected in ABO incompatible matings. Because of these Rh findings, it was postulated that the antigen was carried across the placenta into the maternal circulation by intact erythrocytes.

The significance of diverticula of the colon in massive melena.

Massive melena without hematemesis is often a challenging diagnostic problem. Diverticula of the colon demonstrated in such cases are often overlooked as the source of bleeding. Furthermore, both the clinician and the pathologist have been reluctant to accept diverticula as the source of hemorrhage because a bleeding point may be difficult to demonstrate, even at autopsy. To evaluate the frequency and magnitude of hemorrhage from these lesions, 317 unselected patients with diverticula of the colon were surveyed. The incidence of diverticulosis of the colon has been estimated at 5 to 10% of all the population over 40 years of age. This has been substantiated by Sauer 1 who found them in 5.2% of 70,572 subjects examined, and by Pemberton, Black, and Maino 2 who found them in 8.5%. Rankin and Brown 3 have stated that 15 to 20% of all those with diverticulosis will develop diverticulitis. Therefore, it seems logical