Preheparinization improves organ function after hemorrhage and resuscitation

Recent studies indicate that heparinization before hemorrhage maintains microvascular patency in the liver and kidney during and after severe hemorrhagic shock. However, it is not known whether preheparinization has any protective effects on organ function after hemorrhage and resuscitation. To study this, unanesthetized rats (with or without preheparinization) were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximum shed blood volume was returned in the form of Ringer lactate (RL). They were then resuscitated with four times the volume of the shed blood with RL. Cardiac output (CO), [3H]inulin clearance (CIn; renal function), hepatic microvascular blood flow (HMBF), and hepatocellular function (HF), i.e., maximal velocity of indocyanine green clearance (Vmax), were determined 1.5 h after resuscitation. Although CO decreased in both groups, the values in preheparinized rats were significantly higher than in the nonheparinized rats. The improvement in CIn as well as HMBF followed the same trends. HF (Vmax) was significantly depressed in the nonheparinized rats but was maintained in preheparinized rats. Thus administration of heparin before the onset of hemorrhage improves CO and renal function and restores HF to control after hemorrhage and resuscitation. These protective effects of preheparinization could be due to the maintenance of microvascular patency and prevention of blood sludging during and after hemorrhage.

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Effects of nonanticoagulant heparin on cardiovascular and hepatocellular function after hemorrhagic shock

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.270.4.h1294 ◽

1996 ◽

Vol 270 (4) ◽

pp. H1294-H1302 ◽

Cited By ~ 2

Author(s):

P. Wang ◽

Z. F. Ba ◽

S. S. Reich ◽

M. Zhou ◽

K. R. Holme ◽

...

Keyword(s):

Blood Flow ◽

Cardiac Output ◽

Anticoagulant Activity ◽

Cecal Ligation ◽

Cardiovascular Responses ◽

Microvascular Blood Flow ◽

Organ Function ◽

Ringer Lactate ◽

Shed Blood ◽

Beneficial Effects

Although heparinization of animals before hemorrhage improves cell and organ function, the potent anticoagulant activity of conventional heparin sodium precludes its potential clinical use. To determine whether a novel nonanticoagulant heparin, GM1892, would have any beneficial effects on cardiovascular and hapatocellular functions and would decrease susceptibility to sepsis after hemorrhage, laparotomy was performed on rats (i.e., trauma induced), after which they were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximal bleedout volume was returned in the form of Ringer lactate solution (RL). The rats were then resuscitated with three times the volume of shed blood with RL over 45 min, followed by infusion of two times RL plus GM1892 (7 mg/kg body wt; approximately 2% the anticoagulant activity of regular heparin) of saline over 60 min. At 2 and 4 h after the completion of resuscitation, cardiac output, hepatocellular function, and microvascular blood flow were determined. The results indicated that cardiac output, hepatocellular function, and microvascular blood flow in the liver, spleen, and small intestine decreased significantly after hemorrhage and resuscitation. Administration of GM1892, however, restored these parameters. The morphological abnormality observed after hemorrhage in the liver, kidney, and small gut was also attenuated with GM1892 treatment. Moreover, GM1892 normalized the elevated plasma prostaglandin E2 levels. Sepsis was induced in additional rats by cecal ligation and puncture (CLP) 20 h after hemorrhage, and the necrotic cecum was excised 10 h thereafter. GM1892 treatment significantly decreased mortality after CLP and cecal excision. Thus GM1892 appears to be a useful adjunct to fluid resuscitation, since it restores the depressed cardiovascular responses and decreases susceptibility to sepsis after trauma and hemorrhage.

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Testosterone receptor blockade after trauma-hemorrhage improves cardiac and hepatic functions in males

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.273.6.h2919 ◽

1997 ◽

Vol 273 (6) ◽

pp. H2919-H2925 ◽

Cited By ~ 23

Author(s):

Dierk E. Remmers ◽

Ping Wang ◽

William G. Cioffi ◽

Kirby I. Bland ◽

Irshad H. Chaudry

Keyword(s):

Cardiac Output ◽

Blood Volume ◽

Maximum Velocity ◽

Left Ventricular ◽

Male Rats ◽

Microvascular Blood Flow ◽

Receptor Blockade ◽

Ringer Lactate ◽

Ventricular Performance ◽

Shed Blood

Although studies have shown that testosterone receptor blockade with flutamide after hemorrhage restores the depressed immune function, it remains unknown whether administration of flutamide following trauma and hemorrhage and resuscitation has any salutary effects on the depressed cardiovascular and hepatocellular functions. To study this, male rats underwent a laparotomy (representing trauma) and were then bled and maintained at a mean arterial pressure (MAP) of 40 mmHg until the animals could not maintain this pressure. Ringer lactate was given to maintain a MAP of 40 mmHg until 40% of the maximal shed blood volume was returned in the form of Ringer lactate. The rats were then resuscitated with four times the shed blood volume in the form of Ringer lactate over 60 min. Flutamide (25 mg/kg) or an equal volume of the vehicle propanediol was injected subcutaneously 15 min before the end of resuscitation. Various in vivo heart performance parameters (e.g., maximal rate of the pressure increase or decrease), cardiac output, and hepatocellular function (i.e., the maximum velocity and the overall efficiency of indocyanine green clearance) were determined at 20 h after resuscitation. Additionally, hepatic microvascular blood flow (HMBF) was determined using a laser Doppler flowmeter. The results indicate that left ventricular performance, cardiac output, HMBF, and hepatocellular function decreased significantly at 20 h after the completion of trauma, hemorrhage, and resuscitation. Administration of the testosterone receptor blocker flutamide, however, significantly improved cardiac performance, HMBF, and hepatocellular function. Thus flutamide appears to be a novel and useful adjunct for improving cardiovascular and hepatocellular functions in males following trauma and hemorrhagic shock.

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Diltiazem restores cardiac output and improves renal function after hemorrhagic shock and crystalloid resuscitation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.262.5.h1435 ◽

1992 ◽

Vol 262 (5) ◽

pp. H1435-H1440

Author(s):

P. Wang ◽

Z. F. Ba ◽

D. R. Meldrum ◽

I. H. Chaudry

Keyword(s):

Renal Function ◽

Cardiac Output ◽

Hemorrhagic Shock ◽

Filtration Rate ◽

Tissue Water Content ◽

Ringer Lactate ◽

Tissue Water ◽

Midline Laparotomy ◽

Doppler Flowmetry ◽

Shed Blood

Although calcium antagonists produce salutary effects after shock and ischemia, it is unknown whether such agents restore the depressed cardiac output (CO) and renal function in a nonheparinized model of trauma-hemorrhage and resuscitation. To study this, rats underwent a midline laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximum bleedout was returned in the form of Ringer lactate (RL). They were then resuscitated with four times the volume of shed blood with RL over 60 min. Diltiazem (400 micrograms/kg body wt) or an equal volume of saline was infused intravenously over 95 min. This infusion was started during the last 15 min of resuscitation. CO was determined by indocyanine green dilution. Glomerular filtration rate (GFR) was assessed with [3H]inulin clearance, and cortical microcirculation was examined by laser Doppler flowmetry. Results indicate that crystalloid resuscitation alone transiently restored but did not maintain CO after hemorrhage. Diltiazem infusion in conjunction with crystalloid resuscitation, however, restored and maintained CO and cortical microcirculation. Although GFR decreased in both groups, the values in diltiazem-treated animals were significantly higher than those in the sham-operated animals. Furthermore, diltiazem markedly decreased tissue water content. Thus diltiazem appears to be a promising adjunct in the treatment of hemorrhagic shock even in the absence of blood resuscitation.

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Association between decreased splenic ATP levels and immunodepression: amelioration with ATP-MgCl2

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1991.261.2.r351 ◽

1991 ◽

Vol 261 (2) ◽

pp. R351-R357 ◽

Cited By ~ 2

Author(s):

D. R. Meldrum ◽

A. Ayala ◽

P. Wang ◽

W. Ertel ◽

I. H. Chaudry

Keyword(s):

Treated Group ◽

Immune Functions ◽

Proliferative Capacity ◽

Organ Function ◽

Shed Blood ◽

Atp Levels ◽

Liver And Kidney ◽

Nuclear Magnetic Resonance Spectrometry ◽

Magnetic Resonance Spectrometry ◽

Vehicle Treated Group

Although it is known that decreased ATP levels in liver and kidney contribute to organ dysfunction after shock, it remains unknown whether there is any association between decreased splenocyte ATP levels and splenic immune functions. Moreover, although studies have shown that ATP-MgCl2 treatment after shock improves hepatic and renal ATP levels and organ function, it remains unknown whether splenocyte ATP levels and immune functions are similarly affected by this agent. To study this, C3H/HeN mice were bled to a mean blood pressure of 35 mmHg, maintained at that pressure for 60 min, resuscitated with shed blood and Ringer lactate, and treated with ATP-MgCl2 (80 mumol/kg) or vehicle (saline). Splenocytes (SPL) were harvested at various intervals after hemorrhage, ATP levels were assessed by 31P nuclear magnetic resonance spectrometry, and functions were determined by measuring proliferative capacity and interleukin (IL)-2, and IL-3 synthesis. Hemorrhage depleted SPL ATP levels to 1.7 +/- 0.8% of control levels. However, there was a significant increase in ATP levels of ATP-MgCl2-treated mice (77 +/- 11%, P less than 0.05) compared with vehicle-treated animals (13 +/- 4.1%) at 1 h after resuscitation. SPL ATP levels returned to control by 2 h after resuscitation in the ATP-MgCl2 group, whereas ATP levels of the vehicle-treated mice remained significantly depressed (P less than 0.05) for up to 12 h after resuscitation. At 1 h after resuscitation, SPL proliferative capacity and IL-2 and IL-3 synthesis were all profoundly depressed in the vehicle-treated group (P less than 0.05 vs. control).(ABSTRACT TRUNCATED AT 250 WORDS)

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Preinduction of heat shock proteins protects cardiac and hepatic functions following trauma and hemorrhage

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.278.2.r352 ◽

2000 ◽

Vol 278 (2) ◽

pp. R352-R359 ◽

Cited By ~ 30

Author(s):

Yasuaki Mizushima ◽

Ping Wang ◽

Doraid Jarrar ◽

William G. Cioffi ◽

Kirby I. Bland ◽

...

Keyword(s):

Cardiac Output ◽

Heat Stress ◽

Heat Shock ◽

Plasma Levels ◽

Left Ventricular ◽

Hsp 70 ◽

Ringer Lactate ◽

Shed Blood ◽

Tnf Α ◽

Shock Proteins

Although studies have shown that induction of the heat shock proteins (HSPs), such as HSP-70, has various beneficial effects after ischemia-reperfusion, it remains unknown whether prior induction of HSP-70 has any salutary effects on cardiovascular and hepatocellular functions after trauma-hemorrhage and resuscitation. Male rats were exposed to heat stress (41°C, 15 min) and then allowed to recover for 24 h at room temperature (21°C). The rats then underwent laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximal shed blood volume was returned in the form of Ringer lactate. Animals were then resuscitated with four times the volume of shed blood with Ringer lactate over 60 min. The maximal rate of the left ventricular pressure increase or decrease was measured up to 4 h after resuscitation. Cardiac output, hepatocellular function, plasma levels of tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were determined at 4 h after resuscitation. Cardiac and hepatic tissue were examined for HSP-70 by Western blot analysis. Left ventricular performance, cardiac output, and hepatocellular function decreased significantly following trauma-hemorrhage. Plasma levels of TNF-α and IL-6 were also significantly increased. However, prior heat stress attenuated cardiovascular and hepatocellular dysfunction, decreased circulating levels of proinflammatory cytokines following trauma-hemorrhage, and was associated with an increased abundance of HSP-70 in the heart and liver. Our data, therefore, suggest that preinduction of HSP-70 protects cardiovascular and hepatocellular functions following trauma-hemorrhage and resuscitation.

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Red wine extract, resveratrol, on maintenance of organ function following trauma-hemorrhage

Functional Foods in Health and Disease ◽

10.31989/ffhd.v2i10.76 ◽

2012 ◽

Vol 2 (10) ◽

pp. 351

Author(s):

Fu-Chao Liu ◽

Huang-Ping Yu

Keyword(s):

Intracellular Signaling ◽

Red Wine ◽

Antioxidant Properties ◽

Neutrophil Function ◽

Protective Effects ◽

Organ Function ◽

Mitogen Activated Protein ◽

Ros Formation ◽

Anti Inflammatory ◽

And Control

Resveratrol, is a polyphenol that can be extracted from grapes and red wine, possess potential anti-inflammatory effects, which would result in the reduction of cytokine production, the alteration of the expression of adhesion molecule molecules, and the inhibition of neutrophil function. Resveratrol might also act as an antioxidant, anti-aging, and control of cell cycle and apoptosis. Resveratrol has been shown to have protective effects for patients in shock-like states. Such protective phenomenon is reported to be implicated in a variety of intracellular signaling pathways including the regulation of the mitogen-activated protein kinases (MAPK)/ hemeoxygenase-1 (HO-1) pathway, activates estrogen receptor (ER), and the mediation of pro-inflammatory cytokines, reactive oxygen species (ROS) formation and reactive. Moreover, through anti-inflammatory effects and antioxidant properties, the resveratrol is believed to maintain organ function following trauma-hemorrhage.Key words: resveratrol, anti-inflammatory, trauma-hemorrhage.

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Systemic hemodynamics and renal function in hemorrhaged dogs resuscitated with cross-linked hemoglobin

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.278.1.r28 ◽

2000 ◽

Vol 278 (1) ◽

pp. R28-R33 ◽

Cited By ~ 3

Author(s):

John M. Stulak ◽

Luis A. Juncos ◽

John A. Haas ◽

J. Carlos Romero

Keyword(s):

Nitric Oxide ◽

Renal Function ◽

Cardiac Output ◽

Sodium Excretion ◽

Systemic Hemodynamics ◽

Urinary Flow ◽

Excretory Function ◽

Renal Function Recovery ◽

Function Recovery ◽

Hormonal Milieu

Cross-linked hemoglobin (XL-Hb) infused into dogs increases mean arterial pressure (MAP) but decreases blood flow to the renal (RBF), mesenteric (MBF), and iliac (IBF) circulations. These actions differ markedly from dextran infusion (which increases RBF, MBF, and IBF without altering MAP) and may be due to scavenging of nitric oxide by XL-Hb. However, because the hormonal milieu regulating regional circulation is altered during hemorrhage (when XL-Hb may be used), we studied whether systemic hemodynamics, RBF, MBF, IBF, and renal excretory function in hemorrhaged dogs was altered when resuscitated with XL-Hb compared with dextran ( n = 6 each). Hemorrhage decreased MAP by 25% due to a 75% decline in cardiac output. RBF, MBF, and IBF all fell by 33, 64, and 72%, respectively ( P < 0.05 each). There was also a fall in glomerular filtration rate (GFR), urinary flow, and sodium excretion ( P < 0.05 each). After resuscitation, MAP, cardiac output, RBF, MBF, IBF, and GFR all recovered to basal values with either XL-Hb or dextran. Urinary flow and sodium excretion increased to above basal levels with dextran (both by 3.5-fold; P < 0.05) or XL-Hb (by 7.5- and 10-fold, respectively; P < 0.05). We conclude that resuscitation with XL-Hb after hemorrhage not only increases MAP, but also restores RBF, MBF, IBF, GFR, and urinary sodium and volume excretion analogously to dextran. The results contrast with those in normal dogs and suggest that nitric oxide inhibition does not impair hemodynamic and renal function recovery during hemorrhage.

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Oestrogen protects against ischaemic acute renal failure in rats by suppressing renal endothelin-1 overproduction

Clinical Science ◽

10.1042/cs103s434s ◽

2002 ◽

Vol 103 (s2002) ◽

pp. 434S-437S ◽

Cited By ~ 27

Author(s):

Masanori TAKAOKA ◽

Mikihiro YUBA ◽

Toshihide FUJII ◽

Mamoru OHKITA ◽

Yasuo MATSUMURA

Keyword(s):

Renal Failure ◽

Renal Function ◽

Acute Renal Failure ◽

Renal Dysfunction ◽

Tissue Injury ◽

Male Rats ◽

Left Renal Artery ◽

Protective Effects ◽

Endothelin 1 ◽

Ischaemia Reperfusion

We investigated whether the treatment with 17β-oestradiol has renal protective effects in male rats with ischaemic acute renal failure (ARF). We also examined if the effect of 17β-oestradiol is accompanied by suppression of enhanced endothelin-1 production in postischaemic kidneys. Ischaemic ARF was induced by clamping the left renal artery and vein for 45min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine and creatinine clearance were measured to test the effectiveness of the steroid hormone. Renal function in ARF rats markedly decreased 24h after reperfusion. The ischaemia/reperfusion-induced renal dysfunction was dose-dependently improved by pretreatment with 17β-oestradiol (20 or 100µg/kg, intravenously). Histopathological examination of the kidney of untreated ARF rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were markedly improved by the higher dose of 17β-oestradiol. In addition, endothelin-1 content in the kidney after the ischaemia/reperfusion increased significantly by approx. 2-fold over sham-operated rats, and this elevation was dose-dependently suppressed by the 17β-oestradiol treatment. These results suggest that oestrogen exhibits protective effects against renal dysfunction and tissue injury induced by ischaemia/reperfusion, possibly through the suppression of endothelin-1 overproduction in postischaemic kidneys.

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