Evidence for enhanced uptake of ATP by liver and kidney in hemorrhagic shock

1977 ◽  
Vol 233 (3) ◽  
pp. R83-R88 ◽  
Author(s):  
I. H. Chaudry ◽  
M. M. Sayeed ◽  
A. E. Baue
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Beneficial Effect ◽  
Hemorrhagic Shock ◽  
Kidney Slices ◽  
Atp Levels ◽  
Salutary Effect ◽  
Liver And Kidney ◽  
In Vitro Uptake

It has been shown that infusion of ATP-MgCl2 proved beneficial in the treatment of shock; however, it is not known whether this effect is due to improvement in the microcirculation or direct provision of energy or a combination of the above or other effects. To elucidate the mechanism of the salutary effect of ATP-MgCl2, we have now examined the in vitro uptake of ATP by liver and kidney of animals in shock. Rats were bled to a mean arterial pressure of 40 Torr and so maintained for 2 hrs. After the rats were killed, liver and kidney were removed and slices of tissue (0.3-0.5 mm thick) were incubated for 1 h in 1.0 ml of Krebs-HCO3 buffer containing 10 mM glucose, 5 mM MgCl2, and 5 mM [8-14C]ATP or 5 mM [8-14C]ADP, or 5 mM [8-14C]AMP, or 5 mM [8-14C]adenosine in 95% O2-5% CO2 and then homogenized. Tissue and medium samples were subjected to electrophoresis to separate and measure the various nucleotides. The uptake of [14C]ATP but not that of [14C]ADP or [14C]adenosine by liver and kidney slices from animals in shock was 2.5 times greater than the corresponding uptake by control slices. Thus, the beneficial effect of ATP-MgCl2 in shock could be due to provision of energy directly to tissue in which ATP levels were lowered.

Norepinephrine Decreases Fluid Requirements and Blood Loss While Preserving Intestinal Villi Microcirculation during Fluid Resuscitation of Uncontrolled Hemorrhagic Shock in Mice

2015 ◽  
Vol 122 (5) ◽  
pp. 1093-1102 ◽  
Author(s):  
Anatole Harrois ◽  
Nathalie Baudry ◽  
Olivier Huet ◽  
Hiromi Kato ◽  
Laurent Dupic ◽  
...  
Keyword(s):  
Mean Arterial Pressure ◽  
Blood Loss ◽  
Arterial Pressure ◽  
Beneficial Effect ◽  
Hemorrhagic Shock ◽  
Fluid Resuscitation ◽  
Intravital Microscopy ◽  
Intestinal Villi ◽  
Intestinal Microcirculation

Abstract Background: Norepinephrine administration is controversial during hemorrhagic shock resuscitation to stabilize mean arterial pressure (MAP) level because it could have deleterious effects on local circulations. The authors investigated the effect of norepinephrine on intestinal microcirculation during fluid resuscitation in uncontrolled hemorrhagic shock. Methods: Mice (n = 6 per group) submitted to an uncontrolled hemorrhagic shock by tail section were randomly assigned to a resuscitation with fluid but without norepinephrine to target a MAP level of 50 mmHg (FR50) or 60 mmHg (FR60) or a resuscitation with fluid and norepinephrine to target a MAP level of 50 mmHg (FRNE50) or 60 mmHg (FRNE60). Intestinal microcirculation was observed by intravital microscopy. Results: Fluid requirements were lower in groups resuscitated with fluid and norepinephrine than in groups resuscitated with fluid without norepinephrine (74.6 ± 45.1 in FR50vs. 28.1 ± 10.0 µl/g in FRNE50; P = 0.004 and 161.9 ± 90.4 in FR60vs. 44.5 ± 24.0 µl/g in FRNE60; P = 0.041). Blood loss was not statistically different between FR50 and FRNE50 (14.8 ± 8.3 vs. 8.5 ± 2.9 µl/g; P = 0.180) but was significantly lower in FRNE60 than in FR60 (10.1 ± 4.2 vs. 22.6 ± 9.6 µl/g; P = 0.015). This beneficial effect was associated with the restoration of intestinal microcirculation to the same extent in fluid resuscitated groups without norepinephrine (FR50 and FR60) and fluid resuscitated groups with norepinephrine (FRNE50 and FRNE60). Conclusions: During MAP-directed resuscitation of uncontrolled hemorrhagic shock, the administration of norepinephrine decreased blood loss and fluid requirements while preserving intestinal villi microcirculation.

Effect of Hemorrhagic Shock on Tissue Adenine Nucleotides in Conscious Rats

1974 ◽  
Vol 52 (2) ◽  
pp. 131-137 ◽  
Author(s):  
Irshad H. Chaudry ◽  
Mohammed M. Sayeed ◽  
Arthur E. Baue
Keyword(s):  
Skeletal Muscle ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Hemorrhagic Shock ◽  
Subclavian Artery ◽  
Adenine Nucleotides ◽  
Creatine Phosphate ◽  
Atp Content ◽  
Conscious Rats ◽  
Liver And Kidney

Hemorrhagic shock was produced in conscious rats by cannulating the subclavian artery and bleeding the animals to a mean arterial pressure of 40 mm Hg which was maintained for 1 (early shock) or 2 h (late shock). Analysis of tissues showed that there was a significant decrease in ATP and ADP levels in liver and kidney in early and late shock. Associated with the decrease in ATP and ADP levels were increases in AMP and P1 levels. In contrast to the above organs, adenine nucleotides and creatine phosphate levels of skeletal muscle did not decrease in early shock but a significant reduction of these compounds was observed in late shock. The decrease in ATP content was greater in liver and kidney than in skeletal muscle. The present experiments indicate that there is a decrease in the energy available to tissues during severe hemorrhagic shock. This could be due to decreased biosynthesis, to continuing or increased utilization of the nucleotides, or to both.

Preclinical Pharmacology of CW002

2016 ◽  
Vol 125 (4) ◽  
pp. 732-743 ◽  
Author(s):  
Hiroshi Sunaga ◽  
John J. Savarese ◽  
Jeff D. McGilvra ◽  
Paul M. Heerdt ◽  
Matthew R. Belmont ◽  
...  
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Blocking Agent ◽  
Neuromuscular Blocking ◽  
Safety And Efficacy ◽  
Circulatory Effects ◽  
Autonomic Changes ◽  
Train Of Four

Abstract Background CW002, a novel nondepolarizing neuromuscular blocking agent of intermediate duration, is degraded in vitro by l-cysteine; CW002-induced neuromuscular blockade (NMB) is antagonized in vivo by exogenous l-cysteine.1 Further, Institutional Animal Care and Use Committee–approved studies of safety and efficacy in eight anesthetized monkeys and six cats are described. Methods Mean arterial pressure, heart rate, twitch, and train-of-four were recorded; estimated dose producing 95% twitch inhibition (ED95) for NMB and twitch recovery intervals from 5 to 95% of baseline were derived. Antagonism of 99 to 100% block in monkeys by l-cysteine (50 mg/kg) was tested after bolus doses of approximately 3.75 to 20 × ED95 and after infusions. Vagal and sympathetic autonomic responses were recorded in cats. Dose ratios for [circulatory (ED20) or autonomic (ED50) changes/ED95 (NMB)] were calculated. Results ED95s of CW002 in monkeys and cats were 0.040 and 0.035 mg/kg; l-cysteine readily antagonized block in monkeys: 5 to 95% twitch recovery intervals were shortened to 1.8 to 3.6 min after 3.75 to 10 × ED95 or infusions versus 11.5 to 13.5 min during spontaneous recovery. ED for 20% decrease of mean arterial pressure (n = 27) was 1.06 mg/kg in monkeys; ED for 20% increase of HR (n = 27) was 2.16 mg/kg. ED50s for vagal and sympathetic inhibition in cats were 0.59 and >>0.80 mg/kg (n = 14 and 15). Dose ratios for [circulatory or autonomic changes/ED95 (NMB)] were all more than 15 × ED95. Conclusions The data further verify the neuromuscular blocking properties of CW002, including rapid reversal by l-cysteine of 100% NMB under several circumstances. A notable lack of autonomic or circulatory effects provided added proof of safety and efficacy.

Administration of tumor necrosis factor-alpha in vivo depresses endothelium-dependent relaxation

1994 ◽  
Vol 266 (6) ◽  
pp. H2535-H2541 ◽  
Author(s):  
P. Wang ◽  
Z. F. Ba ◽  
I. H. Chaudry
Keyword(s):  
Mean Arterial Pressure ◽  
Tumor Necrosis Factor ◽  
Arterial Pressure ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Vascular Relaxation ◽  
Endothelium Dependent Relaxation ◽  
Necrosis Factor

Although depressed endothelium-dependent relaxation occurs during early sepsis, the precise mechanism responsible for this remains unknown. Because the elevated levels of plasma tumor necrosis factor (TNF) play a major role in the pathophysiology of sepsis, we investigated whether TNF-alpha administration alters endothelium-dependent relaxation. To study this, recombinant TNF-alpha (1.2 x 10(7) U/mg) was infused intravenously (0.25 mg/kg body wt) for 0.5 h in normal rats, and mean arterial pressure was monitored. At 1 h after the completion of TNF-alpha or vehicle infusion, the aorta and a pulmonary artery were isolated, cut into 2.5-mm rings, and placed in organ chambers. Norepinephrine (2 x 10(-7) M) was applied to achieve near-maximal contraction, and dose responses for an endothelium-dependent vasodilator, acetylcholine, and an endothelium-independent vasodilator, nitroglycerine, were determined. In additional studies, aortic rings from normal animals were incubated with TNF-alpha for 2 h in vitro, and vascular reactivity was determined. The results indicate that TNF-alpha administration significantly reduced acetylcholine-induced vascular relaxation both in vivo and in vitro. Such a reduction was sustained at least 80 min after the completion of 2-h incubation with TNF-alpha. In contrast, TNF did not alter nitroglycerine-induced vascular relaxation. Thus TNF-alpha depresses endothelium-dependent relaxation in vitro as well as in vivo. Because TNF-alpha infusion increases plasma TNF levels without decreasing mean arterial pressure, the depressed endothelium-dependent relaxation observed during early sepsis may be due to the elevated circulating levels of TNF.

Mechanisms in the pressor effects of hepatic portal venous fatty acid infusion

1997 ◽  
Vol 273 (1) ◽  
pp. R324-R330 ◽  
Author(s):  
R. J. Grekin ◽  
C. J. Dumont ◽  
A. P. Vollmer ◽  
S. W. Watts ◽  
R. C. Webb
Keyword(s):  
Blood Pressure ◽  
Fatty Acids ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Blood Pressure Elevation ◽  
Pressor Activity ◽  
Venous Infusion ◽  
Hepatic Portal ◽  
Conscious Animals

Portal venous infusion of oleate solution has pressor effects. We have examined efferent mechanisms, measured the response to sustained infusion, and determined the effect of linoleate. Eight conscious animals received concurrent infusions of prazosin or vehicle with portal venous infusion of oleate. Oleate alone increased mean arterial pressure from 109.0 +/- 4.1 to 123.0 +/- 5.8 mmHg (P = 0.02), whereas no increase in blood pressure occurred when oleate was infused with prazosin. In 10 rats, concurrent infusion of losartan had no effect on the pressor activity of portal oleate infusion. Twenty-two animals received portal oleate or vehicle as a continuous infusion for 7 days. Mean arterial pressure (126.1 +/- 2.0 vs. 107.8 +/- 2.6 mmHg, P < 0.001) and heart rate (383 +/- 5 vs. 366 +/- 5, P = 0.0257) were increased in oleate-infused animals. No differences in plasma fatty acids, glucose, insulin, pressor hormones, liver enzymes, or in vitro arterial pressor responsiveness were observed. Portal venous infusion of linoleate increased arterial pressure by 12.2 +/- 3.2 mmHg (P = 0.033). These results indicate that alpha-adrenergic activity is necessary for the acute pressor effects of portal oleate, that sustained portal oleate infusion results in persistent blood pressure elevation, and that other long-chain fatty acids besides oleate have pressor effects.

Characterization of acute reversible systemic hypertension in a model of heme protein-induced renal injury

1999 ◽  
Vol 277 (1) ◽  
pp. F58-F65 ◽  
Author(s):  
David H. Warden ◽  
Anthony J. Croatt ◽  
Zvonimir S. Katusic ◽  
Karl A. Nath
Keyword(s):  
Nitric Oxide ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Sodium Nitroprusside ◽  
Vessel Wall ◽  
Heme Proteins ◽  
Blood Vessel Wall ◽  
Vasodilatory Response

In the glycerol model of renal injury we describe an acute rise in systemic arterial pressure which is attended by a reduced vasodilatory response to acetylcholine in vivo; vasodilatory responses to verapamil, however, were not impaired. Neither arginine nor sodium nitroprusside diminished this rise in blood pressure; N ω-nitro-l-arginine methyl ester (l-NAME) elevated basal mean arterial pressure and markedly blunted the rise in mean arterial pressure following the administration of glycerol. Aortic rings from the glycerol-treated rat demonstrate an impaired vasodilatory response to acetylcholine, an effect not repaired by arginine; the vasodilatory responses to nitric oxide donors, sodium nitroprusside and SIN-1, were also impaired; 8-bromo-cGMP, at higher doses, evinced a vasodilatory response comparable to that observed in the control rings. This pattern of responses was not a nonspecific effect of aortic injury, since aortic rings treated with mercuric chloride, a potent oxidant, displayed an impaired vasodilatory response to acetylcholine but not to sodium nitroprusside. We conclude that in the glycerol model of heme protein-induced tissue injury, there is an acute elevation in mean arterial pressure attended by impaired endothelium-dependent vasodilatation in vitro and in vivo. We suggest that the acute scavenging of nitric oxide by heme proteins depletes the blood vessel wall of its endogenous vasodilator and permeation of heme proteins into the blood vessel wall may contribute to such sustained effects as observed in vitro.

Cardiac hypertrophy and telemetered blood pressure 6 wk after baroreceptor denervation in normotensive rats

1996 ◽  
Vol 271 (6) ◽  
pp. R1759-R1769 ◽  
Author(s):  
B. N. Van Vliet ◽  
L. Hu ◽  
T. Scott ◽  
L. Chafe ◽  
J. P. Montani
Keyword(s):  
Blood Pressure ◽  
Mean Arterial Pressure ◽  
Left Ventricle ◽  
Arterial Pressure ◽  
Wall Thickness ◽  
Free Wall ◽  
Long Evans ◽  
The Right ◽  
Rule Out

We investigated cardiac morphometry 6 wk after sinoaortic baroreceptor denervation (SAD) in Long-Evans rats. SAD (n = 19) was associated with an 11% increase in the weight of the left ventricle (LV) plus septum (P < 0.001) and a 39% increase in that of the right ventricular (RV) free wall (P < 0.001), relative to sham-operated rats (n = 18). RV wall thickness was significantly increased in SAD animals, but there was no difference in the LV wall thickness and volumes of the RV and LV between groups. Constrictor responses to methoxamine and dilation responses to acetylcholine were assessed in an in vitro perfused mesenteric circulation preparation, but neither response was affected by SAD. Baroreceptor denervation was associated with marked and significant increases in the variability (2.8-fold) and daily peak (39 mmHg) levels of telemetered mean arterial pressure (MAP) and small (5%) but significant increases in the daily mean MAP level. Our results are consistent with an effect of increased MAP variability on ventricular weight but cannot rule out possible contributions from other mechanisms.

Vascular Abnormalities and Pulmonary Hypertension in the Berkeley Sickle Mouse.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3185-3185
Author(s):  
David R. Archer ◽  
Shawn Elms ◽  
Joshua Boutwell ◽  
Jennifer Perry ◽  
Roy Sutliff
Keyword(s):  
Pulmonary Hypertension ◽  
Cardiac Output ◽  
Mean Arterial Pressure ◽  
Endothelial Dysfunction ◽  
Mouse Model ◽  
Arterial Pressure ◽  
Right Ventricular ◽  
The Mean

Abstract Clinically, pulmonary hypertension is a major risk factor for mortality in adults with sickle cell disease. Contributing factors probably include red cell hemolysis and vaso-occlusive injury with their associated oxidative and inflammatory stimuli. Previously, we have described RBC hemolysis and endothelial oxidative stress in the Berkeley sickle mouse model and extend those studies in this work to investigate cardiovascular and endothelial dysfunction. Eight to ten month old homozygous and hemizygous Berkeley sickle mice and C57BL/6 control mice were used for all aspects of these experiments. In vivo measurements of mean arterial pressure and right ventricular pressures were conducted in fully anesthetized mice using a pressure transducer inserted in the carotid and right ventricle respectively. Following in vivo readings hearts were excised for measurement of ventricular mass. The ascending aorta was removed and cut into 5 mm rings for in vitro studies of agonist- induced contractility and relaxation. The mean arterial pressure of the hemizygous sickle mice (70.6 ± 3.4) was significantly lower than the control mice (86.0 ± 3.1) and the mean arterial pressure of homozygous sickle mice (59.0 ± 2.2 mmHg) was significantly lower than the hemizygous and control mice (p≤0.05 and p≤0.001, respectively). The right ventricular pressure showed a trend that approached significance (p= 0.08) such that pressures in homozygous mice were ≥ than those in hemizygous which were ≥ than those in control mice. Increased basal cardiac output was suggested by significant left ventricular hypertrophy. In vitro examination of potassium chloride activation of voltage gated calcium channels showed no significant difference in sensitivity or maximal contraction. Similarly, there was no difference in sensitivity to the α1 agonist, phenylephrine. However, both hemi- and homozygous mice showed a significant reduction in maximal force of contraction (normalized to cross sectional area when compared to controls. Maximal acetylcholine induced relaxation of aortic rings was significantly reduced (p≤0.05) in homozygous sickle mice compared to controls. The same effect was not seen with sodium nitroprusside induced relaxation indicating that the acetylcholine effect was not due to effects on the smooth muscle but was endothelium-dependent. The Berkeley mouse model shows cardiac hypertrophy consistent with the increased cardiac output associated with chronic anemia and a reduced basal mean arterial blood pressure similar to that seen in humans. 8–10 month old mice have increased right ventricular pressure and RV mass indicative of pulmonary hypertension. Further endothelial dysfunction is characterized by a reduction in the maximal relaxation elicited by acetylcholine. Therefore, the Berkeley mouse is a good model for investigating sickle related endothelial dysfunction.

scholarly journals Responsiveness to different volume therapies following hemodilution and hemorrhagic shock: a comparative experimental study in rats

2007 ◽  
Vol 22 (5) ◽  
pp. 355-360 ◽  
Author(s):  
Riad Naim Younes ◽  
Fernanda Deutsch ◽  
Mario Itinoshe ◽  
Belchor Fontes ◽  
Renato Poggetti ◽  
...  
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Hemorrhagic Shock ◽  
Hypertonic Saline ◽  
Hypovolemic Shock ◽  
Isotonic Saline ◽  
High Volume ◽  
Subsequent Treatment ◽  
Volume Replacement ◽  
Trauma Patients

Guidelines for volume replacement for acutely hemorrhaged and hemodiluted trauma patients have not been well established. Purpose: To evaluate the effects of acute hemodilution on mean arterial pressure (MAP), and responsiveness of acutely hemodiluted and subsequently hemorrhaged rats to different volume therapies. Methods: 180 rats were hemodiluted to simulate hemorrhaged trauma patients with persistent bleeding after high volume replacement with isotonic solutions. Thirty hemodiluted [Anemia (ANE) group] animals received no further treatment. The remaining 150 animals were subjected to hypovolemic shock and randomized into five groups, according to the treatment option employed: Control (CTL) animals did not receive subsequent treatment after hemorrhagic hypovolemia, SAL4 animals received isotonic saline 4 mL/kg, SAL32 animals received isotonic saline 32 mL/kg, HS animals received hypertonic saline 4 mL/kg and BLD animals received re-infusion of drawn blood. Results: Highest mean arterial pressure (MAP) was achieved by BLD, followed by SAL32 and HS. MAP after treatment of BLD, HS, SAL32 and ANE were higher than CTL (p=0.036). At 85 and 95 minutes of experiment, SAL4, SAL32 and HS presented the lowest hematocrit levels (p<0.01). At day 3, ANE, CTL and HS had the highest hematocrit. SAL4 and CTL groups presented the highest mortality rates. Conclusion: Hypertonic saline is an effective and safe initial therapy for hemodiluted rats undergoing hemorrhagic shock, with an overall outcome comparable to blood replacement or high volume isotonic saline administration.

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