Mechanisms of endothelial cell swelling from lactacidosis studied in vitro

Behmanesh, S.; Kempski, Oliver

doi:10.1152/ajpheart.2000.279.4.h1512

Cited by 31 publications

(23 citation statements)

References 23 publications

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“…This is manifest as both increasing LVR times and higher capillary blood flow to vital organs with impermeant treatment during the low volume period. This is consistent with reduced swelling compression on microcirculatory exchange vessels and reduced obstructive swelling of endothelial cells forming the capillary lumen 23–25 , which allows for better capillary perfusion and more efficient cellular metabolism (lower lactates). All these data are consistent with the hypothesis that circulatory shock states promote cell swelling, which is an important cause of tissue, organ, and systems injury, acting in part, through a microvascular mechanism.…”

Section: Discussionsupporting

confidence: 70%

Cell Impermeant-based Low-volume Resuscitation in Hemorrhagic Shock

et al. 2016

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Objective To determine the role of cell swelling in severe hemorrhagic shock and resuscitation injury. Summary Background Data Circulatory shock induces the loss of energy dependent volume control mechanisms. As water enters ischemic cells, they swell, die, and compress nearby vascular structures, which further aggravates ischemia by reducing local microcirculatory flow and oxygenation. Loading the interstitial space with cell impermeant molecules prevents water movement into the cell by passive biophysical osmotic effects, which prevents swelling injury and no-reflow. Methods Adult rats were hemorrhaged to a pressure of 30–35 mm Hg, held there until the plasma lactate reached 10 mM, and given a low volume resuscitation (LVR) (10–20% blood volume) with saline or various cell impermeants (sorbitol, raffinose, trehalose, gluconate, and Polyethylene glycol-20k (PEG-20k). When lactate again reached 10 mM following LVR, full resuscitation was started with crystalloid and red cells. One hour after full resuscitation, the rats were euthanized. Capillary blood flow was measured by the colored microsphere technique. Results Impermeants prevented ischemia-induced cell swelling in liver tissue and dramatically improved LVR outcomes in shocked rats. Small cell impermeants and PEG-20k in LVR solutions increased tolerance to the low flow state by 2 and 5 fold, respectively, normalized arterial pressure during LVR, and lowered plasma lactate after full resuscitation, relative to saline. This was accompanied by higher capillary blood flow with cell impermeants. Conclusions Ischemia-induced lethal cell swelling during hemorrhagic shock is a key mediator of resuscitation injury, which can be prevented by cell impermeants in low volume resuscitation solutions.

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Section: Discussionsupporting

confidence: 70%

Cell Impermeant-based Low-volume Resuscitation in Hemorrhagic Shock

et al. 2016

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“…23 It is based on the activation of the plasma membrane Na ϩ /H ϩ exchanger inhibited by amiloride analogues as ethylisopropylamiloride. Although aldosterone can exert rapid responses through activation of Na ϩ /H ϩ exchange 24 -27 and can swell endothelial cells, 23 this is not the mechanism of aldosterone-induced HUVEC swelling we describe here. Micromolar amiloride concentrations do not affect the activity of the Na ϩ /H ϩ exchanger to a significant extent, but completely block epithelial sodium channels.…”

Section: Discussionmentioning

confidence: 99%

Human Endothelium: Target for Aldosterone

et al. 2004

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Abstract-Aldosterone has long been known to control water and electrolyte balance by acting on mineralocorticoid receptors in kidney. However, recent studies demonstrated the presence of these receptors in nonclassical locations, including the cardiovascular system. We tested the hypothesis whether endothelial cells respond to aldosterone with changes in cell volume, a measure for ion-mediated water movement across the cell membrane. By means of atomic force microscopy in fluid, we measured volume of adherent human umbilical venous endothelial cells exposed for 72 hours to 10 nmol/L aldosterone. Over this period of time, cells swell by Ϸ18%. Aldosterone-induced swelling is prevented by 100 nmol/L of the mineralocorticoid receptor antagonist spironolactone, added to the primary endothelial cell culture. Aldosterone-treated cells dramatically shrink when 1 mol/L of the diuretic amiloride is applied. Cells deprived of aldosterone do not respond to amiloride. Our conclusions are: (1) aldosterone leads to sustained cell swelling inhibited by administration of spironolactone or the sodium channel blocker amiloride; (2) cells respond to amiloride after aldosterone exposure; (3) renal diuretics act on endothelial cells; and (4) Key Words: endothelium Ⅲ mineralocorticoids T he kidney is known to be the major target for aldosterone, a mineralocorticoid hormone synthesized in the adrenal cortex that acts on electrolyte transport in the distal nephron. 1 However, there is strong evidence that this hormone is also synthesized in heart 2 and blood vessels. 3 At these locations, it is regulated by similar mechanisms comparable to the renin-angiotensin aldosterone system. 4,5 Because of the fact that aldosterone acts on cardiomyocytes, cardiac fibroblasts, and endothelial cells, this hormone plays a major role in the development of heart failure, myocardial fibrosis, and endothelial dysfunction. 6 Moreover, there is much interest in the possibility of the use of aldosterone receptor blockade in patients to diminish pathological effects that can be produced by this hormone. 7 A study applying atomic force microscopy (AFM) on living aortic endothelial cells showed transient cell swelling that occurred over minutes and that was prevented by a high dose of amiloride known to inhibit plasma membrane Na ϩ /H ϩ exchange. 8 Although the underlying mechanism and its physiological relevance were still unclear, attention was placed on data suggesting that endothelial cells not only synthesize aldosterone 3 but also express mineralocorticoid receptors 9 and the epithelial sodium channel. 10 In a recent article, we applied cariporide, a specific Na ϩ /H ϩ exchange inhibitor, to human umbilical venous endothelial cells (HUVECs). 11 To our surprise, we found that the specific Na ϩ /H ϩ exchange inhibitor did not prevent aldosterone-induced cell swelling, whereas, in contrast, a low dose of amiloride known to block plasma membrane sodium channels was most effective. Taken together, these observations indicated that aldosterone triggers the "c...

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“…Our results show a pH-dependent shedding of L-selectin and ␤ 2 -integrin upregulation, and it might be hypothesized that this is related to the extent of NHE activation and the consequent swelling due to Na ϩ influx. Cell swelling has been observed in endothelial cells during hemorrhagic shock (35,36) and during lactacidosis in vitro (3), and in both cases, cell swelling was inhibited by inhibiting NHE. In our study, however, NHE inhibition in an acidic medium did not inhibit but instead enhanced L-selectin shedding (Fig.…”

Section: Cell Swelling Is Unlikely To Be Responsible For Hma-induced mentioning

confidence: 96%

Inhibition of Na⁺/H⁺ exchanger enhances low pH-induced L-selectin shedding and β₂-integrin surface expression in human neutrophils

Kaba¹,

Schultz²,

Law³

et al. 2008

American Journal of Physiology-Cell Physiology

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Ischemia-reperfusion injury is a common pathological occurrence causing tissue damage in heart attack and stroke. Entrapment of neutrophils in the vasculature during ischemic events has been implicated in this process. In this study, we examine the effects that lactacidosis and consequent reductions in intracellular pH (pH(i)) have on surface expression of adhesion molecules on neutrophils. When human neutrophils were exposed to pH 6 lactate, there was a marked decrease in surface L-selectin (CD62L) levels, and the decrease was significantly enhanced by inclusion of Na(+)/H(+) exchanger (NHE) inhibitor 5-(N,N-hexamethylene)amiloride (HMA). Similar effects were observed when pH(i) was reduced while maintaining normal extracellular pH, by using an NH(4)Cl prepulse followed by washes and incubation in pH 7.4 buffer containing NHE inhibitors [HMA, cariporide, or 5-(N,N-dimethyl)amiloride (DMA)]. The amount of L-selectin shedding induced by different concentrations of NH(4)Cl in the prepulse correlated with the level of intracellular acidification with an apparent pK of 6.3. In contrast, beta(2)-integrin (CD11b and CD18) was only slightly upregulated in the low-pH(i) condition and was enhanced by NHE inhibition to a much lesser extent. L-selectin shedding was prevented by treating human neutrophils with inhibitors of extracellular metalloproteases (RO-31-9790 and KD-IX-73-4) or with inhibitors of intracellular signaling via p38 MAP kinase (SB-203580 and SB-239063), implying a transmembrane effect of pH(i). Taken together, these data suggest that the ability of NHE inhibitors such as HMA to reduce ischemia-reperfusion injury may be related to the nearly complete removal of L-selectin from the neutrophil surface.

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Mechanisms of endothelial cell swelling from lactacidosis studied in vitro

Cited by 31 publications

References 23 publications

Cell Impermeant-based Low-volume Resuscitation in Hemorrhagic Shock

Cell Impermeant-based Low-volume Resuscitation in Hemorrhagic Shock

Human Endothelium: Target for Aldosterone

Inhibition of Na⁺/H⁺ exchanger enhances low pH-induced L-selectin shedding and β₂-integrin surface expression in human neutrophils

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Mechanisms of endothelial cell swelling from lactacidosis studied in vitro

Cited by 31 publications

References 23 publications

Cell Impermeant-based Low-volume Resuscitation in Hemorrhagic Shock

Cell Impermeant-based Low-volume Resuscitation in Hemorrhagic Shock

Human Endothelium: Target for Aldosterone

Inhibition of Na+/H+ exchanger enhances low pH-induced L-selectin shedding and β2-integrin surface expression in human neutrophils

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Inhibition of Na⁺/H⁺ exchanger enhances low pH-induced L-selectin shedding and β₂-integrin surface expression in human neutrophils