Hemorrhagic Hypotension Research Articles

Кишечная недостаточность в патогенезе эндотоксикоза при геморрагической гипотензии

Кишечная недостаточность в патогенезе эндотоксикоза при геморрагической гипотензии

Application of wavelet analysis to detect dysfunction in cerebral blood flow autoregulation during experimental hyperhomocysteinaemia.

The purpose of the present study was to investigate the use of laser Doppler flowmetry (LDF) signals coupled with spectral wavelet analysis to detect endothelial link dysfunction in the autoregulation of cerebral blood flow in the setting of hyperhomocysteinaemia (HHcy). Fifty-one rats were assigned to three groups (intact, control, and HHcy) according to the results of biochemical assays of homocysteine level in blood plasma. LDF signals on the rat brain were recorded by LAKK-02 device to measure the microcirculatory blood flow. The laser operating wavelength and output power density were1064nm and 0.051W/mm2, respectively. A Morlet mother wavelet transform was applied to the measured 8-min LDF signals, and periodic oscillations with five frequency intervals were identified (0.01-0.04Hz, 0.04-0.15Hz, 0.15-0.4Hz, 0.4-2Hz, and 2-5Hz) corresponding to endothelial, neurogenic, myogenic, respiratory, and cardiac origins, respectively. In initial state, the amplitude of the oscillations decreased by 38% (P < 0.05) in the endothelial range in HHcy rats than in control rats. Cerebral autoregulation was challenged by hemorrhagic hypotension. The lower limit of autoregulation raised in a rat model of chronic HHcy (71.5 ± 0.7mmHg in HHcy vs. 62.3 ± 0.5mmHg in control). The data obtained indicate that the laser Doppler method and wavelet analysis may be successfully applied to detect the dysfunction of the endothelial link in cerebral vessel tone and to reveal the pathological shift of lower limit of autoregulation.

Biphasic Renal Sympathetic Response to Hemorrhagic Hypotension in Mice.

The inhibitory responses of renal sympathetic nerve activity (RSNA) and heart rate (HR) to sustained hemorrhagic shock occurred in anesthetized rats, but have not yet been determined in mice. Here, we investigated the responses of RSNA and HR to hemorrhagic hypotension in anesthetized mice, with an emphasis on the molecule-based mechanism for roles of afferent vagal nerves. RSNA, HR, and mean systemic arterial pressure were continuously measured in male pentobarbital-anesthetized C57BL/6N mice. Hemorrhagic hypotension of 50 mmHg was evoked and maintained for 10 min. During hemorrhagic hypotension, RSNA initially increased and then sustainedly decreased, while HR progressively decreased. Vagotomy eliminated the second-phase sympathoinhibition and bradycardia, and carotid sinus denervation with vagotomy abolished the initial renal sympathoexcitation. The renal sympathoinihibition during hemorrhagic hypotension of 50 mmHg was eliminated in mice pretreated with a transient receptor potential vanilloid type 1 channel (TRPV1) inhibitor, capsazepine, and in TRPV1 knockout (TRPV1) mice, but not in TRPV4 knockout mice. The bradycardia response to hemorrhagic hypotension was also absent in TRPV1 mice and mice pretreated with capsazepine. Hemorrhagic hypotension in anesthetized mice causes biphasic responses of RSNA with an initial increase, followed by a sustained decrease, and a progressive decrease in HR. The initial sympathoexcitation is mediated by carotid sinus baroreceptors, while the later sympathoinhibition and bradycardia are mediated via the TRPV1 signals of vagal afferents.

Static cerebrovascular pressure autoregulation remains intact during deep hypothermia.

Clinical studies measuring cerebral blood flow in infants during deep hypothermia have demonstrated diminished cerebrovascular pressure autoregulation. The coexistence of hypotension in these cohorts confounds the conclusion that deep hypothermia impairs cerebrovascular pressure autoregulation. We sought to compare the lower limit of autoregulation and the static rate of autoregulation between normothermic and hypothermic piglets. Twenty anesthetized neonatal piglets (5-7days old; 10 normothermic and 10 hypothermic to 20°C) had continuous measurements of cortical red cell flux using laser Doppler flowmetry, while hemorrhagic hypotension was induced without cardiopulmonary bypass. Lower limit of autoregulation was determined for each subject using piecewise regression and SRoR was determined above and below each lower limit of autoregulation as (%change cerebrovascular resistance/%change cerebral perfusion pressure). The estimated difference in lower limit of autoregulation was 1.4mmHg (lower in the hypothermic piglets; 95% C.I. -10 to 14mmHg; P=0.6). The median lower limit of autoregulation in the normothermic group was 39mmHg [IQR 38-51] vs 35mmHg [31-50] in the hypothermic group. Intact steady-state pressure autoregulation was defined as static rate of autoregulation >0.5 and was demonstrated in all normothermic subjects (static rate of autoregulation=0.72 [0.65-0.87]) and in 9/10 of the hypothermic subjects (static rate of autoregulation=0.65 [0.52-0.87]). This difference in static rate of autoregulation of 0.06 (95% C.I. -0.3 to 0.1) was not significant (P=0.4). Intact steady-state cerebrovascular pressure autoregulation is demonstrated in a swine model of profound hypothermia. Lower limit of autoregulation and static rate of autoregulation were similar in hypothermic and normothermic subjects.

Gastric vascular and motor responses to anaphylactic hypotension in anesthetized rats, in comparison to those with hemorrhagic or vasodilator-induced hypotension

Anaphylactic shock is life-threatening, but pathophysiology of the stomach lesion remains unclear. We determined gastric hemodynamics and gastric functions during anaphylactic hypotension, as compared to hypotension induced by hemorrhage or sodium nitroprusside (SNP) in anesthetized and ovalbumin-sensitized Sprague–Dawley rats. Systemic arterial pressure, portal venous pressure, and gastric arterial blood flow were measured, and gastric vascular resistance (GVR) was determined. Separately, the intragastric pressure (IGP) and gastric effluent, as a measure of gastric flux, were continuously measured. During anaphylaxis, GVR decreased only transiently at 0.5 min, followed by an increase. IGP increased markedly, while gastric flux decreased. During hemorrhage, GVR and IGP increased, while gastric flux did not change. When SNP was injected, both GVR and IGP decreased and gastric flux increased only just after injection. In conclusion, gastric vasodilatation occurs only transiently after antigen injection, and gastric motility increases, but gastric emptying deceases during anaphylactic hypotension in anesthetized rats.

Refrigerated platelets stored in whole blood up to 5 days adhere to thrombi formed during hemorrhagic hypotension in rats

Background There is renewed interest in the therapeutic use of cold-stored platelets for bleeding patients. However, critical information is absent or partially available in vitro. Therefore, thrombus formation and platelet adhesion were studied in vivo, in situ, using bleeding and thrombosis models in instrumented rats, and confocal intravital videomicroscopy. Objectives We tested the hypothesis that refrigerated (4 °C) platelets (stored for 24 h or 5 days) participated in thrombus formation as well as platelets stored at room temperature (RT, 22 °C). This hypothesis was tested in normovolemia and hemorrhagic hypotension. Methods & Results After fluorescently-labeled platelet infusion, endothelial injury and vessel rupture were laser-induced in cremaster microvessels and platelet adhesion in > 230 developing thrombi was evaluated. Blood samples were collected for biochemistry and coagulation assays while multiple systemic physiologic parameters were recorded. Hemorrhagic hypotension study animals were subjected to 40% hemorrhage, leading to hypotension and hemodilution, during in vivo platelet adhesion assessments. The fluorescence intensity associated with labeled platelet adherence provided a quantitative index of adhesion. Cold-stored platelets performed as well as those stored at RT in normovolemic animals. During hypotension, cold-stored platelets still performed as well as RT-stored platelets, whereas platelet adhesion and thrombus formation were increased relative to normovolemic animals, in bleeding model experiments. Conclusions We found the methodology suitable for evaluating platelet function in vivo after different storage conditions in fully monitored animals. Refrigerated platelets (stored up to 5 days) participated as well as RT-stored platelets in thrombi formed after hemorrhage, suggesting that refrigerated platelets are effective during hypotensive situations.

Abstract PR161

Background & Objectives: Hydrogen gas is widely considered to be a novel antioxidant1). It has been demonstrated that inhalation of hydrogen gas reduced ischemic cerebral injury in several investigations. However, it remains unclear whether the neuroprotective effect of hydrogen gas is reproducible in a rat transient forebrain ischemia model (i.e. the Smith model). The current study was conducted to evaluate the effect of hydrogen gas on histological outcome after 7-day recovery period in rats subjected to transient forebrain ischemia. Materials & Methods: After approval by the animal research committee, male Sprague-Dawley rats were randomly assigned to one of the following 2 groups: control group, or hydrogen gas group (n=6 in each group). In the hydrogen gas group, transient forebrain ischemia was induced by a combination of hemorrhagic hypotension (mean arterial pressure= 40 mmHg) and bilateral carotid artery occlusion following 2.5% of sevoflurane anesthesia. The brain was reperfused 10 minutes after the onset of ischemia, and after 1 hour, the sevoflurane anesthesia was discontinued. 1.3% hydrogen gas inhalation began 10 min prior to the onset of ischemia, and was continued until the discontinuation of the anesthesia. Temporalis muscle temperature was maintained at approximately 37.5 degrees throughout the procedure. In the control group, all treatments were the same as the hydrogen gas group except for the hydrogen gas inhalation. Seven days after ischemia, the rats were sacrificed for histological evaluation. The brain slices were stained with hematoxilin and eosin, and the coronal sections at hippocampal level were examined light-microscopically. The degree of neuronal damage in the CA1 subfield of the hippocampus was assessed using the following scale: 1 = no ischemic neurons; 2 = less than 20% ischemic neurons; 3 = 20~50% ischemic neurons; 4 = 50~80% ischemic neurons; 5 = more than 80% ischemic neurons; 6 = no intact neurons. Statistical analysis was performed with Mann-Whitney U test for group comparison. Results: The median hippocampal injury scale was greater in the control group than in the hydrogen gas group (5[0] vs. 4[2]; median [interquartile range], respectively, p=0.07). Conclusion: The current study indicates that the treatment with 1.3% hydrogen gas is likely to provide a modest neuroprotective effect in a rat transient forebrain ischemia model.

Histamine restores hemorrhage induced hypotension by activating cholinergic neurons in nucleus tractus solitarius

The purpose of the current study is to investigate the functional connections between the central histaminergic and cholinergic systems at NTS level in hypotensive condition.Experiments were carried out in male Wistar Albino rats. The hypotension was achieved by withdrawing a total volume of 1.5ml blood/100g bodyweight over a period of 10min. A microdialysis study was performed in NTS area to measure extracellular ACh and Ch levels. The hemorrhage produced a severe and long-lasting decrease in mean arterial blood pressure (MAP) and increase in extracellular ACh and Ch levels in NTS. Administration of histamine intracerebroventricularly (i.c.v.) or into the NTS reversed the hemorrhagic hypotension by increasing MAP and heart rate. I.c.v. injection of histamine also caused the additional increase in extracellular ACh and Ch levels. Moreover, central histamine injection augmented intracytoplasmic AChE immunoreactivity in NTS. These changes were completely blocked by histaminergic H1 receptor antagonist chlorpheniramine, but histaminergic H2 receptor blocker ranitidine and histaminergic H3/H4 receptor antagonist thioperamide failed to produce these effects.In conclusion, these findings are interpreted that brain histaminergic H1 receptor activation by central histamine injection may promote cholinergic stimulation in the NTS and subsequently reverses the hypotension.

Remote cerebellar hemorrhage and intracranial hypotension syndrome following pituitary surgery.

Remote cerebellar hemorrhage and intracranial hypotension syndrome following pituitary surgery.

Controlled hypotensive Hemorrhage sensitizes angiotensin II‐elicited hypertension

Hemorrhagic shock is associated with increased renin‐angiotensin system (RAS) activity and elevated levels of proinflammatory cytokines (PICs) in the circulation and in central nervous system (CNS) regions controlling arterial pressure and vasopressin release. Using an Induction‐Delay‐Expression (IND‐DEL‐EXP) experimental paradigm, our previous studies demonstrated that activation of the central RAS and inflammation produced by various challenges sensitizes angiotensin (ANG) II‐elicited hypertension. The present study tested the hypothesis that controlled hypotensive hemorrhage also sensitizes the ANG II‐elicited hypertensive response. Male rats were prepared for telemetry recording of blood pressure (BP). During IND, rats were hemorrhaged (5 ml/rat at 1.5 ml/min) via the jugular vein on two occasions separated by 1 day. The blood was collected in heparin and centrifuged, and the cells re‐suspended in saline for re‐infusion. Hemorrhage lowered BP to ~40 mmHg that was maintained for 30 min after which time the rats were reinfused. After a one‐week DEL, the rats were administrated ANG II (120 ng/kg/min, SC) for 2 weeks (EXP). Hemorrhaged rats had a significantly enhanced hypertensive response to the ANG II infusion when compared to control rats (Δ52.3±3.8 mmHg vs. Δ29.8±2.8 mmHg). RT‐PCR analysis of tissue from the lamina terminalis and the hypothalamic paraventricular nucleus indicated that the ANG II treatment upregulated mRNA expression of several components of the RAS and PICs including angiotensinogen, angiotensin type 1 receptor, angiotensin converting enzyme, TNF‐α, interleukin (IL)‐1β and IL‐6 in both control and hemorrhaged rats. Notably, the increases in PIC expression were greater in hemorrhaged rats than that in control rats. The results indicate that controlled hypotensive hemorrhage sensitizes ANG II‐elicited hypertension and that this is associated with upregulation of the central RAS and of brain PICs.Support or Funding InformationNIH grants HL‐14388, HL‐98207 and MH‐80241

Hypovolemic hemorrhage induces Fos expression in the rat hypothalamus: Evidence for involvement of the lateral hypothalamus in the decompensatory phase of hemorrhage

This study tested the hypothesis that the hypothalamus participates in the decompensatory phase of hemorrhage by measuring Fos immunoreactivity and by inhibiting neuronal activity in selected hypothalamic nuclei with lidocaine or cobalt chloride. Previously, we reported that inactivation of the arcuate nucleus inhibited, but did not fully prevent, the fall in arterial pressure evoked by hypotensive hemorrhage. Here, we report that hemorrhage (2.2ml/100g body weight over 20min) induced Fos expression in a high percentage of cells in the paraventricular, supraoptic and arcuate nuclei of the hypothalamus as shown previously. Lower densities of Fos immunoreactive cells were also found in the medial preoptic area (mPOA), anterior hypothalamus, lateral hypothalamus (LH), dorsomedial hypothalamus, ventromedial hypothalamus (VMH) and posterior hypothalamus. Bilateral injection of lidocaine (2%; 0.1μl or 0.3μl) or cobalt chloride (5mM; 0.3μl) into the tuberal portion of the LH immediately before hemorrhage was initiated reduced the magnitude of hemorrhagic hypotension and bradycardia significantly. Lidocaine injection into the VMH also attenuated the fall in arterial pressure and heart rate evoked by hemorrhage although inactivation of the mPOA or rostral LH was ineffective. These findings indicate that hemorrhage activates neurons throughout much of the hypothalamus and that a relatively broad area of the hypothalamus, extending from the arcuate nucleus laterally through the caudal VMH and tuberal LH, plays an important role in the decompensatory phase of hemorrhage.

Vitamin C Attenuates Hemorrhagic Hypotension Induced Epithelial-Dendritic Cell Transformation in Rat Intestines by Maintaining GSK-3β Activity and E-Cadherin Expression.

To investigate the roles of epithelial-dendritic cell transformation (EDT) characterized by the expression of dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) in the occurrence of tissue inflammation induced by hemorrhagic hypotension (HH), the protective effect of vitamin C (VitC), and the potential mechanisms. We conducted an in vitro study using the rat intestinal epithelial cells (IEC-6). After hypoxic culture with or without VitC for 2, 6, 24, and 48 h (n = 3 per group), the expression levels of DC-SIGN, E-cadherin, and Glycogen synthase kinase-3β-S9 (GSK-3β-S9) in IEC-6 cells, IL-1β, and IL-6 concentrations in the cell culture medium were measured. To investigate the potential mechanism, we inhibited E-cadherin expression by siRNA and GSK-3β activity by TDZD-8, respectively. The in vivo study was conducted by establishing SD rat HH model. We observed the expression levels and location of DC-SIGN in the intestines. We also showed histological damage, TNF-α and IL-6 concentrations, and organ injury scores at 2, 6, and 24 h after HH (n = 6 per group), with or without VitC pretreatment. Hypoxia-induced DC-SIGN expression in IEC-6 cells in a time-dependent manner and the inflammatory factors were also increased. VitC inhibited all these phenomena. Hypoxia inhibited GSK-3β activity and E-cadherin expression. VitC could ease these inhibitions. The inhibitory effect of VitC on DC-SIGN was diminished when E-cadherin expression was inhibited in advance. TDZD-8 diminished the protective effect of VitC on E-cadherin and abolished inhibitory effect of VitC on DC-SIGN expression. HH-induced DC-SIGN expression in rat intestine epithelial cells and the histological damage scores and pro-inflammatory cytokine levels were also increased. HH induces EDT in rat intestine epithelial cells. VitC maintains GSK-3β activity, attenuates the suppression of E-cadherin caused by hypoxia, and ultimately decreases DC-SIGN expression.

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multi-Organ Dysfunction: Final Results from a Pivotal, Historically Controlled, Phase 3 Trial

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multi-Organ Dysfunction: Final Results from a Pivotal, Historically Controlled, Phase 3 Trial

Increased expression of macrophage migration inhibitory factor in the nucleus of solitary tract attenuates the renovascular hypertension

We investigatedwhether hemorrhagic hypotension (HH) altered the sensitivity of vagal pulmonary C-fibers in this study. The fiber activity (FA) of single vagal pulmonary C-fiber was continuously recorded in anesthetized rats before, during, and after HH was induced by bleeding from the femoral arterial catheter into a blood reservoir and lowering the mean systemic arterial blood pressure (MSAP) to ~40 mmHg for 20 min. Our results showed: 1)AfterMSAP reached a steady state of HH, the peak FA response to intravenous injection of capsaicin was elevated by ~5 folds. The enhanced C-fiber sensitivity continued to increase during HH and sustained even after MSAP returned to baseline during the recovery, but slowly returned to control ~20 min later. 2) Responses of FA to intravenous injections of other chemical stimulants of pulmonary Cfibers (phenylbiguanide, lactic acid and adenosine) and a constantpressure lung hyperinflation were all significantly potentiated by HH. 3) Infusion of sodium bicarbonate alleviated the systemic acidosis during HH, and it also attenuated, but did not completely prevent the HHinduced C-fiber hypersensitivity. In conclusion, the pulmonary C-fiber sensitivity was elevated during HH, probably caused by the endogenous release of chemical substances (e.g., lactic acid) that were produced by tissue ischemia during HH. This enhanced C-fiber sensitivity may heighten the pulmonary protective reflexes mediated through these afferents (e.g., J reflex) during hemorrhage when the body is more susceptible to other hazardous insults and pathophysiological stresses. (Supported in part by NHLBI and DoD grants)

Hypersensitivity of vagal pulmonary C-fibers is induced by hemorrhagic hypotension in anesthetized rats

Hypersensitivity of vagal pulmonary C-fibers is induced by hemorrhagic hypotension in anesthetized rats

Effect of Perfluorane on the Amplitude-Frequency Spectrum of Fluctuations in Cerebral Blood Flow in Hemorrhagic Hypotension and During the Reperfusion Period

Objective: to use laser Doppler flowmetry (LDF) to investigate the effect of perfluorane on the time course of microhemocirculato ry changes in the rat pial vessels in acute blood loss and after autohemotransfusion. Material and methods. Experiments were car ried out on 31 outbred male rats weighing 300—400 g under anesthesia with intraperitoneal Nembutal 45 mg/kg. The caudal artery was catheterized to measure blood pressure (BP), to sample and reinfuse blood, and to administer infusion solutions. LDF (ЛАКК 02 device, LAZMA, Russia) was used to record blood flow in the pial vessels of the left parietal region (the center coordinates were 3 mm caudal to bregma and 2 mm left of the sagittal suture. A volumefixed acute blood loss model was applied. The goal amount of blood loss was 30% of the circulating blood volume. At 10 minutes after blood sampling, the animals were administered 0.9% NaCl solution (physiologic saline (PS), n=15) or perfluorane (PF), n=16)) in a dose of 3 ml/kg body weight. At 60 minutes following blood sampling, autohemotransfusion was used, after which there was a 60min reperfusion period. The investigators analyzed LDF readings and determined the following indicators: microcirculation index; the maximum amplitudes of blood flow fluctuations in the endothelial, neurogenic, and myogenic frequency ranges by a wavelet analysis. The data were statistically processed using Statistica 7.0 software. Results. Hypovolemia caused a more than 50% reduction in BP; moreover, blood flow in the pial vessels decreased by less than 20% of its baseline level (p<0.05). In the same period, there was an increase in the amplitude of flux motions mainly in the neurogenic (NA) frequency. The differences in microcirculatory parameters between the PS or PF groups were in the retention of higher NA in the PS group throughout hypovolemia; at the same time the groups did not differ in the arterial blood levels of the index of perfusion (IP), рСО2, and lactate. After blood reinfusion and BP elevation, the examined microcirculatory parameters did not dif fer between the groups and were similar to the baseline values, suggesting that there were compensatory changes in the amplitude of flux motions in response to evolving blood loss. Conclusion. The findings suggest that PF versus PS leads to the reduced tension of compensatory mechanisms for cerebral blood flow regulation at a risk for hypoxia during hypovolemia.

The role of centrally injected nesfatin-1 on cardiovascular regulation in normotensive and hypotensive rats.

This study investigated the cardiovascular effects of nesfatin-1 in normotensive rats and animals subjected to hypotensive hemorrhage. Hemorrhagic hypotension was induced by withdrawal 2 mL blood/100 g body weight over a period of 10 min. Acute hemorrhage led to a severe and long-lasting decrease in mean arterial pressure (MAP) and heart rate (HR). Intracerebroventricularly (i.c.v.) administered nesfatin-1 (100 pmol) increased MAP in both normotensive and hemorrhaged rats. Nesfatin-1 also caused bradycardia in normotensive and tachycardia in hemorrhaged rats. Centrally injected nesfatin-1 (100 pmol, i.c.v.) also increased plasma catecholamine, vasopressin and renin concentrations in control animals and potentiated the rise in all three cardiovascular mediators produced by hemorrhage. These findings indicate that centrally administered nesfatin-1 causes a pressor response in conscious normotensive and hemorrhaged rats and suggest that enhanced sympathetic activity and elevated vasopressin and renin concentrations mediate the cardiovascular effects of the peptide.

Short-term sleep deprivation stimulates hippocampal neurogenesis in rats following global cerebral ischemia/reperfusion.

BackgroundSleep deprivation (SD) plays a complex role in central nervous system (CNS) diseases. Recent studies indicate that short-term SD can affect the extent of ischemic damage. The aim of this study was to investigate whether short-term SD could stimulate hippocampal neurogenesis in a rat model of global cerebral ischemia/reperfusion (GCIR).MethodsOne hundred Sprague-Dawley rats were randomly divided into Sham, GCIR and short-term SD groups based on different durations of SD; the short-term SD group was randomly divided into three subgroups: the GCIR+6hSD*3d-treated, GCIR+12hSD-treated and GCIR+12hSD*3d-treated groups. The GCIR rat model was induced via the bilateral occlusion of the common carotid arteries and hemorrhagic hypotension. The rats were sleep-deprived starting at 48 h following GCIR. A Morris water maze test was used to assess learning and memory ability; cell proliferation and differentiation were analyzed via 5-bromodeoxyuridine (BrdU) and neuron-specific enolase (NSE), respectively, at 14 and 28 d; the expression of hippocampal BDNF was measured after 7 d.ResultsThe different durations of short-term SD designed in our experiment exhibited improvement in cognitive function as well as increased hippocampal BDNF expression. Additionally, the short-term SD groups also showed an increased number of BrdU- and BrdU/NSE-positive cells compared with the GCIR group. Of the three short-term SD groups, the GCIR+12hSD*3d-treated group experienced the most substantial beneficial effects.ConclusionsShort-term SD, especially the GCIR+12hSD*3d-treated method, stimulates neurogenesis in the hippocampal dentate gyrus (DG) of rats that undergo GCIR, and BDNF may be an underlying mechanism in this process.

Interaction of sodium bicarbonate and Na+/H+ exchanger inhibition in the treatment of acute metabolic acidosis in pigs.

Administration of NaHCO3 does not improve cellular function or reduce the mortality of acute lactic acidosis. This might be related to aggravation of intracellular acidosis, but it could also be due to activation of Na+/H+ exchanger with a deleterious increment in intracellular calcium ([Ca2+]i). This study examined the impact of coadministration of NaHCO3 and a selective inhibitor of Na+/H+ exchanger, sabiporide on cardiovascular function, changes in proinflammatory cytokines, and organ function in a model of acute lactic acidosis produced by hemorrhagic hypotension followed by infusion of lactic acid. Experimental, prospective study. Medical Center research laboratory. Male Yorkshire pigs. Anesthetized pigs were subjected to hypovolemia for 30 minutes and followed by DL-lactic acid infusion, and then either saline or sodium bicarbonate was infused. Hypovolemia followed by a DL-lactic acid infusion resulted in severe acidemia with a blood pH~6.8. Administration of NaHCO3 did not improve cardiovascular performance or decrease the levels of proinflammatory responses, whereas administration of sabiporide prior to acid or NaHCO3 infusion improved cardiopulmonary performance and blood oxygenation, reduced nuclear factor-κB activation, neutrophil accumulation, and proinflammatory cytokine production, and attenuated organ injury. Exposure of rat cardiac myocytes to a pH of 7.2 led to a marked increase of [Ca2+]i, and release of lactate dehydrogenase from cells which were further augmented after increase in external pH by addition of NaHCO3. Both the increase in [Ca2+]i and release of lactate dehydrogenase were attenuated in the presence of sabiporide. Coadministration of Na/H exchanger inhibitor with sodium bicarbonate improves cardiovascular performances, reduces proinflammatory responses, and attenuates organ injury. This improvement in these variables appears to be related to prevention of a rise in intracellular calcium occurring after both exposures to acid and bicarbonate.

5-HT1Areceptors of the nucleus tractus solitarii facilitate sympathetic recovery following hypotensive hemorrhage in rats

The role of serotonin in the hemodynamic response to blood loss remains controversial. Caudal raphe serotonin neurons are activated during hypotensive hemorrhage, and their destruction attenuates sympathetic increases following blood loss in unanesthetized rats. Caudal raphe neurons provide serotonin-positive projections to the nucleus tractus solitarii (NTS), and disruption of serotonin-positive nerve terminals in the NTS attenuates sympathetic recovery following hemorrhage. Administration of 5-HT1A-receptor agonists following hemorrhage augments sympathetic-mediated increases in venous tone and tissue hypoxia. These findings led us to hypothesize that severe blood loss promotes activation of 5-HT1A receptors in the NTS, which facilitates sympathetic recovery and peripheral tissue perfusion. Here, we developed an adeno-associated viral vector encoding an efficacious small hairpin RNA sequence targeting the rat 5-HT1A receptor. Unanesthetized rats subjected to NTS injection of the anti-rat 5-HT1A small hairpin RNA-encoding vector 4 wk prior showed normal blood pressure recovery, but an attenuated recovery of renal sympathetic nerve activity (-6.4 ± 12.9 vs. 42.6 ± 15.6% baseline, P < 0.05) 50 min after 21% estimated blood volume withdrawal. The same rats developed increased tissue hypoxia after hemorrhage, as indicated by prolonged elevations in lactate (2.77 ± 0.5 vs. 1.34 ± 0.2 mmol/l, 60 min after start of hemorrhage, P < 0.05). 5-HT1A mRNA levels in the commissural NTS were directly correlated with renal sympathetic nerve activity (P < 0.01) and inversely correlated with lactate (P < 0.05) 60 min after start of hemorrhage. The data suggest that 5-HT1A receptors in the commissural NTS facilitate tissue perfusion after blood loss likely by increasing sympathetic-mediated venous return.