Increase In Mean Arterial Blood Pressure Research Articles

Rapid Sequence Induction is Superior to Morphine for Intubation of Preterm Infants: A Randomized Controlled Trial

To compare rapid sequence intubation (RSI) premedication with morphine for intubation of preterm infants. Preterm infants needing semi-urgent intubation were enrolled to either RSI (glycopyrrolate, thiopental, suxamethonium, and remifentanil, n = 17) or atropine and morphine (n = 17) in a randomized trial. The main outcome was "good intubation conditions" (score ≤10 assessed with intubation scoring), and secondary outcomes were procedural duration, physiological and biochemical variables, amplitude-integrated electroencephalogram, and pain scores. Infants receiving RSI had superior intubation conditions (16/17 versus 1/17, P < .001), the median (IQR) intubation score was 5 (5-6) compared with 12 (10.0-13.5, P < .001), and a shorter procedure duration of 45 seconds (35-154) compared with 97 seconds (49-365, P = .031). The morphine group had prolonged heart rate decrease (area under the curve, P < .009) and mean arterial blood pressure increase (area under the curve, P < .005 and %change: mean ± SD 21% ± 23% versus -2% ± 22%, P < .007) during the intubation, and a subsequent lower mean arterial blood pressure 3 hours after the intubation compared with baseline (P = .033), concomitant with neurophysiologic depression (P < .001) for 6 hours after. Plasma cortisol and stress/pain scores were similar. RSI with the drugs used can be implemented as medication for semi-urgent intubation in preterm infants. Because of circulatory changes and neurophysiological depression found during and after the intubation in infants given morphine, premedication with morphine should be avoided.

The acute effects of FK-506 on renal haemodynamics, water and sodium excretion and plasma levels of angiotensin II, aldosterone, atrial natriuretic peptide and vasopressin in pigs.

FK-506 has been shown to be an effective immunosuppressive drug with possible nephrotoxic side effects. In this study we have investigated the acute effects of FK-506 on renal haemodynamics, water, sodium and lithium excretion rates and plasma levels of angiotensin II, aldosterone, atrial natriuretic peptide (ANP) and vasopressin in 29 anaesthetized Lancaster/Yorkshire female pigs. A continuous intravenous infusion was given over a 2-h period to 4 groups: A: 0.075 mg kg-1 (n = 7), B: 0.15 mg kg-1 (n = 8), C: 0.3 mg kg-1 (n = 6) and P: placebo vehicle (n = 8). Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the constant infusion clearance technique using 125-I-iothalamate and 131-I-hippuran as reference substances. Hormonal parameters were measured by radioimmunoassay. In all three FK-506 groups, fractional lithium excretion was significantly decreased 2 h after FK506 infusion (P: +0.4%, A: -8.8% (P < 0.05), B: -12.9% and C: -11.2% (P < 0.01 for both). Mean arterial blood pressure (MBP) was significantly increased in the two highest dosage groups (B,C) at 2 h of infusion: (MBP; P: +2.9%, A: +3.5%, B: +12.0%, C: +15.3% (P < 0.01 for both). GFR and RPF showed minor and inconsistent changes while all other parameters measured showed similar or no changes. In conclusion, acute infusion of FK-506 to pigs does not change overall renal function significantly, but increases mean arterial blood pressure and decreases fractional excretion of lithium.

A meta-analysis of dopamine use in hypotensive preterm infants: blood pressure and cerebral hemodynamics

Dopamine administration results in variable effects on blood pressure in hypotensive preterm infants. The clinical benefits of dopamine administration in increasing cerebral blood flow (CBF) and reducing adverse neurological outcomes in hypotensive preterm neonates are unclear. The objective of this study was to examine the efficacy of dopamine for treatment of hypotension and investigate the changes in cerebral hemodynamics and central nervous system injury in hypotensive preterm infants following dopamine administration. Standard meta-analytic techniques, including random and fixed effects models, were used to calculate combined effect size correlations and significance levels. Random effects meta-analysis found that dopamine increases mean arterial blood pressure (12 studies; N=163; r=0.88, 95% confidence interval (CI)=0.76 to 0.94) and systolic blood pressure (8 studies; N=142; r=0.81, 95% CI=0.42 to 0.94). For the increase in blood pressure, dopamine administration was associated with a significantly greater overall efficacy than dobutamine (seven studies; N=251; r=0.26; 95% CI=0.20 to 0.32), colloid (two studies; N=67; r=0.60; 95% CI=0.41 to 0.74) and hydrocortisone (one study; N=28; r=0.40; 95% CI=0.034 to 0.67). CBF increased following dopamine administration (five studies; N=75; r=0.36; 95% CI=-0.059 to 0.67) and the increase in CBF was greater in hypotensive than normotensive preterm infants (eight studies; N=153; r=0.16; 95% CI=-0.0080 to 0.32). There were no statistically significant differences in adverse neurological outcome between dopamine and dobutamine (three studies; N=118; r=-0.13; 95% CI=-0.31 to 0.059), epinephrine (two studies; N=46; r=0.06; 95% CI=-0.23 to 0.34), colloid (two studies; N=80; r=0.0070; 95% CI=-0.218 to 0.23) or hydrocortisone administration (one study; N=40; r=-0.10; 95% CI=-0.40 to 0.22). Dopamine administration increases mean and systolic blood pressure in hypotensive preterm infants, and is more effective than dobutamine, colloid or hydrocortisone alone. Dopamine administration is associated with increased CBF, with greater increases in CBF in hypotensive than in normotensive preterm infants. Dopamine is not associated with a greater incidence of adverse effects than other therapies used to treat hypotension.

Effects of isoflurane anesthesia on cerebrovascular autoregulation in horses

To test a hypothesis predicting that isoflurane would interfere with cerebrovascular autoregulation in horses and to evaluate whether increased mean arterial blood pressure (MAP) would increase cerebral blood flow and intracranial pressure (ICP) during isoflurane anesthesia. 6 healthy adult horses. Horses were anesthetized with isoflurane at a constant end-tidal concentration sufficient to maintain MAP at 60 mm Hg. The facial, carotid, and dorsal metatarsal arteries were catheterized for blood sample collection and pressure measurements. A sub-arachnoid transducer was used to measure ICP Fluorescent microspheres were injected through a left ventricular catheter during MAP conditions of 60 mm Hg, and blood samples were collected. This process was repeated with different-colored microspheres at the same isoflurane concentration during MAP conditions of 80 and 100 mm Hg achieved with IV administration of dobutamine. Central nervous system tissue samples were obtained after euthanasia to quantify fluorescence and calculate blood flow. Increased MAP did not increase ICP or blood flow in any of the brain tissues examined. However, values for blood flow were low for all tested brain regions except the pons and cerebellum. Spinal cord blood flow was significantly decreased at the highest MAP. Results suggested that healthy horses autoregulate blood flow in the CNS at moderate to deep planes of isoflurane anesthesia. Nonetheless, relatively low blood flows in the brain and spinal cord of anesthetized horses may increase risks for hypoperfusion and neurologic injury.

Delayed Resuscitation with Physostigmine Increases End Organ Damage in Alcohol Intoxicated Rats

Previous studies from our laboratory have identified a role for blunted central sympathetic activation in the acute alcohol intoxication (AAI)-induced impairment of the counterregulatory response to hemorrhagic shock (HS). Immediate fluid resuscitation (FR) with acetylcholinesterase inhibitors restores the neuroendocrine and pressor responses to FR in AAI + HS. We hypothesized this intervention would remain beneficial after delay and that restoration of mean arterial blood pressure (MABP) during FR would attenuate organ damage. Male Sprague-Dawley rats received a primed constant alcohol infusion (2.5 g · kg + 0.3 g · kg · h for 15 h) or isocaloric dextrose (DEX) before HS (40 mmHg for 60 min) and FR with lactated Ringer's (LR) solution ± physostigmine (PHYS; 100 µg · kg) immediately or after a 60-min delay after HS. Immediate LR solution elevated MABP in DEX + HS. Acute alcohol intoxication delayed the initial MABP recovery. Delayed LR solution did not further increase MABP in DEX- or AAI + HS. LR solution + PHYS increased MABP in DEX- and AAI + HS after immediate and delayed FR. No differences were noted in markers of organ dysfunction (alanine aminotransferase [ALT], aspartate aminotransferase, blood urea nitrogen, creatinine) after DEX + HS, and this was unaltered by immediate or delayed LR solution + PHYS. Acute alcohol intoxication + HS increased ALT, which was attenuated by immediate LR solution + PHYS. In contrast, delayed LR solution + PHYS exacerbated tissue injury in AAI + HS, as reflected by increased ALT, aspartate aminotransferase, blood urea nitrogen, creatinine, and liver protein carbonylation over time-matched LR solution. In conclusion, PHYS enhanced blood pressure recovery independent of time of FR and presence of AAI. However, in AAI + HS, delayed LR solution + PHYS accentuated organ damage and dysfunction. These findings suggest that although enhancing the sympathetic response can improve hemodynamic recovery during AAI, it may compromise tissue perfusion and enhance tissue injury.

Hypersensitivity to Thromboxane Receptor Mediated Cerebral Vasomotion and CBF Oscillations during Acute NO-Deficiency in Rats

BackgroundLow frequency (4–12 cpm) spontaneous fluctuations of the cerebrovascular tone (vasomotion) and oscillations of the cerebral blood flow (CBF) have been reported in diseases associated with endothelial dysfunction. Since endothelium-derived nitric oxide (NO) suppresses constitutively the release and vascular effects of thromboxane A2 (TXA2), NO-deficiency is often associated with activation of thromboxane receptors (TP). In the present study we hypothesized that in the absence of NO, overactivation of the TP-receptor mediated cerebrovascular signaling pathway contributes to the development of vasomotion and CBF oscillations.Methodology/Principal FindingsEffects of pharmacological modulation of TP-receptor activation and its downstream signaling pathway have been investigated on CBF oscillations (measured by laser-Doppler flowmetry in anesthetized rats) and vasomotion (measured by isometric tension recording in isolated rat middle cerebral arteries, MCAs) both under physiological conditions and after acute inhibition of NO synthesis. Administration of the TP-receptor agonist U-46619 (1 µg/kg iv.) to control animals failed to induce any changes of the systemic or cerebral circulatory parameters. Inhibition of the NO synthesis by nitro-L-arginine methyl esther (L-NAME, 100 mg/kg iv.) resulted in increased mean arterial blood pressure and a decreased CBF accompanied by appearance of CBF-oscillations with a dominant frequency of 148±2 mHz. U-46619 significantly augmented the CBF-oscillations induced by L-NAME while inhibition of endogenous TXA2 synthesis by ozagrel (10 mg/kg iv.) attenuated it. In isolated MCAs U-46619 in a concentration of 100 nM, which induced weak and stable contraction under physiological conditions, evoked sustained vasomotion in the absence of NO, which effect could be completely reversed by inhibition of Rho-kinase by 10 µM Y-27632.Conclusion/SignificanceThese results suggest that hypersensitivity of the TP-receptor – Rho-kinase signaling pathway contributes to the development of low frequency cerebral vasomotion which may propagate to vasospasm in pathophysiological states associated with NO-deficiency.

Chlorine Gas Exposure Causes Systemic Endothelial Dysfunction by Inhibiting Endothelial Nitric Oxide Synthase–Dependent Signaling

Chlorine gas (Cl(2)) exposure during accidents or in the military setting results primarily in injury to the lungs. However, the potential for Cl(2) exposure to promote injury to the systemic vasculature leading to compromised vascular function has not been studied. We hypothesized that Cl(2) promotes extrapulmonary endothelial dysfunction characterized by a loss of endothelial nitric oxide synthase (eNOS)-derived signaling. Male Sprague Dawley rats were exposed to Cl(2) for 30 minutes, and eNOS-dependent vasodilation of aorta as a function of Cl(2) dose (0-400 ppm) and time after exposure (0-48 h) were determined. Exposure to Cl(2) (250-400 ppm) significantly inhibited eNOS-dependent vasodilation (stimulated by acetycholine) at 24 to 48 hours after exposure without affecting constriction responses to phenylephrine or vasodilation responses to an NO donor, suggesting decreased NO formation. Consistent with this hypothesis, eNOS protein expression was significantly decreased (∼ 60%) in aorta isolated from Cl(2)-exposed versus air-exposed rats. Moreover, inducible nitric oxide synthase (iNOS) mRNA was up-regulated in circulating leukocytes and aorta isolated 24 hours after Cl(2) exposure, suggesting stimulation of inflammation in the systemic vasculature. Despite decreased eNOS expression and activity, no changes in mean arterial blood pressure were observed. However, injection of 1400W, a selective inhibitor of iNOS, increased mean arterial blood pressure only in Cl(2)-exposed animals, suggesting that iNOS-derived NO compensates for decreased eNOS-derived NO. These results highlight the potential for Cl(2) exposure to promote postexposure systemic endothelial dysfunction via disruption of vascular NO homeostasis mechanisms.

Use and Effect of Vasopressors after Pediatric Traumatic Brain Injury

Background: Vasopressors are commonly used to increase mean arterial blood pressure (MAP) and cerebral perfusion pressure (CPP) after traumatic brain injury (TBI), but there are few data comparing vasopressor effectiveness after pediatric TBI. Objective: To determine which vasopressor is most effective at increasing MAP and CPP in children with moderate-to-severe TBI. Methods: After institutional review board approval, we performed a retrospective cohort study of children 0–17 years old admitted to a level 1 trauma center (Harborview Medical Center, Seattle, Wash., USA) between 2002 and 2007 with moderate-to-severe TBI who received a vasopressor to increase blood pressure. Baseline demographic and physiologic characteristics and hourly physiologic monitoring for 3 h after having started a vasopressor were abstracted. We evaluated differences in MAP and CPP at 3 h after initiation of therapy between phenylephrine, dopamine and norepinephrine among patients who did not require a second vasopressor during this time. Multivariate linear regression was used to adjust for age, gender, injury severity score and baseline MAP or CPP and to cluster by subject. Results: Eighty-two patients contributed data to the entire dataset. The most common initial medication was phenylephrine for 47 (57%). Patients receiving phenylephrine and norepinephrine tended to be older than those receiving dopamine and epinephrine. Thirteen (16%) of the patients received a second vasopressor during the first 3 h of treatment and were thus not included in the regression analyses; these patients received more fluid resuscitation and exhibited higher in-hospital mortality (77 vs. 32%; p = 0.004) compared to patients receiving a single vasopressor. The norepinephrine group exhibited a 5 mm Hg higher MAP (95% CI: –4 to 13; p = 0.31) and a 12 mm Hg higher CPP (95% CI: –2 to 26; p = 0.10) than the phenylephrine group, and a 5 mm Hg higher MAP (95% CI: –4 to 15; p = 0.27) and a 10 mm Hg higher CPP (95% CI: –5 to 25; p = 0.18) than the dopamine group. However, in post hoc analysis, after adjusting for time to start of vasopressor, hypertonic saline and pentobarbital, the effect on MAP was lost, but the CPP was 8 mm Hg higher (95% CI: –10 to 25; p = 0.39) than in the phenylephrine group, and 5 mm Hg higher (95% CI: –14 to 24; p = 0.59) than in the dopamine group. Conclusions: Vasopressor use varied by age. While there was no statistically significant difference in MAP or CPP between vasopressor groups, norepinephrine was associated with a clinically relevant higher CPP and lower intracranial pressure at 3 h after start of vasopressor therapy compared to the other vasopressors examined.

Combretastatin-induced hypertension and the consequences for its combination with other therapies

PurposeCombretastatin A-4 phosphate (CA4P) is a promising vascular disrupting agent in cancer treatment, but elicits hypertension in patients. The aim of this study was to use a mouse model to investigate whether hypertension or its modification influenced the treatment efficacy of CA4P in combination with other therapies. Material and methodsC3H mammary carcinoma bearing or non-bearing CDF1 mice were used. The effects of CA4P alone or in combination with the antihypertensive drug hydralazine (HDZ) on mean arterial blood pressure (MABP), hematocrit (Hct) and hemoglobin concentration ([Hb]) were characterized in non-tumor-bearing animals. Tumor-bearing mice were also treated locally with radiation and/or hyperthermia (41.5°C; 60min) in combination with CA4P alone or CA4P plus HDZ, and TCD50 values (radiation dose that controls 50% of tumors) determined. ResultsHct, [Hb] and MABP respectively increased from 49.3±0.3%, 9.1±0.1mM and 110±7mm Hg, to 54.7±0.2%, 10.3±0.1mM and 127±5mm Hg, within 1h after injecting 100mg/kg CA4P. For each parameter the magnitude of the peak increase was largely dose independent within the CA4P dose range tested (10–250mg/kg). However, high CA4P doses delayed the return to baseline and Hct and [Hb] recovered more slowly than MABP. Co-administration of HDZ (0.2mg/kg) was able to suppress the CA4P-induced increase in MABP for several hours but did not noticeably affect the changes in Hct and [Hb]. The TCD50 value (±95% confidence interval) for radiation alone was 53 (51–55)Gy. Tumor irradiation followed by injection of either CA4P (100mg/kg) or CA4P+HDZ 30min later reduced the TCD50 values to 50 (46–54)Gy and 48 (45–52)Gy, respectively. Heating tumors after irradiating further decreased the TCD50 value to 46 (43–48)Gy. When all treatments were combined the TCD50 was 35 (32–38)Gy, regardless of whether the drugs were CA4P or CA4P+HDZ. ConclusionsCA4P significantly increased Hct, [Hb] and MABP. Hypertension, but not increases in Hct and [Hb], could be reversed with the antihypertensive drug HDZ. CA4P significantly improved tumor response to radiation or thermoradiation, neither of which was influenced by the addition of HDZ.

Vasopressor Agents After Experimental Brain Death: Effects of Dopamine and Vasopressin on Vitality of the Small Gut

Background Both congenital and acquired short bowel syndrome frequently leads to the necessity for long-term parenteral nutrition, which in turn may lead to any of several complications or death. Transplantation of the small bowel from brain-dead organ donors has been successfully performed over the last years. However, systemic blood pressure and blood perfusion to the splanchnic area decrease rapidly after brain death, which comprises the vitality of the small bowel. Objective To evaluate the differences between dopamine and low-dose vasopressin on perfusion and vitality of the small bowel after brain death. Methods Fifteen pigs were randomized into 3 groups: vasopressin (n = 6), dopamine (n = 6), or control (n = 3). Brain death was induced via stepwise filling of an epidural balloon. When the hypotensive phase was achieved, vasopressin, maximum dose of 0.04 IU/kg/h, or dopamine, maximum dose of 20 μg/kg/min, was administered for 5 hours with the objective of increasing mean arterial blood pressure by 15 mm Hg. Results Target blood pressure was achieved in the vasopressin group but not the dopamine group. Vasopressin reduced cardiac output, superior mesenteric artery (SMA) blood flow and oxygen delivery, and systemic oxygen delivery and consumption, and increased oxygen extraction. Dopamine increased SMA blood flow, and had no effect on systemic oxygen delivery or consumption. Conclusions Vasopressin reversed hypotension but compromised both the systemic and SMA blood flow. Vasopressin was associated with inadequate oxygen delivery, estimated from decreased oxygen delivery and increased oxygen extraction. These adverse effects were not observed with dopamine.

Effects of the crude extract of the fruit rind of rambutan (Nephelium lappaceum L.) on blood pressure, heart rate and respiratory rate in anaesthetized male rats

The bark of rambutan (Nephelium lappaceum L.), which is normally discarded was found to contain extremely high antioxidant activity [1]. Since polyphenols found in plants are widely known to affect the cardiovascular system, there is no evidence suggesting how polyphenols found in the crude extract of the fruit rind of rambutan did. We, therefore, investigated acute effects of rambutan on cardiovascular and respiratory responses in male rats. The ethanolic rambutan bark extract with a total phenolic content of 18.69±0.2mg gallic acid/g dry sample extract were used in this experiment. Invasive arterial blood pressure, heart rate and respiratory rate were recorded in pentobarbital-anaesthetized male rats for 2 hours after single i.p. injected with vehicle (n=8) and 1g/kg rambutan bark extract (n=8). Intragroup comparison showed that rambutan rind extract markedly increased mean arterial blood pressure (MABP) and systolic blood pressure (p<0.05, compared to baseline). In comparison between groups, significant increases in MABP, systolic blood pressure, diastolic blood pressure and heart rate can be observed 60 minutes after rambutan bark extract (p<0.05, two way repeated measures ANOVA). Significant increases in those parameters were found over the rest period of investigation. However, there were no changes in respiratory rate In conclusion, this study provided the first evidence of prolonged cardiovascular response (increases in MABP, systolic blood pressure and heart rate) following acute rambutan rind extract in anesthetized male rats. The mechanism of which rambutan rind extract regulating blood pressure in normotensive, hypotensive and hypertensive conditions should be further investigated.

The variability of blood pressure due to small changes of hematocrit

The hematocrit (Hct) of awake hamsters was lowered to 90% of baseline by isovolemic hemodilution using hamster plasma to determine the acute effect of small changes in Hct and blood viscosity on systemic hemodynamics. Mean arterial blood pressure increased, reaching a maximum of about 10% above baseline (8.6 +/- 5.5 mmHg) when Hct decreased 8.4 +/- 1.9% (P < 0.005). Cardiac output increased continuously with hemodilution. These conditions were reached at approximately 60 min after exchange transfusion and remained stationary for 1 h. Peripheral vascular resistance was approximately constant up to a decrease of Hct of about 10% and then fell continuously with lowering Hct. Vascular hindrance or vascular resistance independent of blood viscosity increased by about 20% and remained at this level up to an Hct decrease of 20%, indicating that the vasculature constricted with the lowered Hct. The results for the initial 2-h period are opposite but continuous with previous findings with small increases in Hct. In conclusion, limited acute anemic conditions increase mean arterial blood pressure during the initial period of 2 h, an effect that is quantitatively similar but opposite to the acute increase of Hct during the same period.

NPY Y 1 receptors are involved in cardio-respiratory responses to intravenous injection of neuropeptide Y in anaesthetized rats

The respiratory effects evoked by systemic injection of neuropeptide Y (NPY) were studied in anaesthetized, spontaneously breathing rats that were (i) neurally intact; (ii) subjected to bilateral midcervical vagotomy (MC vagi cut); (iii) midcervically vagotomized and treated by supranodosal denervation (NG vagi cut); (iv) neurally intact, before and after pharmacological blockade of the NPY Y 1 and NPY Y 2 receptors. An intravenous (iv) bolus of NPY (100 μg/kg) induced slowing down of the respiratory rate, decreased tidal volume and heart rate, and increased mean arterial blood pressure. After section of midcervical vagi, NPY still evoked the cardio-respiratory changes. Supranodose vagotomy abolished the fall in respiratory rate and reduced significantly the decreases in tidal volume and minute ventilation. This level of vagotomy did not affect vasopressor and bradycardic effects of NPY. Blockade of NPY Y 1 receptors with an intravenous dose of 5 mg/kg of BMS 193885, reduced significantly the cardio-respiratory effects of NPY injection. Pre-treatment with BIIE 0246, NPY 2 receptor antagonist at a dose of 1–2.5 mg/kg was not effective in blocking the response to NPY. The results of this study indicate that NPY-evoked activation of NPY Y 1 receptors decreases both components of the breathing pattern, and this response is primarily mediated central to the cervical vagi. Bradycardia and hypertensive effect of NPY are attributed to the excitation of peripheral and central NPY Y 1 receptors and occur outside of the vagal pathways.

Simvastatin Reduces Pressor Response to Centrally Administered Angiotensin II

Angiotensin II (Ang II) plays a pivotal role in regulation of the circulatory system. Activation of angiotensin type 1 (AT1) receptors in several brain regions leads to an increase in blood pressure. Accumulating data suggest that statins affect the peripheral action of Ang II; however, their central effects are poorly recognized. The study was aimed to determine whether simvastatin interferes with the brain angiotensin system in rats. Twelve-week-old, Sprague-Dawley rats were divided into two groups. Untreated group was maintained on tap water, whereas simvastatin group received water containing simvastatin for the following 12 weeks. Later, both groups were subjected to experiments in which mean arterial blood pressure (MABP) and heart rate (HR) were recorded during baseline conditions and after intracerebroventricular (ICV) infusion of either saline, Ang II, or losartan. ICV infusion of Ang II elicited a significant increase in MABP in both groups. However, the pressor response in the simvastatin group was significantly smaller than that in the untreated group. There was no significant change in MABP after ICV infusion of saline or losartan. ICV infusion of Ang II elicited a significant increase in HR in the untreated group but not in the simvastatin group. There was no significant change in HR after ICV infusion of saline or losartan. The results show that simvastatin reduces the pressor response to ICV-infused Ang II in rats. This implies that statins may affect the central regulation of the circulatory system, especially when the brain angiotensin system is stimulated.

The effects of methylene blue infusion on gastric tonometry and intestinal fatty acid binding protein levels in septic shock patients

Objective We prospectively studied the effect of methylene blue (MB) infusion on gastric mucosal metabolism perfusion ratio, assessed by gastric tonometry, and on mucosal cell damage, assessed by urinary levels of intestinal fatty acid binding protein, in septic shock patients. Methods Methylene blue (MB) infusion (1 mg/kg per hour) during 4 hours in 10 consecutive patients with a proven or suspected bacterial infection and with severe vasodilatory shock, defined as a mean arterial pressure 70 mm Hg or lower for at least 1 hour despite adequate volume resuscitation and norepinephrine infusion at a rate ≥0.2 μg/kg per minute. Results Methylene blue infusion did not significantly change the P(g-a)CO 2 gradient ( P = .16). Post hoc analysis of the subgroup of patients with an elevated baseline P(g-a)CO 2 gradient, defined as ≥20 mm Hg, showed that the median P(g-a)CO 2 gradient (interquartile range [IQR]) decreased from 45 (41-56) mm Hg before infusion to 41 (28-52) at the end of the 4-hour infusion and decreased further to 32 (26-36) mm Hg 2 hours after cessation of MB infusion ( P = .012). The median urinary intestinal fatty acid binding protein concentration at baseline was elevated (210 [79-437] pg/ μmol creatinine) and did not change significantly after 24 hours (116 [53-601] pg/ μmol creatinine, P = .15). The median mean arterial blood pressure (IQR) increased from 70 (69-71) mm Hg at baseline to 77 (67-83) mm Hg after 1 hour ( P = .04), the norepinephrine dose did not change significantly. The median (IQR) cardiac index decreased from 4.4 (3.2-5.5) L min -1 m -2 at baseline to 3.6 (3.3-4.7) L min -1 m -2 after 2 h, returning back to baseline values after cessation of MB infusion P = .02). Conclusion Although MB infusion in patients with septic shock and advanced multi-organ failure increases mean arterial blood pressure and decreases cardiac index, it does not compromise the gastric mucosal perfusion metabolism ratio as indicated by tonometry, and by the release of a mucosal cellular injury marker.

Differential effects of Angiotensin II on intra‐renal hemodynamics in rats

Renal medullary blood flow (MBF) has been shown to differ qualitatively from cortical flow in response to certain vasoactive agents. The effect of AII infusion on intrarenal hemodynamics was investigated in rats testing the hypothesis that AT2 receptor mediates AII‐induced increase in renal MBF. AII (100, 300 and 1000 ng/kg/min) increased mean arterial blood pressure (MAP; 24±7%), decreased cortical blood flow (CBF; 30 ± 2%), but increased MBF (21±8%). Indomethacin (5 mg/kg), a COX inhibitor enhanced AII effects on MAP (154 ± 26%; p&lt;0.05), MBF (141±46 %; p&lt;0.05) and CBF (74±54%; p&lt;0.05). NG nitro‐L‐arginine (L‐NNA), an inhibitor of NO synthase (100 mg/L orally) or 1H‐[1,2,4]oxadiazolo[4,3,‐a]quinoxalin‐1‐one (ODQ), a guanylyl cyclase inhibitor (2 mg/kg) enhanced AII effects on MAP (169±75 or 118±32%, p&lt;0.05), CBF(107±50 or 85±47%, p&lt;0.05) but blunted the effects of AII on MBF(150±21 or 96±15%, p&lt;0.05). However, glibenclamide (20 μg/kg), a KATP+ channel blocker, was without effect. PD123319 (50 μg/kg/min), an AT2 blocker did not change basal or AII‐induced changes in MAP or CBF but blunted AII effects on MBF (60 ±11 %; p&lt;0.05). CGP42112 (10 μg/kg/min), an AT2 agonist, reduced MAP but increased CBF and MBF ‐ effects were antagonised by PD123319. These findings demonstrate that AT2 receptors mediate AII‐induced increase in MBF by mechanisms involving guanylyl cyclase and NO but not prostanoids or KATP+ channels.

Reduced reactive oxygen species generation in rostral ventrolateral medulla suppresses the pressor response induced by the excitation of the paraventricular nucleus of the hypothalamus in spontaneously hypertensive rats

BackgroundIncreased generation of reactive oxygen species (ROS) in the rostral ventrolateral medulla (RVLM) contribute to the neural mechanism of hypertension. The RVLM receives excitatory synaptic inputs from the paraventricular nucleus (PVN). It is also suggested that the angiotensin II type 1 receptors in the RVLM are activated by the PVN stimulation. Therefore, we examined whether the excitatory synaptic inputs derived from the PVN mediate the ROS in the RVLM or not.Methods and ResultsWe used 14 to 18‐week‐old male Wistar‐Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). We transfected adenovirus vectors encoding manganese superoxide dismutase gene (AdMnSOD) into the bilateral RVLM. Then, we microinjected bicuculline (BIC) (100pmol) into the unilateral PVN on day 7 after gene transfer. Microinjection of BIC into the PVN increased mean arterial blood pressure (MAP) in both SHR and MnSOD‐transfected SHR, however, the pressor response was significantly attenuated in MnSOD‐transfected SHR (SHR: 33±2 mmHg; MnSOD‐transfected SHR: 20±1 mmHg, n=5, P&lt;0.05). Overexpression of MnSOD in the RVLM did not suppress BIC‐elicited MAP elevation in WKY rats (WKY rats: 14±1 mmHg; MnSOD‐transfected WKY rats: 13±1 mmHg, n=3).ConclusionExcitatory synaptic inputs arising from activation of the PVN to the RVLM are mediated, at least in part, by ROS generation in SHR, but not in WKY.

Apelin Antagonizes Myocardial Impairment in Sepsis

Background Apelin is a cardiovascular peptide with multiple functions regulating homeostasis of the circulatory system and is the endogenous ligand of angiotensin II receptor like-1 (AGTRL1). Apelin has anti-inflammatory and inhibitory effects on release of inflammatory mediators. We aimed to analyze whether apelin antagonizes myocardial impairment in sepsis by attenuating inflammatory responses. Methods and Results Male rats underwent sepsis by cecal ligation and puncture (CLP) after receiving low- or high-dose apelin for 3 days. Twenty hours later, rats with sepsis showed severe disturbance of hemodynamic features. Reverse transcription-polymerase chain reaction revealed decreased mRNA levels of apelin and AGTRL1 in myocardia of rats with sepsis. Enzyme immune assay detected a lower level of apelin in plasma and myocardia. Western blot analysis revealed decreased level of myocardial AGTRL1 protein. Low- and high-dose apelin administration ameliorated disorders of cardiac function: increased mean arterial blood pressure, attenuated heart rate, elevated +LVdp/dt max and LVdp/dt max, and lowered left ventricular end-diastolic pressure. Rats treated with low- or high-dose apelin showed lower content of plasma monocyte chemoattractant protein 1and interleukin 8. In cultured rat peritoneal macrophages, apelin directly inhibited the production of monocyte chemoattractant protein 1 and interleukin-8 induced by lipopolysaccharide. Conclusions These results suggest that apelin antagonizes cardiac impairment in sepsis by attenuating inflammatory responses and might be a promising therapeutic target for severe sepsis and septic shock.

Stimulation of Sigma-1 receptor by dehydroepiandrosterone ameliorates hypertension-induced kidney hypertrophy in ovariectomized rats

The incidence of chronic renal disease in women increases with aging, especially after menopause, suggesting that loss of sex hormones contributes to the development and progression of renal diseases. Recent studies revealed that decreased dehydroepiandrosterone (DHEA) levels are associated with endothelial dysfunction, renal injury and increased cardiovascular mortality in postmenopausal women. We here investigate the role of DHEA, also known as Sigma-1 receptor (Sigma-1R) agonist, on kidney injury induced by pressure overload (PO) after ovariectomy (OVX) and defined mechanisms underlying its protective action. Wistar rats subjected to bilateral OVX were further treated with abdominal aortic stenosis between the right and left renal arteries. DHEA (15 and 30 mg/kg) was administered orally once a day for 14 days starting from two weeks after aortic banding. Time course study indicated that the right kidney (RK) weight-to-body weight (BW) ratio increases time-dependently from one to four weeks along with increased mean arterial blood pressure (MABP) after banding in the abdominal aorta with no change in the left kidney (LK) weight-to-BW ratio. Similarly, we found significant time-dependent decrease in Sigma-1R expression in the RK with no changes in the LK. Administration of the Sigma-1R agonist, DHEA, significantly inhibited hypertension-induced increases in the RKW-to-BW ratio and increased expression of Sigma-1R in the RK. DHEA also attenuated PO-induced disturbance of heart rate and MABP. DHEA administration significantly restored PO-induced impaired endothelial nitric oxide synthase (eNOS) activity with concomitant increased phosphorylation of eNOS (Ser1179) and Akt activity with increased phosphorylation at Ser 473 and at Thr 308 in the RK. We here documented, for the first time, the potential role of Sigma-1R to protect the kidney from PO-induced injury in ovariectomized rats. DHEA administration protects hypertension-induced kidney injury via upregulation of Sigma-1R and stimulation of Akt-eNOS signaling in ovariectomized rats.

Impairment of baroreflex control of heart rate and structural changes of cardiac ganglia in conscious streptozotocin (STZ)-induced diabetic mice

Baroreflex control of heart rate (HR) is impaired in human diabetes mellitus and in large experimental models. However, baroreflex impairment in diabetic mouse models and diabetes-induced remodeling of baroreflex circuitry are not well studied. We examined the impairment of baroreflex control of heart rate (HR) and assessed structural remodeling of cardiac ganglia in the streptozotocin (STZ)-induced diabetic mouse model. FVB mice were either injected with vehicle or STZ. Group 1: mice were anesthetized and the femoral artery and vein were catheterized at the 30th day after vehicle or STZ injection. On the second day after surgery, baroreflex-mediated HR responses to sodium nitroprusside (SNP) and phenylephrine (PE)-induced mean arterial blood pressure (MABP) changes were measured in conscious mice. Group 2: Fluoro-Gold was administered (i.p.) to label cardiac ganglia in each mouse at the 25th day after vehicle or STZ injection. After another five days, animals were perfused and cardiac ganglia were examined using confocal microscopy. Compared with control, we found in STZ mice: 1) the HR decreased, but MABP did not. 2) The PE-induced increases of MABP were decreased. 3) Baroreflex bradycardia was attenuated in the rapid MABP ascending phase but the steady-state ΔHR/ΔMABP was not different at all PE doses. 4) SNP-induced MABP decreases were not different. 5) Baroreflex tachycardia was attenuated. 6) The sizes of cardiac ganglia and ganglionic principal neurons were decreased. 7) The ratio of nucleus/cell body of cardiac ganglionic neurons was increased. We conclude that baroreflex control of HR is impaired in conscious STZ mice. In addition, diabetes may induce a significant structural remodeling of cardiac ganglia. Such an anatomical change of cardiac ganglia may provide new information for the understanding of diabetes-induced remodeling of the multiple components within the baroreflex circuitry.