Abstract 2046: Hypercapnic Resuscitation Improves Survival and Neurological Outcomes by Nitric Oxide Synthase-Mediated Enhancement of Brain Perfusion

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Wei-Tien Chang ◽  
Lay-San Gan ◽  
Chiang-Ting Chien ◽  
Chien-Hua Huang ◽  
Huei-Wen Chen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Cardiac Arrest ◽  
Apoptotic Cell ◽  
Brain Perfusion ◽  
No Synthase ◽  
Neurological Injury ◽  
Neurological Outcomes ◽  
Arterial Blood ◽  
The Brain

Neurological injury is one of the major causes of morbidity and mortality following cardiac arrest and cardiopulmonary resuscitation (CPR). Brain perfusion is usually compromised in the post-resuscitation phase, which inevitably lengthens the ischemic insult of the brain. Hypercapnia has been reported to cause cerebral vasodilatation. We therefore sought to study the potentials of hypercapnic resuscitation in improving the brain perfusion as well as survival and neurological prognoses. Using an established rat model of asphyxial cardiac arrest (6 min) and CPR, we employed hypercapnic (5% CO 2 , 95% O 2 ) ventilation during CPR and the first 2 h post-resuscitation, and compared the brain perfusion with normocapnia (5% N 2 , 95% O 2 ) control. The blood pressure was continuously monitored, with arterial blood sampled regularly for gas analysis. The tissue perfusion of the brain was measured by OxyLyte 2000E perfusion sensor. In a subgroup the survival and neurological outcomes were monitored up to 3 days. TdT-mediated dUTP nick-ends labeling (TUNEL) stain and Bax/Bcl2 of the brain were assessed as indicators of apoptotic cell death. The PaCO 2 was significantly higher ( P <0.001) and pH significantly lower ( P <0.001) in hypercapnia group during the first 2 h post-resuscitation. No difference was noted in PaO 2 or blood pressure. In normocapnia control, the brain perfusion was significantly reduced in the first 30 min post-resuscitation. Hypercapnic ventilation enhanced brain perfusion during this period ( P <0.05). The survival and neurological outcomes were also improved (LogRank P <0.05), which was consistent with the decrease in TUNEL stain and Bax/Bcl2. If nitric oxide (NO) synthase inhibitor N ω -nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) was cotreated with hypercapnia, the increased brain perfusion and reduced TUNEL and Bax/Bcl2 were reversed. The improved survival and neurological outcomes were also abrogated. Hypercapnic ventilation during CPR and early post-resuscitation phase improves brain perfusion and hence survival and neurological outcomes. This is in part mediated by NO synthase-related vasodilatation.

Abstract 21: Remote Limb Ischemic Postconditioning Improves Postresuscitation Cerebrovascular Circulation and Survival/Neurological Prognoses via In Situ and Remote Activation of Akt-eNOS-NO Signaling Pathway

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Wei-Tien Chang ◽  
Woan-Yi Wang ◽  
Chun-Pei Lee ◽  
Hsiao-Ching Wei ◽  
Sung-Chun Tang ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Femoral Artery ◽  
Cerebral Perfusion ◽  
Cerebrovascular Circulation ◽  
Neurological Outcomes ◽  
Arterial Blood ◽  
Left Femoral Artery ◽  
No Signaling ◽  
The Brain

Introduction: Cerebrovascular circulation is usually compromised after cardiac arrest and CPR. Remote limb ischemic post-conditioning (RLIP) is clinically feasible and can potentially mitigate post-resuscitation neurological deficits. Since nitric oxide (NO) is implicated in post-conditioning protection, we aim to investigate if RLIP impacts post-resuscitation cerebral perfusion and prognosis via NO-related mechanism. Hypothesis: RLIP improves post-CPR cerebral perfusion and prognosis through in situ and remote activation of Akt-eNOS-NO signaling. Methods: Using an established rat model of asphyxia cardiac arrest and CPR, we randomized the rats to the following groups: (1) sham, (2) standard CPR, (3) RLIP 5 min after return of spontaneous circulation (ROSC). RLIP was done by 3 cycles of 5 min of left hind limb ischemia followed by 5 min of reperfusion. Arterial blood was sampled for colorimetric determination of nitrate/nitrite. The cerebral perfusion was continuously recorded by OxyFLO probe. Two hours after ROSC, the brain and left femoral artery were harvested for measuring phosphorylated endothelial NO synthase (p-eNOS at Ser1177) and protein kinase B (p-Akt at Ser473). In a subgroup the survival and neurological outcomes were monitored up to 3 days. Results: The cerebral perfusion was significantly decreased (0.6-0.8 folds that of baseline) after ROSC in standard CPR group. If RLIP was employed, the cerebral perfusion was significantly augmented (up to 1.6 folds, P < 0.001) in the post-resuscitation phase. This was associated with improved survival (log-rank P < 0.05) and neurological scores at 6, 24, 48 and 72 h (all P < 0.05). Plasma NO as indicated by nitrate/nitrite was significantly increased in the RLIP group ( P < 0.05). Most of all, p-eNOS and p-Akt were significantly increased not only in left femoral artery but also in brain. If NOS inhibitor N ω -nitro-L-arginine methyl ester (10 mg/kg) was used, not only the NO increase was reversed, the improvement in survival and neurological outcomes were also abrogated. Conclusions: RLIP enhances post-resuscitation cerebral perfusion and improves survival and neurological prognoses not only via in situ limb artery derived NO but remote activation of Akt-eNOS signaling in the brain.

Role of nitrosyl factors in the hindlimb vasodilation elicited by baroreceptor afferent nerve stimulation

2006 ◽  
Vol 290 (3) ◽  
pp. R741-R748 ◽  
Author(s):  
Olga S. Possas ◽  
Alan Kim Johnson ◽  
Stephen J. Lewis
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Vascular Resistance ◽  
Specific Inhibitor ◽  
No Synthase ◽  
Nerve Terminals ◽  
Aortic Depressor Nerve ◽  
Arterial Blood ◽  
Afferent Fibers

This study determined whether electrical stimulation (ES) of the baroreceptor afferent fibers in the aortic depressor nerve (ADN) produces hindlimb vasodilation in pentobarbital-anesthetized rats via the release of nitric oxide (NO)-containing (nitrosyl) factors from NO synthase-positive lumbar sympathetic nerve terminals. ES of the ADN (1–10 Hz for 15 s) produced frequency-dependent reductions in mean arterial blood pressure (MAP) and mesenteric and hindlimb vascular resistance (MR and HLR, respectively). The falls in resistance were substantially smaller in hindlimb beds in which the ipsilateral lumbar sympathetic chain had been transected 7–10 days previously. The maximal falls in MR and hindquarter vascular resistance (HQR) produced by 1- to 10-Hz ES of the ADN were unaffected by the specific inhibitor of neuronal NO synthase 7-nitroindazole (7-NI, 45 mg/kg iv). However, the total falls in HQR (mmHg·kHz−1·s) produced by these stimuli were significantly diminished by 7-NI, whereas the total falls in MR were not affected. Four successive episodes of 10-Hz ES produced equivalent reductions in MAP, MR, and HQR. The peak changes in these parameters were not affected by 7-NI. However, the total falls in HQR progressively diminished with each successive stimulus, whereas the total falls in MR remained unchanged. These results provide evidence that the hindlimb vasodilation produced by ES of baroreceptor afferents within the ADN may involve the activation of postganglionic lumbar sympathetic vasodilator fibers, which release newly synthesized and preformed nitrosyl factors.

scholarly journals Increased nitric oxide activity in a rat model of acute pancreatitis

Gut ◽  
1998 ◽  
Vol 43 (4) ◽  
pp. 564-570 ◽  
Author(s):  
R A Al-Mufti ◽  
R C N Williamson ◽  
R T Mathie
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Acute Pancreatitis ◽  
Arterial Blood Pressure ◽  
Tissue Damage ◽  
No Synthase ◽  
Arterial Blood ◽  
Inducible No Synthase ◽  
Cellular Localisation ◽  
Male Wistar Rats

Background—Overproduction of nitric oxide (NO) via induction of the inducible NO synthase (iNOS) is an important factor in the haemodynamic disturbances of several inflammatory states.Aims—To identify the role of NO in a caerulein induced model of acute pancreatitis in the rat.Methods—Arterial blood pressure and plasma NO metabolites were measured at zero and seven hours in adult male Wistar rats administered caerulein (n=10) or saline (n=10). Pancreatic activity of NOS (inducible and constitutive) was assayed biochemically. The pancreatic expression and cellular localisation of NOS and nitrotyrosine (a marker of peroxynitrite induced oxidative tissue damage) were characterised immunohistochemically.Results—Compared with controls at seven hours, the pancreatitis group displayed raised plasma NO metabolites (mean (SEM) 70.2 (5.9) versus 22.7 (2.2) μmol/l, p<0.0001) and reduced mean arterial blood pressure (88.7 (4.6) versus 112.8 (4.1) mm Hg, p=0.008). There was notable iNOS activity in the pancreatitis group (3.1 (0.34) versus 0.1 (0.01) pmol/mg protein/min, p<0.0001) with reduced constitutive NOS activity (0.62 (0.12) versus 0.96 (0.08) pmol/mg protein/min, p=0.031). The increased expression of iNOS was mainly localised within vascular smooth muscle cells (p=0.003 versus controls), with positive perivascular staining for nitrotyrosine (p=0.0012 versus controls).Conclusions—In this experimental model of acute pancreatitis, iNOS induction and oxidative tissue damage in the pancreas is associated with raised systemic NO and arterial hypotension. Excess production of NO arising from the inducible NO synthase may be an important factor in the systemic and local haemodynamic disturbances associated with acute pancreatitis.

Renal effects of nitric oxide synthase inhibition in conscious water-loaded dogs

2001 ◽  
Vol 281 (2) ◽  
pp. R584-R590 ◽  
Author(s):  
Thomas V. Peterson ◽  
Claus Emmeluth ◽  
Peter Bie
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Sodium Excretion ◽  
Volume Expansion ◽  
Excretion Rate ◽  
No Synthase ◽  
Urine Flow ◽  
Water Diuresis ◽  
Renal Effects ◽  
Arterial Blood

The renal effects of the nitric oxide (NO) synthase inhibitor nitro-l-arginine methyl ester (l-NAME) were investigated in conscious dogs undergoing sustained water diuresis and replacement of urinary sodium losses. Experiments were performed with and without additional extracellular volume expansion (isotonic saline, 2% body wt). l-NAME (10 μg · kg−1 · min−1) infused during water diuresis decreased urine flow (2.5 ± 0.2 to 1.5 ± 0.3 ml/min), free water clearance (1.9 ± 0.2 to 1.0 ± 0.2 ml/min), and sodium excretion (4.0 ± 1.7 to 2.1 ± 0.6 μmol/min). Arterial blood pressure increased from 112 ± 2 to 126 ± 3 mmHg, but creatinine clearance did not measurably change. Plasma endothelin and vasopressin concentrations and plasma renin activity (PRA) were unchanged. Urinary endothelin concentration increased (3.4 ± 0.8 to 6.2 ± 1.7 pg/ml), but the excretion rate remained constant. l-Arginine infusion (0.6 mg · kg−1 · min−1) along withl-NAME abolished the renal effects but not the blood pressure increase. Volume expansion increased urine flow (2.5 ± 0.4 to 5.7 ± 0.5 ml/min) and sodium excretion (3.8 ± 1.6 to 76.5 ± 14.5 μmol/min). l-NAME attenuated the renal effects of volume expansion: urine flow increased to 2.8 ± 0.7 ml/min and sodium excretion to 34 ± 17 μmol/min. PRA decreased with control volume expansion but not during l-NAME. Urinary endothelin levels were elevated by l-NAME, decreased with volume expansion in all series, but excretion rate remained constant. Infusion of l-arginine partially reversed these effects of l-NAME. The results demonstrate that NO synthase inhibition increases blood pressure and blunts the renal responses to water and saline loading.

NO-containing factors mediate hindlimb vasodilation produced by superior laryngeal nerve stimulation

1997 ◽  
Vol 273 (1) ◽  
pp. H234-H243 ◽  
Author(s):  
O. S. Possas ◽  
S. J. Lewis
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Electrical Stimulation ◽  
Specific Inhibitor ◽  
Superior Laryngeal Nerve ◽  
Sympathetic Nerves ◽  
No Synthase ◽  
Laryngeal Nerve ◽  
Lower Intensity ◽  
Arterial Blood

The electrical stimulation (ES) of the superior laryngeal nerve (SLN) produces reflex vasodilation in the rat hindlimb. This study determined whether this vasodilation is mediated by the release of nitric oxide (NO)-containing factors (NOF) from NO synthase (NOS)-positive postganglionic lumbar sympathetic fibers that innervate the rat hindlimb vasculature. ES of the SLN (1-10 Hz for 15 s) produced frequency-dependent reductions in mean arterial blood pressure (MAP) and hindlimb and mesenteric (MR) vascular resistances. The hindlimb vasodilation was not observed in rats in which the lumbar sympathetic trunk was transected 7-10 days previously. The falls in hindquarter vascular resistance (HQR) produced by lower intensity ES of the SLN were virtually abolished by the specific inhibitor of neuronal NOS 7-nitroindazole (7-NI, 45 mg/kg i.v.). The fall in HQR produced by 10 Hz ES of the SLN was not affected by 7-NI. The falls in MR produced by 1-10 Hz ES of the SLN were unaffected by 7-NI. Four consecutive episodes of ES at 10 Hz produced pronounced and equivalent reductions in MAP, HQR, and MR. After administration of 7-NI, the first ES produced similar hemodynamic responses to those observed before injection. However, each subsequent ES produced progressively and markedly smaller falls in HQR, whereas each episode of ES produced similar falls in MR. These results suggest that the reflex vasodilation in the rat hindlimb produced by ES of the SLN involves the release of newly synthesized and performed stores of NOF from NOS-positive postganglionic lumbar sympathetic nerves.

Effects of Neuroactive Amino Acids Derivatives on Cardiac and Cerebral Mitochondria and Endothelial functions in Animals Exposed to Stress

2017 ◽  
Vol 2 (2) ◽  
pp. 34
Author(s):  
TA Popova ◽  
II Prokofiev ◽  
IS Mokrousov ◽  
Valentina Perfilova ◽  
AV Borisov ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Platelet Aggregation ◽  
Atp Synthesis ◽  
Elevated Concentration ◽  
Blood Pressure Monitor ◽  
Pressure Monitor ◽  
Griess Reagent ◽  
Arterial Blood ◽  
Endothelial Functions

Introduction: To study the effects of glufimet, a new derivative of glutamic acid, and phenibut, a derivative of γ-aminobutyric acid (GABA), on cardiac and cerebral mitochondria and endothelial functions in animals following exposure to stress and inducible nitric oxide synthase (iNOS) inhibition. Methods: Rats suspended by their dorsal cervical skin fold for 24 hours served as the immobilization and pain stress model. Arterial blood pressure was determined using a non-invasive blood pressure monitor. Mitochondrial fraction of heart and brain homogenates were isolated by differential centrifugation and analysed for mitochondrial respiration intensity, lipid peroxidation (LPO) and antioxidant enzyme activity using polarographic method. The concentrations of nitric oxide (NO) terminal metabolites were measured using Griess reagent. Hemostasis indices were evaluated. Platelet aggregation was estimated using modified version of the Born method described by Gabbasov et al., 1989. Results: The present study demonstrated that stress leads to an elevated concentration of NO terminal metabolites and LPO products, decreased activity of antioxidant enzymes, reduced mitochondrial respiratory function, and endothelial dysfunction. Inhibition of iNOS by aminoguanidine had a protective effect. Phenibut and glufimet inhibited a rise in stress-induced nitric oxide production. This resulted in enhanced coupling of substrate peroxidation and ATP synthesis. The reduced LPO processes caused by glufimet and phenibut normalized the endothelial function which was proved by the absence of average daily blood pressure (BP) elevation episodes and a significant increase in platelet aggregation level. Conclusion: Glufimet and phenibut restrict the harmful effects of stress on the heart and brain possibly by modulating iNOS activity.

Systemic and regional hemodynamics after nitric oxide synthase inhibition: role of a neurogenic mechanism

1994 ◽  
Vol 267 (1) ◽  
pp. R84-R88 ◽  
Author(s):  
M. Huang ◽  
M. L. Leblanc ◽  
R. L. Hester
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Cardiac Output ◽  
No Synthase ◽  
Before And After ◽  
Regional Hemodynamics ◽  
Autonomic Blockade ◽  
Infusion Of Norepinephrine ◽  
Oxide Synthase

The study tested the hypothesis that the increase in blood pressure and decrease in cardiac output after nitric oxide (NO) synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME) was partially mediated by a neurogenic mechanism. Rats were anesthetized with Inactin (thiobutabarbital), and a control blood pressure was measured for 30 min. Cardiac output and tissue flows were measured with radioactive microspheres. All measurements of pressure and flows were made before and after NO synthase inhibition (20 mg/kg L-NAME) in a group of control animals and in a second group of animals in which the autonomic nervous system was blocked by 20 mg/kg hexamethonium. In this group of animals, an intravenous infusion of norepinephrine (20-140 ng/min) was used to maintain normal blood pressure. L-NAME treatment resulted in a significant increase in mean arterial pressure in both groups. L-NAME treatment decreased cardiac output approximately 50% in both the intact and autonomic blocked animals (P < 0.05). Autonomic blockade alone had no effect on tissue flows. L-NAME treatment caused a significant decrease in renal, hepatic artery, stomach, intestinal, and testicular blood flow in both groups. These results demonstrate that the increase in blood pressure and decreases in cardiac output and tissue flows after L-NAME treatment are not dependent on a neurogenic mechanism.

scholarly journals Beneficial haemodynamic effect of indomethacin during endotoxin shock in anaesthetized pigsputative involvement of nitric oxide?

1995 ◽  
Vol 4 (2) ◽  
pp. 117-123 ◽  
Author(s):  
T. Mózes ◽  
E. M. van Gelderen ◽  
E. J. Mylecharane ◽  
P. R. Saxena
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Beneficial Effect ◽  
Endotoxic Shock ◽  
Haemodynamic Effect ◽  
Experimental Period ◽  
Endotoxin Shock ◽  
Arterial Blood ◽  
Imminent Death ◽  
Beneficial Haemodynamic Effect

Endotoxin shock was induced in 31 anaesthetized pigs by infusion of 5 μg/kg of Escbeicbia coli endotoxin (LPS) over 60 min into the superior mesenteric artery. Fifteen of these pigs died within 30 min of the start of LPS infusion whereas the remaining 16 survived the experimental period of 2 h. In a group of nine pigs indomethacin (2 mg/kg, i.v.)was inected 20–25 rain after the start of LPS infusion at which time mean arterial blood pressure (MABP) had decreased below 40 mmHg indicating imminent death. Indomethacin immediately reversed the hypotension. In another group of five pigs, NG-nitro L-arginine-methyl ester (L-NAME, 1 and 3 mg/kg)was iniected 10 and 5 min, respectively, before the expected death without any beneficial effect on the hypotension. Three rain after the last dose of L-NAME, indomethacin (2 mg/kg, i.v.) was iniected. In three animals the hypotension was reserved by indomethacin, although this beneficial effect was delayed in comparison with the LP-Streated group not receiving L-NAME. Four pigs were pretreated with L-NAME, 3 mg/kg, i.v., 10 min prior to LPS infusion. All pretreated animals tended to die within 30 min of the start of the LPS infusion. Five rain before the expected death (20–25 rain after the start of LPS infusion) indomethacin (2 mg/kg) was inected. In three of these animals indomethacin reversed hypotenston and prevented death. Interestingly, this rise in the MABP developed very slowly. These results suggest that the beneficial effect of indomethacin in endotoxin shock might be related partially to interference with nitric oxide, which is not the only factor determining blood pressure levels during endotoxic shock.

Interleukin-1β and neurogenic control of blood pressure in normal rats and rats with chronic renal failure

2000 ◽  
Vol 279 (6) ◽  
pp. H2786-H2796 ◽  
Author(s):  
Shaohua Ye ◽  
Pantea Mozayeni ◽  
Michael Gamburd ◽  
Huiqin Zhong ◽  
Vito M. Campese
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Renal Failure ◽  
Nervous System ◽  
Chronic Renal Failure ◽  
Lateral Ventricle ◽  
Mrna Abundance ◽  
And Control ◽  
The Brain ◽  
Local Expression

Increased sympathetic nervous system (SNS) activity plays a role in the genesis of hypertension in rats with chronic renal failure (CRF). The rise in central SNS activity is mitigated by increased local expression of neuronal nitric oxide synthase (NOS) mRNA and NO2/NO3 production. Because interleukin (IL)-1β may activate nitric oxide in the brain, we have tested the hypothesis that IL-1β may modulate the activity of the SNS via regulation of the local expression of neuronal NOS (nNOS) in the brain of CRF and control rats. To this end, we first found that administration of IL-1β in the lateral ventricle of control and CRF rats decreased blood pressure and norepinephrine (NE) secretion from the posterior hypothalamus (PH) and increased NOS mRNA expression. Second, we observed that an acute or chronic injection of an IL-1β-specific antibody in the lateral ventricle raised blood pressure and NE secretion from the PH and decreased NOS mRNA abundance in the PH of control and CRF rats. Finally, we measured the IL-1β mRNA abundance in the PH, locus coeruleus, and paraventricular nuclei of CRF and control rats by RT-PCR and found it to be greater in CRF rats than in control rats. In conclusion, these studies have shown that IL-1β modulates the activity of the SNS in the central nervous system and that this modulation is mediated by increased local expression of nNOS mRNA.

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