Antioxidant Properties of Whole Body Periodic Acceleration (pGz).

The recognition that oxidative stress is a major component of several chronic diseases has engendered numerous trials of antioxidant therapies with minimal or no direct benefits. Nanomolar quantities of nitric oxide released into the circulation by pharmacologic stimulation of eNOS have antioxidant properties but physiologic stimulation as through increased pulsatile shear stress of the endothelium has not been assessed. The present study utilized a non-invasive technology, periodic acceleration (pGz) that increases pulsatile shear stress such that upregulation of cardiac eNOS occurs, We assessed its efficacy in normal mice and mouse models with high levels of oxidative stress, e.g. Diabetes type 1 and mdx (Duchene Muscular Dystrophy). pGz increased protein expression and upregulated eNOS in hearts. Application of pGz was associated with significantly increased expression of endogenous antioxidants (Glutathioneperoxidase-1(GPX-1), Catalase (CAT), Superoxide, Superoxide Dismutase 1(SOD1). This led to an increase of total cardiac antioxidant capacity along with an increase in the antioxidant response element transcription factor Nrf2 translocation to the nucleus. pGz decreased reactive oxygen species in both mice models of oxidative stress. Thus, pGz is a novel non-pharmacologic method to harness endogenous antioxidant capacity.

Non-invasive technology that improves cardiac function after experimental myocardial infarction: Whole Body Periodic Acceleration (pGz).

Myocardial infarction (MI) may produce significant inflammatory changes and adverse ventricular remodeling leading to heart failure and premature death. Pharmacologic, stem cell transplantation, and exercise have not halted the inexorable rise in the prevalence and great economic costs of heart failure despite extensive investigations of such treatments. New therapeutic modalities are needed. Whole Body Periodic Acceleration (pGz) is a non-invasive technology that increases pulsatile shear stress to the endothelium thereby producing several beneficial cardiovascular effects as demonstrated in animal models, normal humans and patients with heart disease. pGz upregulates endothelial derived nitric oxide synthase (eNOS) and its phosphorylation (p-eNOS) to improve myocardial function in models of myocardial stunning and preconditioning. Here we test whether pGz applied chronically after focal myocardial infarction in rats improves functional outcomes from MI. Focal MI was produced by left coronary artery ligation. One day after ligation animals were randomized to receive daily treatments of pGz for four weeks (MI-pGz) or serve as controls (MI-CONT), with an additional group as non-infarction controls (Sham). Echocardiograms and invasive pressure volume loop analysis were carried out. Infarct transmurality, myocardial fibrosis, and markers of inflammatory and anti-inflammatory cytokines were determined along with protein analysis of eNOS, p-eNOS and inducible nitric oxide synthase (iNOS).At four weeks, survival was 80% in MI-pGz vs 50% in MI-CONT (p< 0.01). Ejection fraction and fractional shortening and invasive pressure volume relation indices of afterload and contractility were significantly better in MI-pGz. The latter where associated with decreased infarct transmurality and decreased fibrosis along with increased eNOS, p-eNOS. Additionally, MI-pGz had significantly lower levels of iNOS, inflammatory cytokines (IL-6, TNF-α), and higher level of anti-inflammatory cytokine (IL-10). pGz improved survival and contractile performance, associated with improved myocardial remodeling. pGz may serve as a simple, safe, non-invasive therapeutic modality to improve myocardial function after MI.

Biological basis of neuroprotection and neurotherapeutic effects of Whole Body Periodic Acceleration (pGz).

Exercise is a well known neuroprotective and neurotherapeutic strategy in animal models and humans with brain injury and cognitive dysfunction. In part, exercise induced beneficial effects relate to endothelial derived nitric oxide (eNO) production and induction of the neurotrophins; Brain Derived Neurotrophic Factor (BDNF) and Glial Derived Neurotrophic Factor (GDNF). Whole Body Periodic Acceleration (WBPA (pGz), is the motion of the supine body headward to footward in a sinusoidal fashion, at frequencies of 100-160 cycles/min, inducing pulsatile shear stress to the vascular endothelium. WBPA (pGz) increases eNO in the cardiovascular system in animal models and humans. We hypothesized that WBPA (pGz) has neuroprotective and neurotherapeutic effects due to enhancement of biological pathways that include eNOS, BDNF and GDNF. We discuss protein expression analysis of these in brain of rodents. Animal and observational human data affirm a neuroprotective and neurotherapeutic role for WBPA (pGz). These findings suggest that WBPA (pGz) in addition to its well known beneficial cardiovascular effects can be a simple non-invasive neuroprotective and neurotherapeutic strategy with far reaching health benefits.

Preconditioning with periodic acceleration (pGz) provides second window of cardioprotection.

AIMS: Whole body periodic acceleration (pGz) is achieved with a motorized platform that moves the supine body with repetitive, sinusoidal head to foot motion. This increases pulsatile shear stress to the endothelium thereby activating endothelial nitric oxide synthase (eNOS) to produce increased release of nitric oxide (eNO). The current investigation was undertaken to determine whether or not pGz preconditioning can induce second window of protection (SWOP) cardioprotective affects in an in-vivo rat model of myocardial infarction. MAIN METHODS: Rats received 1, 3 or 7 daily pGz treatments of 60 minutes, or no pGz (CONT). Twenty-four hours after the last pGz treatment, ischemia reperfusion injury was produced by ligation of the left coronary artery (LCA) for 30 minutes followed by 90 minutes of reperfusion. KEY FINDINGS: All pGz preconditioned animals survived 90 minutes. Three and 7 days of pGz preconditioning reduced myocardial infarct size by 41 and 38% respectively, with better left ventricular function. Additionally, pGz preconditioning increased eNOS, p-eNOS, Akt and p-Akt, HSP70 and nNOS proteins. L-NAME (NOS inhibitor) or Wortmannin (PI3/Akt inhibitor) 15 minutes prior to LCA ligation abolished pGz's cardioprotective effects. SIGNIFICANCE: pGz preconditioning provides SWOP, with increased survival, infarct size reduction, and improved contractility, in part due to up regulation of HSP70 and the PI3/Akt/eNOS , which last at least 72 hours.

Microcirculatory and therapeutic effects of whole body periodic acceleration (pGz) applied after cardiac arrest in pigs.

AIMS: Cardiac arrest (CA) and resuscitation are models of whole body ischemia reperfusion injury. Interventions performed prior to (pre-treatment) or after (post-treatment) can result in cardioprotection. Myocardial stunning, characterized by microcirculatory and contractile dysfunction after CA, is an important component of the post-cardiac arrest syndrome. Periodic acceleration (pGz), produced by the cyclical motion of the supine body headward to footward, increases microcirculatory blood flow to vital organs and elicits production of endothelial derived cytoprotective factors in normal animals. We tested the hypothesis that application of pGz 30 min after return of circulation from CA, as a delayed post-treatment strategy, would improve regional microcirculatory blood flow to vital organs and functional indices of myocardial stunning in pigs. METHODS: 8 min of unsupported VF followed by cardiopulmonary resuscitation and defibrillation was carried out in twenty anesthetized and paralyzed male swine who were randomized to delayed post-treatment with pGz (dPost) or none (CONT). pGz was begun 30 min after return of circulation along with conventional mechanical ventilation. Hemodynamics, echocardiogram, and regional blood flows were measured as well as biochemical index of cardiac tissue injury. RESULTS: All animals had spontaneous return of circulation after cardiopulmonary resuscitation (CPR) and defibrillation. dPost animals had less myocardial stunning and greater regional blood flows to the heart, brain, kidneys, ileum and stomach than CONT. Post-treatment with pGz blunted the increase in Troponin I produced by CA and resuscitation, and, induced a greater rise in endothelial derived nitric oxide synthase (eNOS) and its phosphorylation (p-eNOS). CONCLUSIONS: Delayed post-treatment with pGz as a therapeutic strategy, protects against early myocardial stunning in VF cardiac arrest by improving microcirculatory blood flow to the heart and also protects other vital organs by this mechanism.

Whole body periodic acceleration (pGz) improves survival and allows for resuscitation in a model of severe hemorrhagic shock in pigs.

BACKGROUND: Whole body periodic acceleration (pGz), the repetitive, head-foot sinusoidal motion of the body, increases pulsatile shear stress on the vascular endothelium producing increased release of endothelial derived nitric oxide (eNO) into circulation. Based upon prior CPR investigations, we hypothesized that pGz instituted prior to and during hemorrhagic shock (HS) should improve survival. MATERIALS AND METHODS: Sixteen anesthetized male pigs, 23 ± 5 kg, were randomized to receive 1 h pGz or no pGz (CONT) prior to and during severe controlled graded HS up to 2-1/2 h. HS was induced by removing blood at 10 mL/kg increments from the circulation at 30-min intervals up to a maximum blood loss of 50 mL/kg. Thirty minutes after maximum blood loss, shed blood and lactated Ringers solution was infused intravenously. RESULTS: All animals survived up to 30 mL/kg blood loss. Survival and return to normal blood pressure to 120 min was achieved in 50% of animals receiving pGz compared with none in CONT. Cardiac output, blood pressure, and oxygen delivery decreased equally in both groups but oxygen consumption was significantly lower with pGz than CONT during all hemorrhage time points. Regional blood flow (RBF) was preserved in brain, heart, kidneys, ileum, and stomach in both groups up to 40 mL/kg of blood loss. After 40 mL/kg blood loss, RBF was much better preserved in pGz than CONT. CONCLUSIONS: pGz applied 1 h prior to and during severe graded hemorrhagic shock delays onset of irreversible shock, enabling potential restoration of blood loss and survival.

Periodic acceleration (pGz) prior to whole body ischemia reperfusion injury provides early cardioprotective preconditioning.

AIMS: Periodic acceleration (pGz) is a method that applies repetitive sinusoidal head-to-foot motion to the horizontally positioned body. pGz adds pulses to the circulation as a function of frequency, thereby increasing shear stress to the endothelium. Pulsatile shear stress increases release of cardioprotective endothelial-derived nitric oxide prostaglandin E-2 and prostacyclin into the circulation. We investigated whether pGz may be effective as an early preconditioning strategy when applied one hour prior to whole body ischemia reperfusion injury induced by ventricular fibrillation (VF). MAIN METHODS: Twenty anesthetized and paralyzed male swine were randomized to one hour of pGz and conventional mechanical ventilation [PC] or solely conventional mechanical ventilation [Control] prior to VF and resuscitation. After eight minutes of unsupported VF, cardiopulmonary resuscitation was carried out followed by defibrillation. Hemodynamics, electrocardiogram, echocardiogram, regional blood flows, and markers of global myocardial injury were measured. Protein expression of endothelial-derived nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS), serine/threonine kinase Akt total (t-Akt), and phosphorylated (p-Akt) were determined by immunoblotting. KEY FINDINGS: All animals had spontaneous return of circulation after cardiopulmonary resuscitation (CPR) and defibrillation. Preconditioned animals had less hemodynamically significant arrhythmias, less myocardial stunning, and greater regional blood flows to the brain, heart, kidneys, and ileum than Controls. Troponin I and creatine phosphokinase values in PC were 65% of the values present in Controls. In addition, preconditioned animals had higher protein expression of cardiac eNOS, p-eNOS, t-Akt, and p-Akt than Controls. SIGNIFICANCE: pGz preconditioning confers early cardioprotection in a model of whole body ischemia reperfusion injury.

In vivo upregulation of nitric oxide synthases in healthy rats.

Periodic acceleration (pGz), sinusoidal motion of the whole body in a head-foot direction in the spinal axis, is a novel noninvasive means for cardiopulmonary support and induction of pulsatile shear stress. pGz increases plasma nitrite levels, in vivo and in vitro. Additionally, pGz confers cardioprotection in models of ischemia reperfusion injury. We hypothesize that pGz may also confer a cardiac phenotypic change by upregulation of the expression of the various NO synthase (NOS) isoforms in vivo. pGz was applied for 1h to awake restrained male rats at 2 frequencies (360 and 600 cpm) and acceleration (Gz) of +/-3.4 m/s(2). pGz did not affect arterial blood gases or electrolytes. pGz significantly increased total nitrosylated protein levels, indicating increased NO production. pGz also increased mRNA and protein levels of eNOS and nNOS, and phosphorylated eNOS in heart. pGz increased Akt phosphorylation (p-AKT), but not total Akt, or phosphorylated ERK1/2. Inducible (i) NOS levels were undetectable with or without pGz. Immunoblotting revealed the localization of nNOS, exclusively in cardiomyocyte, and pGz increased its expression. We have demonstrated that pGz changes myocardial NOS phenotypes. Such upregulation of eNOS and nNOS was still evident 24h after pGz. Further studies are needed to understand the biochemical and biomechanical signal transduction pathway for the observed NOS phenotype changed induced by pGz.

Low-amplitude pulses to the circulation through periodic acceleration induces endothelial-dependent vasodilatation.

Low-amplitude pulses to the vasculature increase pulsatile shear stress to the endothelium. This activates endothelial nitric oxide (NO) synthase (eNOS) to promote NO release and endothelial-dependent vasodilatation. Descent of the dicrotic notch on the arterial pulse waveform and a-to-b ratio (a/b; where a is the height of the pulse amplitude and b is the height of the dicrotic notch above the end-diastolic level) reflects vasodilator (increased a/b) and vasoconstrictor effects (decreased a/b) due to NO level change. Periodic acceleration (pG(z)) (motion of the supine body head to foot on a platform) provides systemic additional pulsatile shear stress. The purpose of this study was to determine whether or not pG(z) applied to rats produced endothelial-dependent vasodilatation and increased NO production, and whether the latter was regulated by the Akt/phosphatidylinositol 3-kinase (PI3K) pathway. Male rats were anesthetized and instrumented, and pG(z) was applied. Sodium nitroprusside, N(G)-nitro-l-arginine methyl ester (l-NAME), and wortmannin (WM; to block Akt/PI3K pathway) were administered to compare changes in a/b and mean aortic pressure. Descent of the dicrotic notch occurred within 2 s of initiating pG(z). Dose-dependent increase of a/b and decrease of mean aortic pressure took place with SNP. l-NAME produced a dose-dependent rise in mean aortic pressure and decrease of a/b, which was blunted with pG(z). In the presence of WM, pG(z) did not decrease aortic pressure or increase a/b. WM also abolished the pG(z) blunting effect on blood pressure and a/b of l-NAME-treated animals. eNOS expression was increased in aortic tissue after pG(z). This study indicates that addition of low-amplitude pulses to circulation through pG(z) produces endothelial-dependent vasodilatation due to increased NO in rats, which is mediated via activation of eNOS, in part, by the Akt/PI3K pathway.

Periodic acceleration (pGz) acutely increases endothelial and neuronal nitric oxide synthase expression in endomyocardium of normal swine.

INTRODUCTION: Periodic acceleration (pGz) is a non-invasive method of increasing pulsatile shear stress to the endothelium. pGz is achieved by the sinusoidal head to foot motion to the supine body. pGz increases endogenous production of nitric oxide in whole animal models and isolated perfused vessel preparations, and is cardioprotective when applied prior to, during and after ischemia reperfusion. In part, the protective effects of pGz are attributable to nitric oxide (NO). The purpose of this investigation was to determine whether pGz up-regulates NOS isoforms in the endomyocardium. METHODS AND RESULTS: Fifteen swine weight 15-20 kg, were anesthetized, instrumented to measure hemodynamics and randomized. Ten animals received 1h of pGz at 180 cycles/min and Gz+/-3.9 m/s(2) [pGz] in addition to conventional ventilatory support and five served as time controls. RESULTS: pGz produced a 2.3+/-0.4 and a 6.6+/-0.1 fold significant increase in eNOS and phosphorylated eNOS, 3.6+/-1.1 fold increase in nNOS, and no significant change in iNOS. pGz also produced a 2.4+/-0.3 and 3.9+/-0.2 folds significant increase in both total(t-Akt) and phosphorylated (p-Akt) Akt. CONCLUSIONS: pGz is associated with an increase in both total and phosphorylated eNOS and nNOS protein expression in endomyocardium, and induced significant increase in total and phosphorylated-Akt. The data indicates that pGz is a novel method to induce eNOS and nNOS production in the endomyocardium. Therefore, pGz may serve as a powerful non-invasive intervention to activate the beneficial cardiac effects of endothelial and neuronal NOS.

Acute effects of "delayed postconditioning" with periodic acceleration after asphyxia induced shock in pigs.

Asphyxia cardiac arrest and shock are models for whole body ischemia reperfusion injury. Periodic acceleration (pGz) achieved by moving the body on a platform is a novel method for inducing pulsatile vascular shear stress and endogenous production of endothelial nitric oxide, prostaglandin E2, tissue plasminogen activator, and adrenomedullin. The aforementioned are cardioprotective during and after ischemia reperfusion injury. We investigated whether pGz, applied 15 min after return of spontaneous circulation (ROSC) would serve as an effective "delayed" post conditioning tactic to lessen acute reperfusion injury markers in a pediatric swine model of asphyxia induced shock. Asphyxia shock was induced in 20 swine weight 3.9 +/- 0.6 kg. Fifteen minutes after ROSC, the animals were randomized to receive conventional mechanical ventilation (CMV, [Control]) or CMV with pGz. All animals had ROSC and no significant differences in blood gases or hemodynamics after ROSC. pGz treated had significantly less myocardial dysfunction post resuscitation, (i.e. better % ejection fraction (EF), % fractional shortening (FS), and wall motion score index) and lower biochemical indices of reperfusion injury (lower TNF-alpha, IL-6, and Troponin I, and myeloperoxidase activity). Delayed postconditioning with pGz ameliorates acute post resuscitation reperfusion injury and improves myocardial dysfunction after asphyxia-induced shock.

Non-selective cyclooxygenase inhibition before periodic acceleration (pGz) cardiopulmonary resuscitation (CPR) in a porcine model of ventricular fibrillation.

Whole body periodic acceleration (pGz) along the spinal axis is a novel method of cardiopulmonary resuscitation (CPR). Oscillatory motion of the supine body in a horizontal fashion provides ventilation and blood flow to vital organs during cardiac arrest and pulsatile shear stress to the vascular endothelium. We previously showed in pigs that pGz-CPR affords better overall survival, post resuscitation myocardial function, and neurological outcomes compared to conventional chest compression CPR. pGz through pulsatile shear stress on the vascular endothelium elicits acute production of prostaglandins and endothelial-derived nitric oxide (eNO) in whole animal models and in vitro preparations. The salutary effects associated with pGz-CPR compared to chest compression CPR are in part related to endothelial-derived nitric oxide. Both eNO and prostaglandins are cardioprotective in ischemia reperfusion models. To differentiate between the roles of these mediators, indomethacin a non-selective cyclooxygenase inhibitor (COX) was used as a tool to investigate prostaglandin effects during pGz-CPR by acute outcomes of survival, cardioprotection and regional blood flows (RBF). Two groups of anesthetized, intubated pigs weighing 25-36kg were studied. Prior to electrical induction of ventricular fibrillation (VF) animals received equal volumes of either saline placebo Control (CONT) (n=9) or indomethacin (INDO), (n=8), (2mg/kg). After 3min of unsupported VF, both groups received 15min of pGz-CPR followed by pharmacologic and electrical attempts for resuscitation. Return of circulation (ROSC) to 3h occurred in (78%) in CONT and (63%) in INDO pretreated animals. There was no statistically significant difference in hemodynamics between groups at baseline or during the protocol. At baseline, INDO caused a decrease in brain RBF. Two hours after ROSC, INDO blunted the hyperemia response to brain and heart. Echocardiographic evidence of myocardial dysfunction was most notable for the INDO group in the wall motion score index (WMSI). After 3h of ROSC there was a 4-fold difference in both creatine phosphokinase (CPK) and Troponin I concentration between INDO and CONT. Therefore, non-specific acute inhibition of COX in part blunts the salutary effects of pGz-CPR. These data suggest that prostaglandins in part are involved in the cardio protection induced by pGz during CPR.

Periodic acceleration (pGz) CPR in a swine model of asphyxia induced cardiac arrest. Short-term hemodynamic comparisons.

BACKGROUND: Asphyxia is one of the most common causes of pediatric cardiac arrest, and becoming a more frequently recognized cause in adults. Periodic acceleration (pGz) is a novel method of cardiopulmonary resuscitation (CPR). pGz is achieved by rapid motion of the supine body headward-footward that generates adequate perfusion and ventilation during cardiac arrest. In a swine ventricular fibrillation cardiac arrest model, pGz produced a higher return of spontaneous circulation (ROSC), superior neurological outcome, less echocardiography evidence of post resuscitation myocardial stunning, and decreased indices of tissue injury. In contrast to standard chest compression CPR, pGz does not produce rib fractures. We investigated the feasibility of pGz in severe asphyxia cardiac arrest and assessed whether beneficial effects seen in the VF model of cardiac arrest could be realized. METHODS AND RESULTS: Sixteen swine weight 4+/-1 kg were anesthetized, tracheally intubated, and instrumented to measure, hemodynamics and echocardiography. Asphyxia was induced by occlusion of the tracheal tube. After loss of aortic pulsations (median time 10 min) animals were observed for three additional minutes following which all were in cardiac arrest. The animals were then randomized to receive 10 min of pGz or standard chest compression ventilation performed with a commercial device (Thumper). A single dose of epinephrine (adrenaline) and sodium bicarbonate were given and defibrillation attempted if appropriate for a maximum of 10 min. Both groups received fractional inspired O2 concentration of 100% during CPR and after resuscitation. Four animals in each group (50%) had an initial ROSC, however only two of the four initial survivors remained alive 3h after ROSC. There were no significant differences in blood pressure, coronary perfusion pressure during CPR and after early ROSC between groups. pGz treated animals had significantly lower pulmonary artery pressure; 20+/-4 mmHg compared to Thumper 46+/-5 mmHg, 30 min after ROSC (p<0.01). Surviving animals in both groups had severe myocardial dysfunction at 30 min after ROSC. At necropsy, 25% of the Thumper treated animals had rib fractures, while none occurred in the pGz group. CONCLUSIONS: In a lethal model of asphyxia cardiac arrest, pGz is equivalent to standard CPR, with respect to acute outcomes and resuscitation survival rates but is associated with significantly lower pulmonary artery pressures and does not produce traumatic rib fractures.

The effects of prostaglandin inhibition on whole-body ischemia-reperfusion in swine.

BACKGROUND: Prostaglandins (PGs), particularly PGE2 and PGI2, have a salutary effect on myocardial ischemia-reperfusion-induced myocardial damage. OBJECTIVE: We investigated acute PG synthesis inhibition on outcomes from whole-body ischemia-reperfusion injury using a well-characterized model of ventricular fibrillation (VF)-induced cardiac arrest in pigs. In addition, we assessed early postresuscitation myocardial function in survivors using echocardiography as well as a biochemical measure of myocardial tissue damage. METHODS: Twenty-six animals (weight range, 25-35 kg) received indomethacin (INDO; 2 mg/kg, nonselective cyclooxygenase (COX) 1 and 2 inhibitor), celecoxib (2 mg/kg; selective COX-2 inhibitor [COX-2-I]), or saline placebo 30 minutes before induction of VF. After 3 minutes of VF with no intervention, the animals received standard chest compression using an automated chest compression device (Thumper; Michigan Instruments, Grand Rapids, Mich) for 15 minutes. After 18 minutes of VF, a single dose of vasopressin and bicarbonate were administered and defibrillation attempted. Hemodynamics, regional blood flow, echocardiography, and serum troponin I measurements were performed before and after drug infusion or placebo, during cardiopulmonary resuscitation (CPR), and after return of spontaneous circulation (ROSC). RESULT: Return of spontaneous circulation to 180 minutes occurred in 9 of 10 animals receiving placebo, 7 of 8 animals given COX-2-I, and 3 of 8 animals given INDO (P = .01, placebo or COX-2-I vs INDO). Hemodynamics did not differ among groups over time. Indomethacin and COX-2-I attenuated the increase in regional blood flow in the heart and brain, observed in the placebo group, 30 minutes after ROSC. All 3 study groups had significant decrease in percentage of ejection fraction and fractional shortening after ROSC and significant increase in wall motion score index after ROSC. In the COX-2-I group, troponin I increased 9-fold compared with placebo, 180 minutes after ROSC. Whole-body ischemia-reperfusion and CPR significantly increased PGE2 and PGI2 levels. The latter were blunted by pretreatment with COX inhibition. CONCLUSION: These findings suggest that PGs have a critical role in myocardial function and viability during low-blood-flow states produced by CPR and possibly other low-blood-flow clinical conditions.

Adrenomedullin is increased by pulsatile shear stress on the vascular endothelium via periodic acceleration (pGz).

Periodic acceleration (pGz) is produced by a platform which moves the supine body repetitively in a headward to footward direction. The imparted motion produces pulsatile shear stress on the vascular endothelium. Pulsatile shear stress on the vascular endothelium has been shown to elicit production of a host of cardioprotective, cytoprotective mediators. The purpose of this study was to ascertain if pGz also enhances production of adrenomedullin (AM) in normal healthy swine. Twelve pigs (weight range 20-30 kg) were anesthetized, intubated and placed on conventional mechanical ventilation. All animals were secured to the motion platform. In one group (pGz) (n=7) was activated for 1h, and monitored for an additional 3h. A control group (CONT) (n=5) served as time control. Arterial blood gases, hemodynamic measurements, and serum for AM, interleukin 4, 6 and thromboxane B(2) (TBXB2) were measured at baseline, immediately after pGz, and 3h after pGz had been discontinued. There was no significant change from baseline value in IL-4, IL-6 or TBXB2. Mean arterial blood pressure decreased in pGz-treated animals from 115+/-10 at baseline to 90+/-8 after 60 min of pGz (p<0.01). AM levels increase from 776+/-176 pg/ml baseline to 1160+/-68 pg/ml immediately after pGz, and remained elevated to 1584+/-160 pg/ml, 3h after pGz (p<0.01 vs. BL). This is the first report of AM-enhanced production using a non-invasive method of increasing pulsatile shear stress on the vascular endothelium. pGz increases production of AM in normal healthy swine. These changes are independent of IL-4, IL-6 or TBXB2 production.

Na+/H+ exchange inhibition delays the onset of hypovolemic circulatory shock in pigs.

Severe blood loss is a major cause of death occurring within hours of traumatic injury. Na+/H+ exchange (NHE-1) activity is an important determinant of the extent of ischemic myocardial injury. The goal of the present study was to test the hypothesis that NHE-1 inhibition delays the onset of hypovolemic circulatory shock, thereby preventing early death due to severe hemorrhage in pigs. Severe hypovolemia was studied in 16 (25.2 kg) anesthetized male pigs in steps of 10-, 20-, 30-, 40-, and 50-mL kg(-1) blood loss, each in 30-min intervals. Shed blood resuscitation was started 30 min after 50 mL kg(-1) blood loss. The experiment was terminated after 3 h of resuscitation. Eight pigs were used as seline control. Eight pigs received 3 mg kg(-1) benzamide, N-(aminoiminomethyl)-4-[4-(2-furanylcarbonyl)-1-piperazinyl]-3-(methylsulfonyl), methanesulfonate (NHE-1 inhibitor) 15 min before hemorrhage. Seven control pigs died at 40- to 50-mL kg(-1) blood loss. One control pig survived initial resuscitation but died soon after. In contrast, all animals treated with NHE-1 inhibitor survived the entire protocol. In control animals, cardiac output and MAP gradually decreased at each step of blood loss with marked increase in heart rate. Cardiovascular decompensation occurred at 40 mL kg(-1) blood loss. Na+/H+ exchange inhibition increased oxygen delivery, attenuated cardiovascular decompensation, delayed the onset of irreversible hypovolemic circulatory shock, and enabled resuscitation to survival. Echocardiography analysis showed that myocardial hypercontracture gradually developed with each step of blood loss in control animals, but this hypercontracture was attenuated in the animals receiving the NHE-1 inhibitor. We conclude that NHE-1 inhibition attenuates ischemic myocardial hypercontracture, cardiovascular decompensation, delays the onset of hypovolemic circulatory shock, and prevents early death in severe hemorrhage.

Nitric oxide synthase isoform inhibition before whole body ischemia reperfusion in pigs: vital or protective?

BACKGROUND: Nitric oxide (NO) is a critical regulator of vascular tone, and signal transduction. NO is produced via three unique synthases (NOS); endothelial (eNOS), and neuronal (nNOS) are both constitutively expressed and inducible (iNOS) produced primarily after stimulation. NO has been implicated during and after ischemia reperfusion injury as both a detrimental and cardioprotective mediator. Since cardiopulmonary resuscitation (CPR) in ventricular fibrillation (VF) is a model of whole body ischemia reperfusion injury, it provides an opportunity to assess the effects of NO from the three NOS isoforms. OBJECTIVE: To determine the differential role of nitric oxide synthase isoforms inhibition in ventricular fibrillation CPR and investigate whether inhibition of the NOS isoforms afford any cardioprotection in this model. METHODS: Thirty-two pigs, weight range 25-35 kg, were assigned to four groups of eight animals each. The animals were randomized to receive (1) N(G)-nitro-L-arginine methyl ester (LNAME), a non-selective endothelial nitric oxide synthase inhibitor, (2) 1-(2-trifluoromethylphenyl) imidazole (TRIM), a selective neuronal NOS inhibitor, (3) aminoguanidine (AMINOG), a selective inducible NOS inhibitor or (4) saline control (Control) in equal volumes, 30 min before induction of ventricular fibrillation (VF). After 3 min VF with no intervention, the animals received standard chest compressions using an automated chest compression device (Thumper) for 15 min. After 18 min of VF, single doses of vasopressin and bicarbonate were given and defibrillation attempted. Hemodynamics, regional blood flows, and echocardiography and were performed, before and after drug infusion, during CPR, and after return of spontaneous circulation (ROSC). RESULTS: ROSC for 3 h occurred in 5/8 (63%), 1/8 (13%), 0/8 (0%), and 6/8 (75%) in Control, LNAME, TRIM, and AMINOG treated animals, respectively. After infusion of LNAME, there was a significant increase from baseline in blood pressure [127+/-6 mmHg versus 169+/-3 mmHg, p<0.002] and coronary perfusion pressure [119+/-6 mmHg versus 149+/-6 mmHg, p<0.003]. During CPR, there were no differences among groups in hemodynamics or regional blood flow. In surviving animals, AMINOG had significantly better myocardial function (left ventricular ejection fraction, fractional shortening, and wall motion score index) than control or LNAME treated animals, and attenuated the post-resuscitation hyperemic response in heart and brain. CONCLUSIONS: Intact basal nNOS activity is vital for survival from whole body ischemia reperfusion injury. iNOS inhibition prior to ischemia reperfusion, protects myocardial function after ROSC and decreases myocardial and brain hyperemic response after ROSC.

Different roles of nitric oxide synthase isoforms in cardiopulmonary resuscitation in pigs.

The purpose of the present study was to identify the roles of the three nitric oxide synthase (NOS) isoforms on whole body ischemia-reperfusion injury during cardiopulmonary resuscitation (CPR) with periodic acceleration (pGz) in pigs. Thirty-two anesthetized pigs (27.6+/-3.4 kg) were monitored for hemodynamics and selected echocardiographic variables. Twenty minutes after NOS inhibition or placebo administration, ventricular fibrillation (VF) was induced and remained untreated for 3 min, followed by CPR with pGz for 15 min, plus 3 min of manual chest compressions and defibrillation attempt. Four groups were studied: (1) saline control; (2) L-NAME (non-selective NOS inhibitor); (3) aminoguanidine (inducible NOS inhibitor); (4) TRIM (neuronal NOS inhibitor). Return of spontaneous circulation (ROSC) to 180 min occurred in 6/8 controls, 4/8 L-NAME, 7/8 aminoguanidine, and 2/8 TRIM animals. The L-NAME group had significantly lower organ blood flow, impaired cardiac function, but higher vascular tone than control group. The aminoguanidine group had the highest organ blood flows and survival rate. Six out of eight TRIM treated animals had initial return of heartbeat; however, with impaired heart contractility and could not survive more than 20 min of ROSC. This study reveals the differential role of endogenous NO produced from the three NOS isoforms during pGz-CPR. Both endothelial and neuronal NOS derived NO show predominantly protective effects while inducible NOS derived NO plays a detrimental role in pGz-CPR. The present study has shown that cardiac arrest and resuscitation appears to be associated with a different expression of NOS isoforms which appear to affect resuscitation outcomes differently.

Whole-body periodic acceleration modifies experimental asthma in sheep.

RATIONALE: Nitric oxide is released from vascular endothelium in response to increased pulsatile shear stress. Nitric oxide inhibits mast cell activation and is antiinflammatory and therefore might be protective in asthma. OBJECTIVES: We determined if a noninvasive motion platform that imparts periodic sinusoidal inertial forces to the whole body along the spinal axis (pGz) causing release of endothelial nitric oxide modulates experimental asthma in sheep. METHODS: Allergic sheep were untreated (control) or were treated with pGz alone or after receiving intravenously the nitric oxide synthase inhibitor N(w)-nitro-L-arginine methyl ester (L-NAME) before aerosol challenge with Ascaris suum, and the effect on antigen-induced airway responses was determined. Bronchoalveolar lavage cells obtained 6 h after antigen challenge were analyzed for nuclear factor-kappaB (NF-kappaB) activity in the respective groups. RESULTS: pGz treatment for 1 h before antigen challenge reduced the early airway response and blocked the late airway response but did not prevent the antigen-induced airway hyperresponsiveness 24 h after challenge. Administration of L-NAME before pGz completely reversed this protection, whereas L-NAME alone did not affect the antigen-induced responses. NF-kappaB activity was 1.9- and 1.8-fold higher in the control and L-NAME + pGz groups, respectively, compared with pGz-treated animals. Extending the pGz treatment to twice daily for 3 d and then 1 h before antigen challenge blocked the early and late airway responses, the 24-h airway hyperresponsiveness, and the airway inflammatory cell response. CONCLUSION: Whole-body pGz modulates allergen-induced airway responses in allergic sheep.

Post-resuscitation reperfusion injury: comparison of periodic Gz acceleration versus Thumper CPR.

The effects of whole body, periodic acceleration (pGz) on cardiopulmonary resuscitation outcome, organ blood flow and tissue inflammatory injury were examined in an experimental pig model, and compared with Thumper (TH)-CPR. VF was induced in 16 pigs, and remained untreated for 3 min, followed by either pGz-CPR or TH-CPR for 15 min. Defibrillation attempts were made at 18 min of VF. Six of eight animals had ROSC in both groups. Post-arrest myocardial dysfunction was present in both groups and progressed over hours. pGz-CPR animals had less wall motion abnormality and higher left ventricular ejection fraction than TH-CPR. The post-resuscitation haemodynamic variables returned to baseline after 3h of ROSC in pGz-CPR group, and remained low in TH-CPR group. The brain blood flow during CPR was similar between TH-CPR and pGz-CPR, 17% and 20% of pre-fibrillation values, respectively. The cardiac blood flow during CPR was significantly lower in pGz-CPR than TH-CPR (TH: 10.2% and pGz: 1.9% of pre-fibrillation value), as well as in other organs. The brain and heart blood flow was significantly higher than pre-fibrillation values after 30 min of ROSC in both groups. The pGz group had significantly higher blood flow in brain, heart and kidney than TH-CPR after 30 min of ROSC. Blood flow in all organs decreased below pre-fibrillation values at 2h of ROSC. Tissue inflammatory injury progressed over hours in the post-resuscitation phase. pGz-CPR group had significantly lower myeloperoxidase (MPO) activity and plasma creatine phosphokinase (CPK) and cardiac troponin I, TNF-alpha, and IL-6 than TH-CPR. Results from the present study demonstrate again that pGz-CPR is an effective method of cardiopulmonary resuscitation, with less post-reperfusion injury compared to TH-CPR.