Reduction In Mean Arterial Pressure Research Articles

Pharmacophore modeling, design, and synthesis of potent antihypertensives, oxazolo/thiazolo-[3,2-a]-pyrimidin-3(2H)-one, and 1,5-dihydroimidazo-[1,2-a]-pyrimidin-3(2H)-one derivatives: A pilot trial

An improved pharmacophore model, molecular properties, geometric analyses, and SAR led to synthesize oxazolo/thiazolo-[3,2-a]-pyrimidin-3(2H)-one, and 1,5-dihydroimidazo-[1,2-a]-pyrimidin-3(2H)-one derivatives exhibiting potent anti-hypertensive activity. The 6-ethoxycarbonyl-2,7-dimethyl-5-phenyl-1,5-dihydroimidazo[3,2-a]pyrimidin-3(2H)-one (4g), and 6-ethoxycarbonyl-2,7-dimethyl-5-(3-methyl-phenyl)-1,5-dihydroimidazo[3,2-a]pyrimidin-3(2H)-one (4h) showed significant reduction in mean arterial blood pressure (MABP, mm/Hg) of 79.78%, and 92.95% in 6 and 12 h durations, respectively, at 1.5 mg/kg body-weight dose, while at 3.0 mg/kg body-weight dose, the MABP reduction was achieved at 95.46%, and 92.02%, respectively, in 6 and 12 h durations, as compared to the standard drug, nifedipine.

Beneficial Effects of Vasopressin Compared With Norepinephrine on Renal Perfusion, Oxygenation, and Function in Experimental Septic Acute Kidney Injury

To compare the effects of restoring mean arterial pressure with vasopressin or norepinephrine on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, and renal function in ovine septic acute kidney injury. Interventional Study. Research Institute. Adult Merino ewes. Flow probes were implanted on the pulmonary and renal arteries (and the mesenteric artery in sheep that received vasopressin). Fiber-optic probes were implanted in the renal cortex and medulla to measure tissue perfusion and oxygen tension (PO2). Conscious sheep were administered Escherichia coli to induce septic acute kidney injury. Vasopressin (0.03 IU/min [0.03-0.05 IU/min]; n = 7) or norepinephrine (0.60 μg/kg/min [0.30-0.70 μg/kg/min]; n = 7) was infused IV and titrated to restore baseline mean arterial pressure during 24-30 hours of sepsis. Ovine septic acute kidney injury was characterized by reduced mean arterial pressure (-16% ± 2%) and creatinine clearance (-65% ± 9%) and increased renal blood flow (+34% ± 7%) but reduced renal medullary perfusion (-44% ± 7%) and PO2 (-47% ± 10%). Vasopressin infusion did not significantly affect renal medullary perfusion or PO2 and induced a sustained (6 hr) ~2.5-fold increase in creatinine clearance. Vasopressin reduced sepsis-induced mesenteric hyperemia (+61 ± 13 to +9% ± 6%). Norepinephrine transiently (2 hr) improved creatinine clearance (by ~3.5-fold) but worsened renal medullary ischemia (to -64% ± 7%) and hypoxia (to -71% ± 6%). In ovine septic acute kidney injury, restoration of mean arterial pressure with vasopressin induced a more sustained improvement in renal function than norepinephrine, without exacerbating renal medullary ischemia and hypoxia or reducing mesenteric blood flow below baseline values.

TRIGEMINAL-CARDIAC REFLEX: A COMMON BUT UNRECOGNIZED PRESENTATION AMONG PATIENTS WITH EPISTAXIS

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Trigeminal-cardiac reflex (TCR), is a neurocardiogenic reflex which can produce sudden onset hemodynamic instability. We describe a case of TCR which was observed in a patient presenting with recurrent epistaxis. CASE PRESENTATION: A 71-year-old gentleman with a past medical history of hypertension and metastatic prostate cancer was admitted to the hospital with a chief complaint of persistent epistaxis. As conventional epistaxis management was unsuccessful, he underwent right-sided sphenoidal artery embolization followed by Foley catheter balloon packing. That night, he abruptly developed hemodynamic instability with a drop in his BP from 150/98 to 83/50mmHg, together with a rapid reduction in his HR by 25%. The patient was afebrile, awake, alert, and following commands. He was immediately started on empiric antibiotic therapy and received gentle fluid boluses. Workup for sepsis and cardiopulmonary etiologies of the hemodynamic changes, including complete blood count, comprehensive metabolic panel, blood cultures, chest imaging, and electrocardiogram, were obtained and were negative. His vitals rapidly returned to the baseline with conservative measures. However, within the next hour, the patient was noted to have another transient episode of a sudden drop in BP and HR. The septic and cardiopulmonary workup remained negative. On further chart review, the patient had reported pulling on the Foley packing due to irritation prior to the onset of the episodes. Therefore, the TCR reflex, induced when the patient applied traction on the Foley catheter, was the likely cause of these transient episodes of hemodynamic instability. The nasal packing was not immediately removed due to the high risk of rebleed. Continuous hemodynamic monitoring was maintained while the patient was advised to avoid manipulation of the packing. Once he became stable, the packing was removed, following which the episodes never recurred. DISCUSSION: Epistaxis is one of the most common causes of ER visits in the United States. TCR is defined as an acute reduction in heart rate and mean arterial blood pressure by more than 20% compared to the baseline and is usually triggered with manipulation near the trigeminal nerve endings [1]. In the case of our patient, there was a definite temporal relationship between the episodes of hemodynamic instability and the traction applied on nasal packing, which likely stimulated the nerve and activated TCR [2]. CONCLUSIONS: Although the clinical course of most epistaxis cases is benign, under-diagnosis of this unique brain stem reflex has resulted in severe consequences including patient death [2]. Therefore, trigeminal-cardiac reflex should be included as one of the differentials of acute hemodynamic instability in patients with nasal packing. Reference #1: Schaller BJ, Filis A, Buchfelder M. Trigemino-cardiac reflex in humans initiated by peripheral stimulation during neurosurgical skull-base operations. Its first description. Acta Neurochir (Wien). 2008;150(7):715-718. doi:10.1007/s00701-008-1602-1 Reference #2: Awasthi D, Roy TM, Byrd RP Jr. Epistaxis and Death by the Trigeminocardiac Reflex: A Cautionary Report. Fed Pract. 2015;32(6):45-49. DISCLOSURES: No relevant relationships by Suganya Chandramohan, source=Web Response No relevant relationships by Graciela Rojas, source=Web Response No relevant relationships by Joseph Sebastian, source=Web Response No relevant relationships by Josee Smith, source=Web Response

Hemodynamic Reserve Predicts Early Right Heart Failure After LVAD Implantation

Background Right heart failure (RHF) remains a major source of morbidity and mortality after left ventricular assist device (LVAD) implantation, yet efforts to predict RHF have proved only modestly successful. Acute pharmacologic unloading of the LV to assess ventricular and hemodynamic reserve may better predict post-implant RHF. Objectives To compare pre-implant baseline and post-vasodilator hemodynamic predictors of INTERMACS defined severe or severe-acute RHF after LVAD implantation. Methods After IRB approval, we performed a retrospective analysis of all subjects implanted with a durable LVAD at our institution between February 2017 and April 2020 (n=108). Only those who underwent vasodilator testing with nitroprusside during their pre-implant right heart catheterization were ultimately included (n=29). Continuous variables were compared with t-test and Levene's test of equality of variances; categorical via Fisher's Exact test. Logistic regression was used to determine predictors of severe or severe-acute RHF. Results Ten subjects met criteria for severe or severe-acute RHF (34%) after implant. There were no significant differences in demographics, HF etiology, INTERMACS profile, echo assessment of LV/RV function, or pre-implant baseline hemodynamics including RAP:PAWP ratio and PAPi between groups (TABLE). Both groups saw a similar reduction in systemic mean arterial pressure with nitroprusside, which led to significant and similar reductions in PAWP and pulmonary pressures. Compared to the group with severe or severe-acute RHF, those without significant RHF achieved higher peak cardiac index (CI) with nitroprusside infusion, suggesting better cardiac reserve. Peak CI was a significant predictor of RHF (p= 0.022), even after controlling for baseline values (p=0.048). No subject achieving a peak CI > 2.66 L/min/m2 developed severe or severe-acute RHF, and every 0.25 L/min/m2 decrease in peak CI was associated with 2.3 fold increased risk. Mortality was higher and hospital length of stay longer in the severe or severe-acute RHF group. Conclusion Peak CI with nitroprusside infusion predicts post-implant LVAD RHF better than resting hemodynamics in this small cohort. Hemodynamic reserve measurements may prove to be an important risk stratification tool when assessing LVAD candidacy.

Eight Weeks of Supervised Indoor Climbing Significantly Reduces Arterial Pressure and Total Cholesterol in Recreational Climbers

The present study sought to investigate physiological adaptations associated with an 8-week supervised climbing intervention in recreational climbers. Nine participants (5 males and 4 females; age: 37 ± 8 years; stature: 169.7 ± 10.6 cm; body mass 83.3 ± 20.3 kg) volunteered to complete the intervention concomitant with their recreational climbing activities. Blood pressure, body composition, peak aerobic capacity, total cholesterol, and handgrip strength were assessed before and after the intervention. Post-intervention, diastolic blood pressure was significantly reduced (pre: 87 ± 6 mmHg, post: 72 ± 10 mmHg, p<0.01), without significant changes in systolic blood pressure (pre: 136 ± 15 mmHg, post: 128 ± 20 mmHg, p=0.19). This resulted in a significant reduction in mean arterial pressure (pre: 103 ± 9 mmHg, post: 90 ± 13 mmHg, p<0.01). A significant reduction in total cholesterol was also observed following the 8-week climbing intervention (pre: 5.09 ± 0.49 mmol/L, post: 4.39 ± 0.63 mmol/L, p<0.01). However, there were no significant changes in body fat percentage (p=0.67), skeletal muscle mass (p=0.76), isometric hand-grip strength (dominant hand: p=0.93, non-dominant hand: p=0.12) or peak aerobic capacity (p=0.37). Supervised indoor climbing exercise may therefore serve as an important non-pharmacological intervention to improve cardiovascular health by reducing mean arterial pressure and total cholesterol levels in recreational climbers, independent of changes in body composition or peak aerobic capacity.

Abstract 17: Early Life Stress Sensitizes The Angiotensin II-elicited Hypertensive Response

Separation of neonatal rodent pups from their mothers has been used as a model to study the effects of early life stress (ELS) on behavioral and physiological responses in adults. Using an Induction-Delay-Expression experimental paradigm, our previous studies demonstrate that a wide range of stressors administered during an induction period produces hypertensive response sensitization (HTRS) in response to a subsequent pro-hypertensive stimulus. HTRS is accompanied by activation of the brain renin-angiotensin system (RAS) and CNS inflammation. The present study investigated whether ELS induces HTRS and changes in brain-related underlying mechanisms. Rat neonates from Sprague-Dawley breeders were subjected to ELS by separating them each morning from their mothers for 3 h on postnatal days 2 to 14. Pups from non-handled litters formed control groups. At 10 weeks of age, male rats were used to evaluate blood pressure and autonomic function using telemetric probes and pharmacological methods. In addition, in separate control and ELS groups, the lamina terminalis (LT) structures and the hypothalamic paraventricular nucleus (PVN) were analyzed for mRNA expression of RAS components and proinflammatory cytokines. Adult ELS rats as compared to non-separated controls exhibited 1) HTRS during expression testing using 2 week ANG II infusions (120 ng/kg/min s.c.; ELS animals, Δ45.5±4.5 mmHg vs. controls, Δ22.4±3.1 mmHg); 2) a greater reduction in mean arterial pressure following ganglionic blockade (hexamethonium, 30 mg/kg, ip), 3) increased sympathetic drive to the heart (atenolol, 8 mg/kg, ip), 4) decreased vagal tone (atropine, 8 mg/kg, ip), and 5) increased mRNA expression of several components of the brain RAS and proinflammatory cytokines in the LT and PVN. These results suggest that maternal ELS may predispose individuals to hypertension that is mediated by upregulation of the brain RAS and proinflammatory cytokines and increased sympathetic drive to the cardiovascular system.

Abstract P208: Imaging The Longitudinal Reduction In Placental Ischemia In Response To Therapeutic Intervention For Preeclampsia

Preeclampsia is believed to be induced by abnormal vascular remodeling and the resulting placental ischemia during early development. Sildenafil, a phosphodiesterase-5 inhibitor, reduces the maternal symptoms of preeclampsia by promoting angiogenesis and enhancing NO-mediated vasodilation. However, the effect of sildenafil on in vivo placental function has not been demonstrated. We performed longitudinal spectral photoacoustic (sPA) imaging of placental therapeutic response to sildenafil in the reduced uterine perfusion pressure (RUPP) model of preeclampsia. Sprague Dawley rats were administered sildenafil (S) via drinking water beginning on gestational day (GD) 11. Imaging was performed on GD14, 16, and 18 with the RUPP procedure implemented after the first imaging session. sPA images of oxygenation show that the placental ischemia induced by the RUPP surgery (RUPP, n=8, 48%; NP, n=8, 54%), was effectively eliminated by treatment with sildenafil (RUPP+S, n=8, 53%, p&lt;0.05). In addition to improved placental oxygenation, sildenafil was also found to reduce mean arterial pressure in RUPP animals by GD18 (RUPP, 110 mmHg; RUPP+S, 98 mmHg; p&lt;0.05), consistent with prior reports. Our studies demonstrate that sPA imaging can detect changes in placental oxygenation which could be used to indicate in vivo placental therapeutic response. Figure 1: Placental hypoxia in the RUPP is improved by treatment with sildenafil on GD16. B-mode US images (a, c) of anatomy were used to manually select the placenta (p) and average placental oxygenation was calculated. A custom red-blue oxygenation colormap was then overlaid for visualization (b, d). Scale bars = 3mm.

Abstract MP40: Hiv Impairs Endothelial Function And Elevates Blood Pressure Via Tnfa Dependent Mechanisms In Male And Female Mice.

HIV is a major health concern with over 37 million individuals worldwide living with HIV. The onset of combination antiretroviral therapy (cART) patients with HIV (PWH) live longer but exhibit accelerated development of cardiovascular disease. Clinical evidence indicates that 35% of PWH exhibit hypertension, however, the etiopathology is still ill-defined. We plan to take advantage of a transgenic mouse model (Tg26) that mimics patients with a repressed virus, to test the hypothesis that viral infection independent of cART induces endothelial dysfunction and hypertension via a TNF-α mediated mechanism. Vascular reactivity was analyzed via wire myography and blood pressure (BP) recorded via radio-telemetry. Results showed that viral infection impaired aorta endothelium-dependent relaxation as reflected by a decrease in acetylcholine-mediated relaxation in both Tg26 mice (P&lt;0.05) which was ameliorated with the NOX 1/4 inhibitor GKT 137831. Smooth muscle cell-dependent relaxation (SNP) and contractility to phenylephrine and KCl remained intact in Tg26 mice. Viral infection increased systolic, diastolic, and mean arterial pressure (MAP: male: WT=112.3±1.3 vs Tg26=121.9±4.0 mmHg/ female: WT=110.6±3.01/ Tg26=120.3±6.9 mmHg) and elevated heart rate (HR) in both sexes (p&lt;0.05). We used atropine, propranolol, and hexamethonium in WT and Tg26 mice to investigate the contribution of the autonomic nervous system to hypertension. HR responses to both atropine (Female: +5.07±2.8% vs. male +4.3±5.4% of baseline) and propranolol (Female: 19.9±6.1% vs. male 12.0±4.3%) revealed no significance or sex differences in WT mice and no effects of viral infection on autonomic control of heart rate in Tg26 mice. BP responses to hexamethonium revealed no effect of sex or viral infection, supporting a limited contribution of the autonomic nervous system to hypertension in Tg26 mice. However, we found that TNFα inhibition with etanercept reduced mean arterial pressure in Tg26 mice to the level of the WT mice (WT=112.3±1.3, Treated=110.1±0.185) and improved endothelial function. These data indicate that HIV infection contributes to cardiovascular disease via inducing endothelial dysfunction and hypertension via NOX and TNFα-dependent mechanisms respectively.

Abstract 286: Targeting Formyl Peptide Receptors as a Novel Approach to Treat Hypertension

Introduction: It is estimated that 15-30% of hypertensive patients are resistant to available drugs; and thus identifying novel therapeutic strategies is imperative. We have previously demonstrated that the formyl peptide receptor-1/2 (FPR) small-molecule agonist, Cmpd17b, exhibits anti-inflammatory and vasodilator actions. We investigated the efficacy of Cmpd17b to reduce hypertension and its associated end-organ damage. Methods: Hypertensive (BPH/2J) and normotensive (BPN/3J) mice underwent 24h conscious blood pressure recordings via telemetry from baseline until 4 weeks post Cmpd17b treatment (50 mg/kg/day, i.p.) or vehicle (8% tween80 in saline with 10% dimethyl sulfoxide, i.p.). The abdominal aorta dimension was assessed via ultrasound imaging at baseline and study end. Results: Hypertensive mice exhibited elevated mean arterial pressure compared to normotensive mice at baseline (Table). Cmpd17b reduced mean arterial pressure, left ventricle fibrosis, angiotensinogen expression and improved vascular distensibility. Conclusion: This study is the first to demonstrate that chronic FPR agonist administration reduces blood pressure in hypertensive mice, and further supports development of FPR-based therapies against hypertension-related organ damage.

Combination of phosphodiesterase-5-inhibitors and beta blockers improves experimental portal hypertension and erectile dysfunction.

Phosphodiesterase-5 inhibitors (PDE-5-I) are used for treatment of erectile dysfunction (ED), which is common in patients with cirrhosis. They may improve portal hypertension (PH), but contradictory data on efficacy and side-effects have been reported. Non-selective beta blockers (NSBB) reduce portal pressure, but might aggravate ED. Thus, we evaluated the combination of PDE-5-I with NSBB and its impact on PH and ED in experimental cirrhosis. ED was assessed in cirrhotic patients (n = 86) using standardized questionnaire. Experimental cirrhosis was induced by bile-duct-ligation or carbon-tetrachloride intoxication in rats. Corpus cavernosum pressure - a surrogate of ED -, as well as systemic and portal haemodynamics, were measured in vivo and in situ after acute administration of udenafil alone or in combination with propranolol. mRNA and protein levels of PDE-5 signalling were analysed using PCR and western Blot. ED in humans was related to severity of liver disease and to NSBB treatment. PDE-5 was mainly expressed in hepatic stellate cells and upregulated in human and experimental cirrhosis. Propranolol reduced corpus cavernosum pressure in cirrhotic rats and it was restored by udenafil. Even though udenafil treatment improved PH, it led to a reduction of mean arterial pressure. The combination of udenafil and propranolol reduced portal pressure and hepatic resistance without systemic side-effects. ED is common with advanced cirrhosis and concomitant NSBB treatment. The combination of PDE-5-I and NSBB improves ED and PH in experimental cirrhosis.

Risk factors for agitation and hyperactive delirium in adult postcardiotomy patients with extracorporeal membrane oxygenation support: an observational study.

Agitation and delirium in critically ill patients after cardiac surgery carry poor in-hospital prognosis. Identifying risk factors may promote its prevention and management. Accordingly, this study aimed to evaluate the incidence of agitation and hyperactive delirium in postcardiotomy patients during the extracorporeal membrane oxygenation support and to identify the risk factors for its development. This single center, retrospective study was conducted at Beijing Anzhen Hospital, Capital Medical University. Data were extracted from the prospective institutional registry database of extracorporeal membrane oxygenation patients. Univariate and multivariate logistic regression analyses were performed to predict risk factors. A total of 170 consecutive adult patients underwent extracorporeal membrane oxygenation in our hospital from January 2016 to December 2017. Ninety-four patients were included in the final analysis. The incidence of agitation and hyperactive delirium was 35% in our population of extracorporeal membrane oxygenation-supported postcardiotomy patients. Agitation and delirium usually occurred within the first 3 days of extracorporeal membrane oxygenation. Multivariable analysis showed that history of previous stroke (without preoperative cognitive dysfunction; odds ratio, 4.425, 95% confidence interval: 1.171-16.716; p = 0.028) and mean arterial pressure reduction (before extracorporeal membrane oxygenation initiation) ⩾ 49 mmHg (odds ratio, 7.570, 95% confidence interval: 2.366-24.219, p = 0.001) were independent risk factors for agitation and hyperactive delirium during extracorporeal membrane oxygenation support. The areas under the receiver operating characteristic curve for the prediction of agitation and hyperactive delirium was 0.704 (95% confidence interval 0.589-0.820, p = 0.001). There was more severe arrhythmia in the agitation patients. Our results suggest that the prevalence of agitation and hyperactive delirium in postcardiotomy patients with extracorporeal membrane oxygenation support is high. In addition, previous stroke and severe mean arterial pressure reduction before extracorporeal membrane oxygenation initiation is predictive of agitation and hyperactive delirium.

Pulling back on the push-pull effect: use of lower body negative pressure to protect against drops in cerebral perfusion during airflight manoeuvres.

Pulling back on the push-pull effect: use of lower body negative pressure to protect against drops in cerebral perfusion during airflight manoeuvres.

Internal carotid artery blood flow is enhanced by elevating blood pressure during combined propofol-remifentanil and thoracic epidural anaesthesia

Anaesthesia reduces mean arterial pressure (MAP), and to preserve organ perfusion, vasopressors are often used to maintain MAP above 60 mmHg. Cognitive dysfunction is common following major surgery and may relate to intra-operative cerebral hypoperfusion. The aim of this study was to evaluate whether internal carotid artery (ICA) blood flow increases when MAP is kept higher than 60 mmHg using noradrenaline. A randomised, cross-over trial. Department of Anaesthesia, Rigshospitalet, Copenhagen, Denmark, from December 2017 to April 2018. Patients with median [IQR] age 71 [63 to 75] years underwent pancreaticoduodenectomy (n = 19), total pancreatic resection (n = 1) or gastro-entero anastomosis (n = 2) during combined propofol-remifentanil and thoracic epidural anaesthesia. MAP was maintained between 60 to 65, 70 to 75 and 80 to 85 mmHg, in a random order, by noradrenaline infusion at a stable level of anaesthesia. Primary outcome was change in ICA flow at MAP 60 to 65 vs. 80 to 85 mmHg. Secondary outcomes were change in ICA flow at MAP 60 to 65 vs. 70 to 75 and 70 to 75 vs. 80 to 85 mmHg. Duplex ultrasound evaluated ICA flow. A (mean ± SD) increase in MAP from 62 ± 1 to 82 ± 1 mmHg elevated ICA flow from 196 ± 53 to 226 ± 61 ml min (mean difference 31 ml min; 95% CI 19 to 42; P < 0.0001). An increase in MAP from 62 ± 1 to 72 ± 1 mmHg elevated ICA flow to 210 ± 52 ml min (P = 0.0271) and ICA flow increased further (P = 0.0165) when MAP was elevated to 82 ± 1 mmHg. During combined propofol-remifentanil and thoracic epidural anaesthesia, ICA flow increased by approximately 15% when the MAP was elevated from about 60 to 80 mmHg. Treatment of a reduction in MAP brought about by anaesthesia seems to enhance ICA flow. Clinicaltrials.gov ID: NCT03309917.

Lower body negative pressure protects brain perfusion in aviation gravitational stress induced by push-pull manoeuvre.

Rapid alterations of gravitational stress during high-performance aircraft push-pull manoeuvres induce dramatic shifts in volume and pressure within the circulation system, which may result in loss of consciousness due to the rapid and significant reduction in cerebral perfusion. There are still no specific and effective countermeasures so far. We found that lower body negative pressure (LBNP), applied prior to and during -Gz and released at the subsequent transition to +Gz, could effectively counteract gravitational haemodynamic stress induced by a simulated push-pull manoeuvre and improve cerebral diastolic perfusion in human subjects. We developed a LBNP strategy that effectively protects cerebral perfusion at rapid -Gz to +Gz transitions via improving cerebral blood flow and blood pressure during push-pull manoeuvres and highlight the importance of the timing of the intervention. Our findings provide a systemic link of integrated responses between the peripheral and cerebral haemodynamic changes during push-pull manoeuvres. The acute negative (-Gz) to positive (+Gz) gravity stress during high-performance aircraft push-pull manoeuvres dramatically reduces transient cerebral perfusion, which may lead to loss of vision or even consciousness. The aim of this study was to explore a specific and effective counteractive strategy. Twenty-three healthy young male volunteers (age 21±1year) were subjected to tilting-simulated push-pull manoeuvres. Lower body negative pressure (LBNP) of -40mmHg was applied prior to and during -Gz stress (-0.50 or -0.87Gz) and released at the subsequent transition to +1.00Gz stress. Beat-to-beat cerebral and systemic haemodynamics were continuously recorded during the simulated push-pull manoeuvre in LBNP bouts and corresponding control bouts. During the rapid gravitational transition from -Gz to +Gz, the mean cerebral blood flow velocity decreased significantly in control bouts, while it increased in LBNP bouts (control vs. LBNP bouts, -6.6±4.6 vs. 5.1±6.8cms-1 for -0.50Gz, and -7.4±4.8 vs. 3.4±4.6cms-1 for -0.87 Gz, P<0.01), which was attributed mainly to the elevation of diastolic flow. The LBNP bouts showed much smaller reduction of mean arterial blood pressure at the brain level than control bouts (control bouts vs. LBNP bouts, -38±12 vs. -23±10mmHg for -0.50 to +1.00Gz, and -62±16 vs. -43±11mmHg for -0.87 to +1.00Gz, P<0.01). LBNP applied at -Gz and released at subsequent +Gz had biphasic counteractive effects against the gravitational responses to the push-pull manoeuvre. These data demonstrate that this LBNP strategy could effectively protect cerebral perfusion with dominant improvement of diastolic flow during push-pull manoeuvres.

Impact of a short-term synbiotic supplementation on metabolic syndrome and systemic inflammation in elderly patients: a randomized placebo-controlled clinical trial.

The connection between gut microbiota imbalance, inflammation and its role in the pathogenesis of metabolic syndrome (MetS) clustering factors has been increasingly recognized. However, data on the efficacy of probiotics supplementation on MetS components are few and almost lacking in the elderly. To address this issue, we conducted a randomized, double-blind, placebo-controlled, parallel-group, clinical study on a large sample of MetS elderly patients. After 14days of diet and physical activity standardization, 60 elderly patients were randomized to treatment with a synbiotic formula of Lactobacillus plantarum PBS067, Lactobacillus acidophilus PBS066 and Lactobacillus reuteri PBS072 with active prebiotics or placebo. Patients were evaluated anamnestically and by the execution of a physical examination and laboratory and haemodynamic analyses at the baseline and after 60days of treatment. At enrollment and at the end of the trial, all enrolled patients complete the EuroQol-5 Dimension (EQ-5D) questionnaire. Through the 2-month period of treatment, patients who received active treatment experienced a statistically significant improvement in waist circumference and in fasting plasma insulin, total cholesterol, high-density lipoprotein cholesterol, non-HDL-C, triglycerides (TG), low-density lipoprotein cholesterol, high-sensitivity C-reactive protein and tumor necrosis factor alpha serum levels, compared both to the baseline and the control group. Visceral adiposity index improvement in the synbiotic treatment group was significantly greater than in placebo group. Compared to baseline, treatment with synbiotics also significantly reduced mean arterial pressure and fasting plasma glucose. All treatment groups demonstrated a significant decrease in TG. TG reduction in the synbiotic group was significantly greater than in the control group. The EQ-5D VAS questionnaire significantly improved only in probiotics-treated subjects. Treatment with a synbiotic formula of L. plantarum PBS067, L. acidophilus PBS066 and L. reuteri PBS072 with active prebiotics decreased MetS syndrome prevalence, several cardiovascular risk factors and markers of insulin resistance in elderly patients.

Effect of Neuraxial Analgesic Procedures on Intraoperative Hemodynamics During Routine Clinical Care of Gynecological and General Surgeries: A Case-Control Query of Electronic Data.

BackgroundThe purpose of this study was to determine whether neuraxial analgesic procedures affect intraoperative hemodynamics and/or postoperative outcomes. Previous studies have examined effects in small samples of patients in highly controlled research environments. This study examined “real-world” data from a large sample of subjects receiving routine clinical cares.MethodsA matched case–control analysis of electronic medical records from a large, academic hospital was performed. Patients who underwent neuraxial procedures preoperatively for postoperative analgesia for abdominal surgery (n=1570) were compared with control patients matched according to age, sex, ASA class and type of surgical procedure. Intraoperative hemodynamic measures, fluids and pressor utilization were quantified. Postoperative outcomes were determined based on the changes in laboratory values, the ordering of imaging studies and admission to an intensive care unit during the seven days following surgery as well as 30-day mortality.ResultsMedical records of 1082 patients who received an epidural catheter placement and 488 patients who received a lumbar intrathecal morphine injection were compared with an equal number of matched control patients. Preoperative placement of an epidural catheter for the management of postoperative pain was demonstrated to be associated with significant reductions in mean arterial pressure intraoperatively and poorer postoperative outcomes (more intensive care unit [ICU] admissions, more myocardial injuries) when compared with controls. A similar analysis of preoperatively administered intrathecal morphine injections was not associated with intraoperative alterations in blood pressure and had improved outcomes (less ICU admissions) in comparison with controls.ConclusionIn a “real-world” sample, intrathecal morphine administration proved to be highly beneficial as a neuraxial analgesic procedure as it was not associated with intraoperative hypotension and was associated with improved clinical outcomes, in contrast to opposite findings associated with epidural catheter placement. There should be a careful consideration of elective neuraxial method utilized for postoperative pain control, with the present study raising significant concerns related to the use of epidural analgesia and its potential effect on clinical outcomes.

NAFLD Aggravates Septic Shock Due to Inadequate Adrenal Response and 11β-HSDs Dysregulation in Rats.

Background: Non-alcoholic fatty liver disease (NAFLD) is linked with metabolic syndrome. Previous studies showed that obesity may disrupt adrenal function and adversely affect its counter-regulations against shock. This study hence evaluated adrenal function abnormalities in NAFLD with shock. Methods: Sprague-Dawley rats were fed with regular chow-diet (control) or high fat diet (HFD, 60% energy derived from fat). Blood tests were performed at the end of the 4th, 6th and 8th week, respectively. Experiments were performed at the end of the 8th week. Results: HFD rats developed NAFLD. HFD rats had 27% and 51% increase in plasma corticosterone at the 6th and 8th week in usual status. However, HFD rats had 5 times more reduction of mean arterial pressure in response to lipopolysaccharide-induced sepsis as compared to control rats. The corticosterone increment ratio was also lower in HFD rats, even after ACTH administration. 11β-HSD system tended to generate more corticosterone in HFD rats under hemodynamic stable status without shock and the trend was lost in HFD rats with septic shock. Conclusion: Rats with NAFLD had profound septic shock due to inadequate corticosterone response. This is, at least partly, due to 11β-HSDs dysregulation in sepsis.

Diurnal Control of Blood Pressure Is Uncoupled From Sodium Excretion.

The diurnal rhythms of sodium handling and blood pressure are thought to be regulated by clock genes, such as Bmal1. However, little is known about the regulation of these factors by Bmal1, especially in rats. Using a novel whole-body Bmal1 knockout rat model (Bmal1-/-), we hypothesized that time of day regulation of sodium excretion is dependent on Bmal1. Using telemetry to continuously record mean arterial pressure, we observed that male and female Bmal1-/- rats had significantly reduced mean arterial pressure over the course of 24 hours compared with littermate controls. The circadian mean arterial pressure pattern remained intact in both sexes of Bmal1-/- rats, which is in contrast to the Bmal1-/- mouse model. Male Bmal1-/- rats had no significant difference in baseline sodium excretion between 12-hour active and inactive periods, indicating a lack of diurnal control independent of maintained mean arterial pressure rhythms. Female Bmal1-/- rats, however, had significantly greater sodium excretion during the active versus inactive period similar to controls. Thus, we observed a clear dissociation between circadian blood pressure and control of sodium excretion that is sex dependent. These findings are consistent with a more robust ability of females to maintain control of sodium excretion, and furthermore, demonstrate a novel role for Bmal1 in control of diurnal blood pressure independent of sodium excretion.

Evaluation of ultra-early and dose-dependent edema and ultrastructural changes in the myocyte during anti-hypertensive drug delivery in the spontaneously hypertensive rat model.

BackgroundQuantifying dose-dependent ultra-early edema and ultrastructural changes in the myocyte after drug delivery is important for the development of new mixed calcium channel blockers (CCBs).Materials and methodsArterial cannulation was used to measure mean arterial pressure in real time; simultaneously, magnetic resonance imaging proton density mapping was used to quantify edema 5–55 min after the delivery of L-type CCBs, T- and L-type CCBs, and solvent to a spontaneously hypertensive rat model. Transmission electron microscopy was used to show ultrastructural changes in the myocyte.ResultsAnalysis of variance showed significant differences among the three groups in mean arterial pressure reduction (F = 246.36, P = 5.75E-25), ultra-early level of edema (ULE) (F = 175.49, P = 5.62E-22), and dose-dependent level of edema (DLE) (F = 199.48, P = 4.28E-23). Compared with the solvent’s mean arterial pressure reduction (2.65±6.56±1.64), ULE (1.16±0.09±0.02), and DLE (0.0010±0.0001±0.0000), post hoc tests showed that T- and L-type CCBs had better mean arterial pressure reduction (90.67±11.58±2.90, P = 1.06E-24 vs. 68.34±15.19±3.80, P = 1.76E-12), lower ULE (1.53±0.14±0.04, P = 4.74E-9 vs. 2.08±0.18±0.04, P = 2.68E-22), and lower DLE (0.0025±0.0004±0.0001, P = 1.14E-11 vs. 0.0047±0.0008±0.0002, P = 2.10E-11) than L- type CCBs. Transmission electron microscopy showed that T- and L-type CCBs caused fewer ultrastructural changes in the myocytes after drug delivery than L-type CCBs.ConclusionT- and L-type CCBs produced less ultra-early and dose-dependent edema, fewer ultrastructural changes in the myocyte, and a greater antihypertensive effect. Proton density mapping combined with arterial cannulation and transmission electron microscopy allowed for quantification of ultra-early and dose-dependent edema, antihypertensive efficacy, and ultrastructural changes in the myocyte. This is important for the evaluation of induced vasodilatory edema.

Hypotensive, vaso-relaxant, cardio-depressant and diuretic effect of crude extract of &lt;i&gt;Crotalaria burhia&lt;/i&gt; (Fabaceae)

Purpose: To examine 70 % aqueous-methanol crude extract of Crotalaria burhia (Cb.Cr) for its hypotensive and diuretic effects.&#x0D; Methods: The effect of intravenous administration of Cb.Cr on blood pressure (BP) of normotensive anesthetized rats was studied. In vitro experiments on rabbit isolated aortic and atrial preparations were performed to elucidate the mechanism of action. The diuretic effect was assessed following oral administration of Cb.Cr in rats.&#x0D; Results: Intravenous administration of Cb.Cr produced 14.70 ± 1.21, 22.00 ± 2.24 and 36.21 ± 2.65 % reduction in mean arterial blood pressure of the rats at doses of 1, 3 and 10 mg/kg, respectively. It was more potent in relaxing potassium (80 mM)- than phenylephrine (1 μM)-induced contractions in isolated aorta of rabbit with half-maximal effective concentration (EC50) values of 0.58 ± 0.03 and 1.58 ± 0.16 mg/mL, respectively, which are similar to verapamil. The extract showed depressant effects on spontaneously beating atrial preparations of rabbit in a dose-dependent manner. Moreover, Cb.Cr also increased urine volume and urinary electrolyte excretion in rats.&#x0D; Conclusion: Crotalaria burhia crude extract exhibits hypotensive and diuretic effects in rats. The hypotensive activity of the extract possibly involves vasodilator, cardio-depressant, calcium channel blocking and diuretic actions.&#x0D; Keywords: Khip, Crotalaria burhia, Calcium channel blocker, Antihypertensive, Diuretic