Processed electroencephalography-guided general anesthesia and norepinephrine requirements: A randomized trial in patients having vascular surgery.

STUDY OBJECTIVE: Processed electroencephalography (pEEG) may help clinicians optimize depth of general anesthesia. Avoiding excessive depth of anesthesia may reduce intraoperative hypotension and the need for vasopressors. We tested the hypothesis that pEEG-guided - compared to non-pEEG-guided - general anesthesia reduces the amount of norepinephrine needed to keep intraoperative mean arterial pressure above 65 mmHg in patients having vascular surgery. DESIGN: Randomized controlled clinical trial. SETTING: University Medical Center Hamburg-Eppendorf, Hamburg, Germany. PATIENTS: 110 patients having vascular surgery. INTERVENTIONS: pEEG-guided general anesthesia. MEASUREMENTS: Our primary endpoint was the average norepinephrine infusion rate from the beginning of induction of anesthesia until the end of surgery. MAIN RESULT: 96 patients were analyzed. The mean ± standard deviation average norepinephrine infusion rate was 0.08 ± 0.04 µg kg-1 min-1 in patients assigned to pEEG-guided and 0.12 ± 0.09 µg kg-1 min-1 in patients assigned to non-pEEG-guided general anesthesia (mean difference 0.04 µg kg-1 min-1, 95% confidence interval 0.01 to 0.07 µg kg-1 min-1, p = 0.004). Patients assigned to pEEG-guided versus non-pEEG-guided general anesthesia, had a median time-weighted minimum alveolar concentration of 0.7 (0.6, 0.8) versus 0.8 (0.7, 0.8) (p = 0.006) and a median percentage of time Patient State Index was <25 of 12 (1, 41) % versus 23 (3, 49) % (p = 0.279). CONCLUSION: pEEG-guided - compared to non-pEEG-guided - general anesthesia reduced the amount of norepinephrine needed to keep mean arterial pressure above 65 mmHg by about a third in patients having vascular surgery. Whether reduced intraoperative norepinephrine requirements resulting from pEEG-guided general anesthesia translate into improved patient-centered outcomes remains to be determined in larger trials.

Gender Differences in Cardiac Organ Damage in Arterial Hypertension: Assessing the Role of Drug Nonadherence.

INTRODUCTION: Cardiac organ damage like left ventricular (LV) hypertrophy and left atrial (LA) enlargement is more prevalent in women than men with hypertension, but the mechanisms underlying this gender difference remain unclear. METHODS: We tested the association of drug nonadherence with the presence of LV hypertrophy and LA enlargement by echocardiography in 186 women and 337 men with uncontrolled hypertension defined as daytime systolic blood pressure (BP) ≥ 135mmHg despite the prescription of at least two antihypertensive drugs. Drug adherence was assessed by measurements of serum drug concentrations interpreted by an experienced pharmacologist. Aldosterone-renin-ratio (ARR) was measured on actual medication. RESULTS: Women had a higher prevalence of LV hypertrophy (46% vs. 33%) and LA enlargement (79% vs 65%, both p < 0.05) than men, while drug nonadherence (8% vs. 9%, p > 0.514) did not differ. Women were older and had lower serum renin concentration and higher ARR than men, while 24-h systolic BP (141 ± 9 mmHg vs. 142 ± 9 mmHg), and the prevalences of obesity (43% vs. 50%) did not differ (all p > 0.10). In multivariable analyses, female gender was independently associated with a two-fold increased risk of LV hypertrophy (OR 2.01[95% CI 1.30-3.10], p = 0.002) and LA enlargement (OR 1.90 [95% CI 1.17-3.10], p = 0.010), while no association with drug nonadherence was found. Higher ARR was independently associated with LV hypertrophy in men only (OR 2.12 [95% CI 1.12-4.00] p = 0.02). CONCLUSIONS: Among patients with uncontrolled hypertension, the higher prevalence of LV hypertrophy and LA enlargement in women was not explained by differences in drug nonadherence. REGISTRATION: URL:  https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03209154.

Time interval between alfentanil and rocuronium administration necessary to prevent rocuronium-induced withdrawal movement.

BACKGROUND: We aimed to determine the time interval between alfentanil and rocuronium administration, at a 50% probability of preventing pain-induced withdrawal movement from rocuronium injection (TimeAR50). METHODS: A total of 64 patients scheduled for general anesthesia were enrolled in this study (33 men and 31 women). Anesthesia was induced with target-controlled infusion of propofol, at an effect-site target concentration of 3 µg/mL. Then, alfentanil 15 µg/kg was injected for 30 s. After 60 s, rocuronium 0.6 mg/kg was administered to the first patient. The Dixon's up-and-down method was used to determine the time interval for each subsequent patient (interval of 5 s). Mean arterial pressure (MAP) and heart rate (HR) were recorded at three time points: T0, pre-induction; T1, before rocuronium injection; and T2, 1 min after rocuronium injection. RESULTS: The TimeAR50 ± standard deviation (SD) was 5.6 ± 3.7 s and 21.9 ± 5.6 s in the male and female patients, respectively. Based on the probit regression, the TimeAR50 was 4.7 s (95% confidence interval [CI], 1.2-7.6 s) and 20.3 s (95% CI, 7.7-26.1 s) in the male and female patients, respectively. The TimeAR95 was 10.6 s (95% CI, 7.7-25.3 s) and 35.0 s (95% CI, 28.1-95.5 s) in the male and female patients, respectively, with significantly higher values in females than in males (P < 0.001). Compared with the T0, MAP and HR decreased significantly at T1 and T2 in both groups. CONCLUSION: The TimeAR50 required for preventing rocuronium-induced withdrawal movement were 4.7 s and 20.3 s in male and female patients, respectively. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trials Registry on April 7, 2021 (URL: http://www.chictr.org.cn . Registry number: ChiCTR2100045137 ) .

Effect of dexmedetomidine on cardiorespiratory regulation in spontaneously breathing adult rats.

PURPOSE: We examined the cardiorespiratory effect of dexmedetomidine, an α2- adrenoceptor/imidazoline 1 (I1) receptor agonist, in spontaneously breathing adult rats. METHODS: Male rats (226-301 g, n = 49) under isoflurane anesthesia had their tail vein cannulated for drug administration and their tail artery cannulated for analysis of mean arterial pressure (MAP), pulse rate (PR), and arterial blood gases (PaO2, PaCO2, pH). After recovery, one set of rats received normal saline for control recording and was then divided into three experimental groups, two receiving dexmedetomidine (5 or 50 µg·kg-1) and one receiving normal saline (n = 7 per group). Another set of rats was divided into four groups receiving dexmedetomidine (50 µg·kg-1) followed 5 min later by 0.5 or 1 mg∙kg-1 atipamezole (selective α2-adrenoceptor antagonist) or efaroxan (α2-adrenoceptor/I1 receptor antagonist) (n = 6 or 8 per group). Recordings were performed 15 min after normal saline or dexmedetomidine administration. RESULTS: Compared with normal saline, dexmedetomidine (5 and 50 µg·kg-1) decreased respiratory frequency (fR, p = 0.04 and < 0.01, respectively), PR (both p < 0.01), and PaO2 (p = 0.04 and < 0.01), and increased tidal volume (both p = 0.049). Dexmedetomidine at 5 µg·kg-1 did not significantly change minute ventilation (V'E) (p = 0.87) or MAP (p = 0.24), whereas dexmedetomidine at 50 µg·kg-1 significantly decreased V'E (p = 0.03) and increased MAP (p < 0.01). Only dexmedetomidine at 50 µg·kg-1 increased PaCO2 (p < 0.01). Dexmedetomidine (5 and 50 µg·kg-1) significantly increased blood glucose (p < 0.01), and dexmedetomidine at 50 µg·kg-1 increased hemoglobin (p = 0.04). Supplemental atipamezole or efaroxan administration similarly prevented the 50 µg·kg-1 dexmedetomidine-related cardiorespiratory changes. PRINCIPAL CONCLUSION: These results suggest that dexmedetomidine-related hypoventilation and hypertension are observed simultaneously and occur predominantly through activation of α2-adrenoceptors, but not I1 receptors, in spontaneously breathing adult rats.

The evolution of mean arterial pressure in critically ill patients on vasopressors before and during a trial comparing a specific mean arterial pressure target to usual care.

BACKGROUND: In randomized clinical controlled trials, the choice of usual care as the comparator may be associated with better clinician uptake of the study protocol and lead to more generalizable results. However, if care processes evolve to resemble the intervention during the course of a trial, differences between the intervention group and usual care control group may narrow. We evaluated the effect on mean arterial pressure of an unblinded trial comparing a lower mean arterial pressure target to reduce vasopressor exposure, vs. a clinician-selected mean arterial pressure target, in critically ill patients at least 65 years old. METHODS: For this multicenter observational study using data collected both prospectively and retrospectively, patients were recruited from five of the seven trial sites. We compared the mean arterial pressure of patients receiving vasopressors, who met or would have met trial eligibility criteria, from two periods: [1] at least 1 month before the trial started, and [2] during the trial period and randomized to usual care, or not enrolled in the trial. RESULTS: We included 200 patients treated before and 229 after trial initiation. There were no differences in age (mean 74.5 vs. 75.2 years; p = 0.28), baseline Acute Physiology and Chronic Health Evaluation II score (median 26 vs. 26; p = 0.47) or history of chronic hypertension (n = 126 [63.0%] vs. n = 153 [66.8%]; p = 0.41). Mean of the mean arterial pressure was similar between the two periods (72.5 vs. 72.4 mmHg; p = 0.76). CONCLUSIONS: The initiation of a trial of a prescribed lower mean arterial pressure target, compared to a usual clinician-selected target, was not associated with a change in mean arterial pressure, reflecting stability in the net effect of usual clinician practices over time. Comparing prior and concurrent control groups may alleviate concerns regarding drift in usual practices over the course of a trial or permit quantification of any change.

KV7.1 channel blockade inhibits neonatal renal autoregulation triggered by a step decrease in arterial pressure.

KV7 channels, the voltage-gated K+ channels encoded by KCNQ genes, mediate heterogeneous vascular responses in rodents. Postnatal changes in the functional expression of KV7 channels have been reported in rodent saphenous arteries, but their physiological function in the neonatal renal vascular bed is unclear. Here, we report that, unlike adult pigs, only KCNQ1 (KV7.1) out of the five members of KCNQ genes was detected in neonatal pig renal microvessels. KCNQ1 is present in fetal pig kidneys as early as day 50 of gestation, and the level of expression remains the same up to postnatal day 21. Activation of renal vascular smooth muscle cell (SMC) KV7.1 stimulated whole cell currents, inhibited by HMR1556 (HMR), a selective KV7.1 blocker. HMR did not change the steady-state diameter of isolated renal microvessels. Similarly, intrarenal artery infusion of HMR did not alter mean arterial pressure, renal blood flow, and renal vascular resistance in the pigs. An ∼20 mmHg reduction in mean arterial pressure evoked effective autoregulation of renal blood flow, which HMR inhibited. We conclude that 1) the expression of KCNQ isoforms in porcine renal microvessels is dependent on kidney maturation, 2) KV7.1 is functionally expressed in neonatal pig renal vascular SMCs, 3) a decrease in arterial pressure up to 20 mmHg induces renal autoregulation in neonatal pigs, and 4) SMC KV7.1 does not control basal renal vascular tone but contributes to neonatal renal autoregulation triggered by a step decrease in arterial pressure.NEW & NOTEWORTHY KV7.1 is present in fetal pig kidneys as early as day 50 of gestation, and the level of expression remains the same up to postnatal day 21. KV7.1 is functionally expressed in neonatal pig renal vascular smooth muscle cells (SMCs). A decrease in arterial pressure up to 20 mmHg induces renal autoregulation in neonatal pigs. Although SMC KV7.1 does not control basal renal vascular resistance, its inhibition blunts neonatal renal autoregulation engendered by a step decrease in arterial pressure.

Considerations for Inotrope and Vasopressor Use in Critically Ill Patients With Pulmonary Arterial Hypertension.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a rare and progressive cardiopulmonary disease, characterized by pulmonary vasculopathy. The disease can lead to increase pulmonary arterial pressures and eventual right ventricle failure due to elevated afterload. The prevalence of PAH in patients admitted to the intensive care unit (ICU) is unknown, and pulmonary hypertension (PH) in the ICU is more commonly the result of left heart disease or hypoxic lung injury (PH due to left heart disease and PH due to lung diseases and/or hypoxia, respectively), as opposed to PAH. Management of patients with PAH in the ICU is complex as it requires a careful balance to maintain perfusion while optimizing right-sided heart function. A comprehensive understanding of the underlying physiology and underlying hemodynamics is crucial for the management of this population. In this review, we summarized the evidence for use of vasopressors and inotropes in the management of PH and extrapolated the data to patients with PAH. We strongly believe that the understanding of the hemodynamic consequences of inotropes and vasopressors, especially from data in the PH population, can lead to better management of this complex patient population.

Efficacy and safety of remimazolam tosylate in hysteroscopy: A randomized, single-blind, parallel controlled trial.

WHAT IS KNOWN AND OBJECTIVE: To compare the effectiveness and safety of remimazolam tosylate and propofol for hysteroscopy. METHODS: From November 2020 to June 2021, a total of 90 patients who underwent hysteroscopy were prospectively enrolled in this study. The patients were randomly assigned to three groups: propofol group (group A), low-dose remimazolam tosylate group (group B), and high-dose remimazolam tosylate group (group C), with 30 cases in each group. All cases received intravenous sufentanil 0.1ug/kg for analgesic preconditioning. Patients in group A were given 2 mg/kg propofol intravenously, and maintained at a rate of 5 mg/kg/h. Patients in groups B and C were given intravenous remimazolam tosylate 0.25 mg/kg. Group B was maintained with remimazolam tosylate at a rate of 0.48 mg/kg/h, while group C was at a rate of 0.6 mg/kg/h. The changes of heart rate (HR), mean arterial pressure (MAP) and saturation of peripheral oxygen (SpO2) were recorded after admission (T0), 1 min after anaesthesia (T1), dilation of the uterine cavity (T2), and the end of hysteroscopy (T3). In addition, Observer's Assessment of Alertness/Sedation Scale (OAA/S) at 1 min, 3 min, and 5 min after hysteroscopy, the incidence of adverse events, and the time from the end of the hysteroscopy to reach the discharge standard, were recorded. RESULTS AND DISCUSSION: The success rate of sedation in each group was 100%. After administration, the adverse event incidence in group A was significantly higher than that in groups B and C (p < 0.05, respectively). Compared with propofol, remimazolam tosylate did not cause injection pain, had less impact on haemodynamics and caused less respiratory depression. WHAT IS NEW AND CONCLUSION: Remimazolam tosylate and propofol have similar success rates for painless hysteroscopy, and both can provide safe and effective sedation. The safety of remimazolam tosylate for hysteroscopy appears to be better than that of propofol.

Prolonged isoflurane anesthesia-induced acidosis decreases penile intracavernous pressure in rats.

BACKGROUND: Intracavernous pressure measurement following cavernous nerve electrostimulation has been extensively adopted for the evaluation of erectile function in animals. However, the effect of measurement time and acidosis during anesthesia is still lacking. OBJECTIVE: To explore the effect of measurement time and acidosis during anesthesia. MATERIALS AND METHODS: Fifty-six male Sprague-Dawley rats were used and anesthetized by a spontaneous inhalation of isoflurane. In the first step, rats were randomly divided into four groups: a control group and three time-delayed measurement groups (intracavernous pressure measurement beginning at 15, 30, and 45 min after cavernous nerve exposure). In the second step, rats were randomly divided into three groups: a control group and two time-delayed measurement groups. Two intravenous fluid support strategies were used in time-delayed measurement groups: a normal saline solution and an isotonic Na2 CO3 solution. RESULTS: Isoflurane-anesthetized rats developed systemic acidosis that worsens with time during intracavernous pressure measurement, which results in a significant decrease in the maximum intracavernous pressure value, intracavernous pressure/mean arterial pressure ratio, and total intracavernous pressure measured. The Na2 CO3 infusion could effectively correct acidosis. The decrease in intracavernous pressure was related to the reduced nitric oxide synthase activity, decreased cyclic guanosine monophosphate concentration, and reactive oxygen species activation in rat penis under acidosis conditions. DISCUSSION AND CONCLUSION: Prolonged isoflurane anesthesia-induced acidosis markedly depresses the erectile response to cavernous nerve electrostimulation in rats. In this situation, it is recommended to supplement with a Na2 CO3 infusion to maintain a normal acid-base balance.

Cardiac Output Assessments in Anesthetized Children: Dynamic Capnography Versus Esophageal Doppler.

BACKGROUND: The objective of this study was to compare esophageal Doppler cardiac output (COEDM) against the reference method effective pulmonary blood flow cardiac output (COEPBF), for agreement of absolute values and ability to detect change in cardiac output (CO) in pediatric surgical patients. Furthermore, the relationship between these 2 methods and noninvasive blood pressure (NIBP) parameters was evaluated. METHODS: Fifteen children American Society of Anesthesiology (ASA) I and II (median age, 8 months; median weight, 9 kg) scheduled for surgery were investigated in this prospective observational cohort study. Baseline COEPBF/COEDM/NIBP measurements were made at positive end-expiratory pressure (PEEP) 3 cm H2O. PEEP was increased to 10 cm H2O and COEPBF/COEDM/NIBP was recorded after 1 and 3 minutes. PEEP was then lowered to 3 cm H2O, and all measurements were repeated after 3 minutes. Finally, 20-µg kg-1 intravenous atropine was given with the intent to increase CO, and all measurements were recorded again after 5 minutes. Paired recordings of COEDM and COEPBF were examined for agreement and trending ability, and all parameters were analyzed for their responses to the hemodynamic challenges. RESULTS: Bias between COEDM and COEPBF (COEDM - COEPBF) was -17 mL kg-1 min-1 (limits of agreement, -67 to +33 mL kg-1 min-1) with a mean percentage error of 32% (95% confidence interval [CI], 25-37) and a concordance rate of 71% (95% CI, 63-80). The hemodynamic interventions caused by PEEP manipulations resulted in significant decrease in COEPBF absolute numbers (155 mL kg-1 min-1 [95% CI, 151-159] to 127 mL kg-1 min-1 [95% CI, 113-141]) and a corresponding relative decrease of 18% (95% CI, 14-22) 3 minutes after application of PEEP 10. No corresponding decreases were detected by COEDM. Mean arterial pressure showed a relative decrease with 5 (95% CI, 2-8) and 6% (95% CI, 2-10) 1 and 3 minutes after the application of PEEP 10, respectively. Systolic arterial pressure showed a relative decrease of 5% (95% CI, 2-10) 3 minutes after application of PEEP 10. None of the recorded parameters responded to atropine administration except for heart rate that showed a 4% relative increase (95% CI, 1-7, P = .02) 5 minutes after atropine. CONCLUSIONS: COEDM was unable to detect the reduction of CO cause by increased PEEP, whereas COEPBF and to a minimal extent NIBP detected these changes in CO. The ability of COEPBF to react to minor reductions in CO, before noticeable changes in NIBP are seen, suggests that COEPBF may be a potentially useful tool for hemodynamic monitoring in mechanically ventilated children.

Compensatory depression of arterial pressure and reversal of ECG abnormalities by Annona muricata and Curcuma longa in hypertensive Wistar rats.

OBJECTIVES: Increasing hypertension incidence in Sub-Sahara Africa and the current cost of management of the metabolic disorder has necessitated research on medicinal plants employed in African Traditional Medicine for hypertension. Thus, this study evaluated antihypertensive effect of Annona muricata leaves or Curcuma longa rhizomes in experimentally-induced hypertensive male Wistar rats (n=70) which were unilaterally nephrectomized and daily loaded with 1% salt. Cardiovascular and haematological changes, as well as urinalysis were determined. METHODS: Rats were uninephrectomized and NaCl (1%) included in drinking water for 42 days. Extract-treated hypertensive rats were compared to normotensive, untreated hypertensive and hypertensive rats treated with lisinopril (5 mg/70 kg) or hydrochlorothiazide (12.5 mg/70 kg). A. muricata extract or C. longa extract were administered at 100, 200 or 400 mg/kg. Blood pressure (systolic, diastolic and mean arterial) and electrocardiogram was measured on day 41. Twenty-four-hour urine samples were collected from day 42. Blood samples were collected on day 43 for haematology (PCV, red cell indices, WBC and its differentials, and platelets). RESULTS: A. muricata or C. longa extracts caused a decline in elevated blood pressure of hypertensive rats. Heart rate and QT segment reduction coupled with prolonged QRS duration were reversed in extract-treated rats, with significant increases in hemogram parameters indicating increased blood viscosity. Also, leukocyturia, proteinuria and ketonuria with increased urine alkalinity, urobilinogen and specific gravity which are classical indicators of poor prognostic outcomes in hypertension were reversed in extract-treated rats. CONCLUSIONS: In conclusion, A. muricata and C. longa have cardioprotective effect with reversal of derangements in haemogram and urinalysis associated with hypertension.

Oral L-Arginine (5 g/day) for 14 Days Improves Microcirculatory Function in Healthy Young Women and Healthy and Type 2 Diabetes Mellitus Elderly Women.

OBJECTIVE: The aim of this study was to investigate the effect of oral supplementation with L-arginine on serum biochemical profile, blood pressure, microcirculation, and vasoreactivity/endothelial function in young controls, and elderly women with and without type 2 diabetes mellitus (T2DM). METHODS: Healthy young (n = 25), healthy elderly (n = 25), and elderly women with type 2 diabetes mellitus (T2DME, n = 23, glycated Hb ≥6.4% and mean of 7.7 years for duration of the disease), aged 18-30 and older than 65 years, respectively, were included in the study. All patients underwent biochemical analysis (fasting glycemia and lipidogram), arterial blood pressure, nailfold videocapillaroscopy (capillary diameters, functional capillary density [FCD], peak red blood cell velocity [RBCVmax] after 1 min ischemia, time to reach peak RBCV [TRBCVmax]), and venous occlusion plethysmography (vasoreactivity), before and after 14 days of oral supplementation with L-arginine (5 g/day). RESULTS: L-Arginine did not change fasting glycemia and lipidogram, but it decreased systolic, diastolic, and mean arterial pressure in elderly women, increased RBCVmax in all groups, and did not decrease TRBCVmax in T2DME. Capillary diameters and FCD remained unchanged in all groups. L-Arginine improved vasoreactivity during reactive hyperemia and after sublingual nitroglycerin (0.4 mg) in all groups. CONCLUSION: L-Arginine supplementation (5g/day during 14 days) was able to improve vascular/microvascular health in the elderly women with or without T2DM.

Regularly swimming exercise modifies opioidergic neuromodulation in rostral ventrolateral medulla in hypertensive rats.

Moderate exercise reduces arterial pressure (AP) and heart rate (HR) in spontaneously hypertensive rats (SHR) and changes neurotransmission in medullary areas involved in cardiovascular regulation. We investigated if regularly swimming exercise (SW) affects the cardiovascular adjustments mediated by opioidergic neuromodulation in the RVLM in SHR and Wistar-Kyoto (WKY) rats. Rats were submitted to 6 wks of SW. The day after the last exercise bout, α-chloralose-anesthetized rats underwent a cannulation of the femoral artery for AP and HR recordings, and Doppler flow probes were placed around the lower abdominal aorta and superior mesenteric artery. Bilateral injection of endomorphin-2 (EM-2, 0.4 mmol/L, 60 nL) into the RVLM increased MAP in SW-SHR (20 ± 4 mmHg, N = 6), which was lower than in sedentary (SED)-SHR (35 ± 4 mmHg, N = 6). The increase in MAP in SW-SHR induced by EM-2 into the RVLM was similar in SED- and SW-WKY. Naloxone (0.5 mmol/L, 60 nL) injected into the RVLM evoked an enhanced hypotension in SW-SHR (-66 ± 8 mmHg, N = 6) compared to SED-SHR (-25 ± 3 mmHg, N = 6), which was similar in SED- and SW-WKY. No significant changes were observed in HR after EM-2 or naloxone injections into the RVLM. Changes in hindquarter and mesenteric conductances evoked by EM-2 or naloxone injections into the RVLM in SW- or SED-SHR were not different. Mu Opioid Receptor expression by Western blotting was reduced in SW-SHR than in SED-SHR and SW-WKY. Therefore, regularly SW alters the opioidergic neuromodulation in the RVLM in SHR and modifies the mu opioid receptor expression in this medullary area.

Ziziphus Oxyphylla hydro-methanolic extract ameliorates hypertension in L-NAME induced hypertensive rats through NO/cGMP pathway and suppression of oxidative stress related inflammatory biomarkers.

ETHNOPHARMACOLOGICAL RELEVANCE: Ziziphus Oxyphylla belongs to family Ziziphus and has been used traditionally in hypertension. It is enriched with quercetin and kaempferol derivatives, catechin and cyclopeptide alkaloids. AIM: The current research evaluates the antihypertensive potential of aqueous methanolic extract of Z. oxyphylla (AMEZO) in NG-nitro-L-arginine methyl ester (LNAME) induced hypertension in rats. MATERIAL AND METHODOLOGY: Phytochemical analysis of AMEZO was carried out using high performance liquid chromatography (HPLC) and electrospray ionization mass spectrometry (ESI-MS/MS). Antihypertensive activities of AMEZO (200 and 400 mg/kg) and Kaempferol were assessed in L-NAME (185 µmol/kg, intraperitoneal) injected hypertensive rats. In normotensive rats, blood pressure was assessed using Power Lab data system. Serum and tissue samples were preserved for estimation of nitric oxide (NO), Cyclic guanosine monophosphate (cGMP), interleukin-6 (IL-6), tumor necrosis factor (TNF- α) and oxidative stress markers respectively. mRNA levels of eNOS, ACE, COX-2 and NF-kB genes were assessed through qPCR. RESULTS: The HPLC and ESI-MS/MS identified kaempferol, quercetin, catechin, ceanothic acid, zizybernalic acid and oxyphylline F. Chronic administration of AMEZO and kaempferol in L-NAME induced hypertensive rats significantly (p < 0.001) reduced systolic, diastolic and mean blood pressure. AMEZO and kaempferol caused meaningfully improved (p < 0.001) serum NO and cGMP levels. AMEZO administration also noticeably decrease the elevated IL-6 and TNF- α concentration in hypertensive animals. Administration of AMEZO and kaempferol also improved oxidative stress markers (MDA, CAT, SOD, GSH). The antihypertensive activity of AMEZO also resulted in upregulation of eNOS and downregulation of ACE. CONCLUSION: These data depict that AMEZO and kaempferol showed antihypertensive activity in LNAME induced hypertensive rats possibly mediated through improvement in NO and cGMP levels, modulation of mRNA expression of eNOS, ACE, COX-2 and NF-kB and suppression of oxidative stress related inflammatory markers, proposing a defensive role in cardiovascular diseases.

Spinally delivered ampakine CX717 increases phrenic motor output in adult rats.

Ampakines are synthetic molecules that allosterically modulate AMPA-type glutamate receptors. We tested the hypothesis that delivery of ampakines to the intrathecal space could stimulate neural drive to the diaphragm. Ampakine CX717 (20 mM, dissolved in 10 % HPCD) or an HPCD vehicle solution were delivered via a catheter placed in the intrathecal space at the fourth cervical segment in urethane-anesthetized, mechanically ventilated adult male Sprague-Dawley rats. The electrical activity of the phrenic nerve was recorded for 60-minutes following drug application. Intrathecal application of CX717 produced a gradual and sustained increase in phrenic inspiratory burst amplitude (n = 10). In contrast, application of HPCD (n = 10) caused no sustained change in phrenic motor output. Phrenic burst rate, heart rate, and mean arterial pressure were similar between CX717 and HPCD treated rats. We conclude that intrathecally delivered ampakines can modulate phrenic motor output. This approach may have value for targeted induction of spinal neuroplasticity in the context of neurorehabiliation.

Perfil dos pacientes com crise hipertensiva atendidos em uma unidade de pronto atendimento / Perfil de los pacientes con crisis hipertensiva atendidos en una unidad de pronta atención / Profile of patients with hypertensive crisis seen in an emergency care unit

RESUMO Objetivo: descrever o perfil dos pacientes com crise hipertensiva atendidos em uma Unidade de Pronto Atendimento. Método: estudo transversal descritivo, realizado por meio da análise de 80 prontuários de pacientes com quadro de crise hipertensiva, atendidos em uma unidade de pronto atendimento, entre o período de março de 2018 a fevereiro de 2019. Os dados foram coletados por meio de roteiro estruturado e receberam tratamento estatístico descritivo. Resultados: Após a análise dos 80 prontuários, constatou-se que a média de idade entre os pacientes atendidos foi de 58,03, sendo a faixa etária adulta a mais prevalente (53,8%). Constatou-se que a média da pressão arterial sistólica foi significativamente maior em homens em relação às mulheres (p=0,013). Quanto à sintomatologia, a cefaleia foi a mais prevalente, com 35,0%. Verificou-se que durante o atendimento da crise hipertensiva, a maioria dos pacientes fez uso de apenas uma droga para redução da PA, sendo o inibidor adrenérgico de ação central o mais citado. Quanto ao desfecho, grande parte dos pacientes recebeu alta (93,8%) logo após o atendimento, porém, 6,3% permaneceram em internamento de curta permanência até a estabilização do quadro. Considerações finais: Este estudo possibilitou a caracterização da população com crise hipertensiva atendida em um pronto atendimento, a qual evidencia uma possível fragilidade existente entre a articulação dos níveis de atenção à saúde.

RESUMEN Objetivo: describir el perfil de los pacientes con crisis hipertensiva atendidos en una Unidad de Pronta Atención. Método: estudio transversal descriptivo, realizado por medio del análisis de 80 registros médicos de pacientes con cuadro de crisis hipertensiva, atendidos en una unidad de pronta atención, entre el período de marzo de 2018 a febrero de 2019. Los datos fueron recogidos por medio de guion estructurado y recibieron tratamiento estadístico descriptivo. Resultados: después del análisis de los 80 registros médicos, se constató que el promedio de edad entre los pacientes atendidos fue de 58,03, siendo la franja etaria adulta la más prevalente (53,8%). Se constató que el promedio de la presión arterial sistólica fue significativamente mayor en hombres que en las mujeres (p=0,013). En cuanto a la sintomatología, la cefalea fue la más prevalente, con 35,0%. Se verificó que, durante la atención de la crisis hipertensiva, la mayoría de los pacientes hizo uso de solo una droga para reducción de la PA, siendo el inhibidor adrenérgico de acción central el más relatado. Respecto al resultado, gran parte de los pacientes recibió el alta (93,8%) inmediatamente después de la atención, sin embargo, el 6,3% permaneció en internamiento de corta estancia hasta la estabilización del cuadro. Consideraciones finales: este estudio posibilitó la caracterización de la población con crisis hipertensiva atendida en una pronta atención, la cual evidencia una posible fragilidad existente entre la articulación de los niveles de atención a la salud.

ABSTRACT Objective: to describe the profile of patients with hypertensive crisis treated at an Emergency Care Unit. Method: descriptive cross-sectional study carried out through the analysis of 80 medical records of patients with hypertensive crisis, treated at an emergency care unit, between March 2018 and February 2019. Data were collected using a structured script and were subjected to descriptive statistical treatment. Results: after analyzing the 80 medical records, it was found that the mean age of the treated patients was 58.03, with the adult age group being the most prevalent (53.8%). It was found that the mean systolic blood pressure was significantly higher in men than in women (p=0.013). As for symptoms, headache was the most prevalent, with 35.0%. It was found that during the treatment of the hypertensive crisis, most patients used only one drug to reduce BP, with centrally acting antiadrenergic drugs being the most cited. Regarding the outcome, most of the patients were discharged (93.8%) soon after treatment; however, 6.3% remained in short-term hospitalization until their condition stabilized. Final considerations: this study made it possible to characterize the population with hypertensive crisis treated in an emergency room, showing a possible fragility in the articulation between health care levell

Indole-3-propionic acid, a tryptophan-derived bacterial metabolite, increases blood pressure via cardiac and vascular mechanisms in rats.

Recent evidence suggests that gut bacteria-derived metabolites interact with the cardiovascular system and alter blood pressure (BP) in mammals. Here, we evaluated the effect of indole-3-propionic acid (IPA), a gut bacteria-derived metabolite of tryptophan, on the circulatory system. Arterial BP, electrocardiographic, and echocardiographic (ECHO) parameters were recorded in male, anesthetized, 12-wk-old Wistar-Kyoto rats at baseline and after intravenous administration of either IPA or vehicle. In additional experiments, rats were pretreated with prazosin or pentolinium to evaluate the involvement of the autonomic nervous system in cardiovascular responses to IPA. IPA's concentrations were measured using ultra-high performance liquid chromatography tandem mass spectrometry. The reactivity of endothelium-intact and -denuded mesenteric resistance arteries was tested. Cells' viability and lactate dehydrogenase (LDH) cytotoxicity assays were performed on cultured cardiomyocytes. IPA increased BP with a concomitant bradycardic response but no significant change in QTc interval. The pretreatment with prazosin and pentolinium reduced the hypertensive response. ECHO showed increased contractility of the heart after the administration of IPA. Ex vivo, IPA constricted predilated and endothelium-denuded mesenteric resistance arteries and increased metabolic activity of cardiomyocytes. IPA increases BP via cardiac and vascular mechanisms in rats. Furthermore, IPA increases cardiac contractility and metabolic activity of cardiomyocytes. Our study suggests that IPA may act as a mediator between gut microbiota and the circulatory system.

Early combination of pulmonary vasodilators prevents chronic kidney disease progression in connective tissue disease-associated pulmonary hypertension.

AIM: Pulmonary hypertension (PH) and chronic kidney disease (CKD) are interdependent for their development and exacerbation. We evaluated the effect of PH on CKD progression in patients with connective tissue disease (CTD)-associated PH. METHODS: We reviewed consecutive patients with CTD who were diagnosed with PH with right heart catheter (RHC) examinations in our hospital. Patients were divided into 2 groups according to the use of vasodilators: monotherapy or combination therapy. We further divided the patients with combination therapy into early and non-early combination groups. Early combination was defined as the addition of the second vasodilator within 1 month after starting the first drug. The clinical course of hemodynamics and CKD progression were compared. RESULTS: Thirty-eight patients were included in the analysis: 10 were treated with monotherapy and 28 with combination therapy (14 with early and 14 with non-early). At baseline, patients who received combination therapy had a significantly higher mean pulmonary arterial pressure with RHC and a higher right ventricular systolic pressure (RVSP) with echocardiography (P = .04) and showed a greater improvement in RVSP after treatment than those who underwent monotherapy. The incidence of CKD progression was significantly lower in patients who received combination therapy than in those who received monotherapy (P = .05). Among patients who received combination therapy, the early combination group had a lower incidence of CKD progression than the non-early combination group (P = .03). CONCLUSIONS: Early combination therapy is associated with a lower incidence of CKD progression in patients with CTD-associated PH.

Pharmacokinetics and pharmacodynamics of sildenafil in fetal lambs on extracorporeal support.

BACKGROUND: Maternal transplacental administration of sildenafil is being considered for a variety of fetal conditions. Clinical translation also requires evaluation of fetal safety in a higher species, such as the fetal lamb. Experiments with the pregnant ewe are curtailed by minimal transplacental transfer as well as limited access to the fetus. The EXTra-uterine Environment for Neonatal Development (EXTEND) model renders the isolated fetal lamb readily accessible and allows for direct fetal administration of sildenafil. METHODS: Five fetal lambs were placed on extracorporeal support in the EXTEND device and received continuous intravenous (IV) sildenafil (0.3-0.5-0.7 mg/kg/24hr) for a duration of one to seven days. Plasma sildenafil concentrations were sampled at regular intervals to establish the pharmacokinetic profile using population pharmacokinetic modeling. Serial Doppler ultrasound examination, continuous non-invasive hemodynamic monitoring and blood gas analysis were done to evaluate the pharmacodynamic effects and fetal response. FINDINGS: The target concentration range (47-500 ng/mL) was attained with all doses. Sildenafil induced an immediate and temporary reduction of pulmonary vascular resistance, mean arterial pressure and circuit flow, without change in fetal lactate levels and acid-base status. The duration of the systemic effects increased with the dose. INTERPRETATION: Immediate temporary pulmonary vascular and systemic hemodynamic changes induced by sildenafil were biochemically well tolerated by fetal lambs on extracorporeal support, with the 0.5 mg/kg/24 h dose balancing rapid attainment of target concentrations with short-lived systemic effects. RESEARCH IN CONTEXT: None. SEARCH STRATEGY BEFORE UNDERTAKING THE STUDY: A literature review was conducted searching online databases (Medline, Embase and Cochrane), using search terms: fetal OR prenatal OR antenatal AND sildenafil, without time-limit and excluding human studies. Where relevant, investigators were contacted in order to avoid duplication of work. EVIDENCE BEFORE THIS STUDY: Prenatal therapy with sildenafil, a phosphodiesterase-5 inhibitor with vasodilatory and anti-remodeling effects on vascular smooth muscle cells, has been considered for a variety of fetal conditions. One multicenter clinical trial investigating the benefit of sildenafil in severe intrauterine growth restriction (the STRIDER-trial) was halted early due to excess mortality in the sildenafil-exposed arm at one treatment site. Such findings demonstrate the importance of extensive preclinical safety assessment in relevant animal models. Transplacentally administered sildenafil leads to decreased pulmonary arterial muscularization, preventing or reducing the occurrence of pulmonary hypertension in rat and rabbit fetuses with diaphragmatic hernia (DH). Validation of these results in a higher and relevant animal model, e.g. fetal lambs, is the next step to advance clinical translation. We recently demonstrated that, in contrast to humans, transplacental transfer of sildenafil in sheep is minimal, precluding the in vivo study of fetal effects at target concentrations using the conventional pregnant ewe model. ADDED VALUE OF THIS STUDY: We therefore used the extracorporeal support model for fetal lambs, referred to as the EXTra-uterine Environment for Neonatal Development (EXTEND) system, bypassing placental and maternal metabolism, to investigate at what dose the target concentrations are reached, and what the fetal hemodynamic impact and response are. Fetal hemodynamic and metabolic tolerance to sildenafil are a crucial missing element on the road to clinical translation. This is therefore the first study investigating the pharmacokinetics, hemodynamic and biochemical effects of clinical-range concentrations of sildenafil in fetal lambs, free from placental and maternal interference. IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE: We demonstrated self-limiting pulmonary vasodilation, a decrease of both systemic arterial pressures and circuit flows, induced by clinical range concentrations of sildenafil, without the development of fetal acidosis. This paves the way for further investigation of prenatal sildenafil in fetal lambs on extracorporeal support. A dose of 0.5 mg/kg/24 h offered the best trade-off between rapid achievement of target concentrations and shortest duration of systemic effects. This is also the first study using the EXTEND as a model for pharmacotherapy during pregnancy.