Transient Increase In Blood Pressure Research Articles

Acute isometric and dynamic exercise do not alter cerebral sympathetic nerve activity in healthy humans.

The impact of physiological stressors on cerebral sympathetic nervous activity (SNA) remains controversial. We hypothesized that cerebral noradrenaline (NA) spillover, an index of cerebral SNA, would not change during both submaximal isometric handgrip (HG) exercise followed by a post-exercise circulatory occlusion (PECO), and supine dynamic cycling exercise. Twelve healthy participants (5 females) underwent simultaneous blood sampling from the right radial artery and right internal jugular vein. Right internal jugular vein blood flow was measured using Duplex ultrasound, and tritiated NA was infused through the participants' right superficial forearm vein. Heart rate was recorded via electrocardiogram and blood pressure was monitored using the right radial artery. Total NA spillover increased during HG (P = 0.049), PECO (P = 0.006), and moderate cycling exercise (P = 0.03) compared to rest. Cerebral NA spillover remained unchanged during isometric HG exercise (P = 0.36), PECO after the isometric HG exercise (P = 0.45), and during moderate cycling exercise (P = 0.94) compared to rest. These results indicate that transient increases in blood pressure during acute exercise involving both small and large muscle mass do not engage cerebral SNA in healthy humans. Our findings suggest that cerebral SNA may be non-obligatory for exercise-related cerebrovascular adjustments.

The impact of GLP-1 receptor agonist liraglutide on blood pressure profile, hydration, natriuresis in diabetic patients with severely impaired kidney function

Chronic treatment with GLP-1R agonists may moderately lower blood pressure due to increased natriuresis and RAAS inhibition. Short-term effect of these drugs on blood pressure may be opposite and its mechanism remains unclear. We investigated the effect of a single dose of liraglutide on diurnal blood pressure profile, natriuresis, hydration and serum concentration of renin, aldosterone and atrial natriuretic peptide (ANP) in diabetic kidney disease (DKD). 17 patients with eGFR < 30 ml/min/1.73 m2 and 17 with > 60 ml/min/1.73 m2 received in a random order a single subcutaneous dose 1.2 mg liraglutide and placebo with subsequent 24 h blood pressure and natriuresis monitoring. Before and after each medication thoracic fluid index and plasma renin, aldosterone and ANP were also assessed. The blood pressure load in the daytime and nighttime were significantly increased after liraglutide compared to placebo in patients with eGFR < 30 ml/min/1.73 m2. In patients with eGFR > 60 ml/min/1.73 m2 the changes of arterial pressure were comparable, while the morning surge was significantly reduced after liraglutide compared to placebo. After liraglutide 24 h urine sodium excretion increased in both groups vs. placebo (p < 0.001), the effect was greatest in subjects with eGFR > 60 ml/min/1.73 m2. Plasma ANP increased after liraglutide in both groups, most in patients with eGFR < 30 ml/min/1.73 m2 group. Plasma aldosterone (p = 0.013) and thoracic fluid index (p = 0.01) decreased after liraglutide compared to placebo (p = 0.013 and p + 0.01, respectively. Plasma renin concentration remained unchanged. In severe chronic kidney disease liraglutide induces a transient increase of blood pressure due to reduced natriuresis. The natriuretic effect of liraglutide in DKD may be related to increased ANP and decreased aldosterone secretion.

Unaltered Long-Term Maternal Endothelin System in a Gestational Hypertensive Rat Model

INTRODUCTION: Cardiovascular diseases (CVDs) are two to four times more likely to affect women with a history of hypertensive disorders of pregnancy (HDPs). One of the etiologies of CVDs is endothelial dysfunction, which results from an imbalance in the production of endothelin-1 (ET-1) and nitric oxide (NO). Although blood pressure (BP) is normalized postpartum, we hypothesize that a transient increase in BP during HDPs may cause ongoing endothelial dysfunction. We aimed to discover the impact of HDPs in the development of cardiovascular diseases after long-term postpartum changes in endothelin-A receptor (ETAR) and endothelin-B receptor (ETBR) expression and the concentration of ET-1 and NO. MATERIALS AND METHOD: Twenty-four female Sprague-Dawley (SD) rats were assigned into four groups (n = 6), including two treatment and two control groups. All rats were sacrificed on Day 30 postpartum. The NO and ET-1 concentrations were determined by ELISA and the ETAR and ETBR expression of the mesenteric arteries were measured by immunohistochemistry studies. RESULTS: The mean concentrations of ET-1 and NO were not significantly different in all groups. There was no significant difference in the mean immunoreactivity of ETAR and ETBR percentages area in the tunica intima and media in all groups. CONCLUSION: No evidence demonstrates significant changes in the endothelin system of the resistance arteries at the proteomic level in the long-term duration following HDP. Further investigation of its potential chronic effect warrants a deeper analysis at the molecular and ultrastructural levels.

Clinical application of esketamine-induced mild sedation technique in outpatient oral surgery

Background &amp; Objective: Sedation is often required in outpatient surgical procedures, performed under local analgesia, to allay the anxiety of the patient, which may lead to involuntary movements of the patient, thus interfering in the smooth course of the surgery. Various sedative drugs have been used by the anesthetists. We compared the effects of mild sedation techniques induced by remifentanil combined with propofol and esketamine combined with propofol on the cardiopulmonary indices of intraoperative patients, and to explore the application of mild sedation techniques in oral outpatient surgery.&#x0D; Methodology: A total of 62 patients undergoing oral surgery were randomly divided into a control group (31 cases, receiving remifentanil combined with propofol) and an observation group (31 cases, receiving esketamine combined with propofol). The vital signs of the patients were monitored at five time points: admission (T0), anesthesia induction (T1), local anesthesia (T2), the beginning of surgery (T3), and the end of surgery (T4), including heart rate (HR), mean arterial pressure(MAP), bispectral index (BIS), respiratory rate, and oxygen saturation(SPO2). Postoperative memory of each step was recorded, and the sedative effect was evaluated by physician and patient using the visual analogue scale (VAS).&#x0D; Results: During surgery, 6 patients in the control group had SpO2 &lt; 90%, and 8 patients experienced coughing or tongue fall, while 1 patient in the observation group had a transient increase in blood pressure. After intravenous administration, all patients had a decrease in HR, and the decrease in the observation group was significantly less than that in the control group (P &lt; 0.05). The BIS values in the observation group were significantly higher than those in the control group during T2 and T3.&#x0D; Conclusion: In oral outpatient surgery, the combination of propofol and esketamine-induced mild sedation can stabilize the hemodynamic indices of patients during surgery, reduce the incidence of complications, and improve patient satisfaction.&#x0D; Abbreviations: BIS- Bispectral Index; HR- Heart Rate; RASS- Richmond Agitation-Sedation Scale; SBP- Systolic Blood Pressure; VAS- Visual Analogue Scale&#x0D; Key words: Mild Sedation; Esketamine; Propofol; Remifentanil; Oral Surgery&#x0D; Citation: Xin Z, Yu T, Wang LL, Qu W, Wang N, Yao M. Clinical application of esketamine-induced mild sedation technique in outpatient oral surgery. Anaesth. pain intensive care 2022;27(6):715−720; DOI: 10.35975/apic.v27i6.2234&#x0D; Received: May 28, 2023; Revised: October 24, 2023; Accepted: November 08, 2023

Relationship Between Age and the Incidence of Postoperative Hypertension

Postoperative hypertension is a significant and transient increase in blood pressure that develops within the first 4 hours to 48 hours after a surgical procedure. These events are associated with increased sympathetic tone and vascular resistance. Hypertension is defined as a systolic blood pressure of 130 mmHg and/or a diastolic blood pressure of 80 mmHg. Postoperative hypertension can lead to complications of increased myocardial oxygen demand, cerebrovascular accident, and even death. This study aims to determine the effect of age on post-operative hypertension at PKU Muhammadiyah Gamping Hospital. This research is an analytical observational study using a cross sectional design and using the chi-square test to determine the relationship between age (p &lt; 0.05) and the incidence of postoperative hypertension. The subjects of this study were 123 men who underwent mild to moderate elective surgery using general anesthesia. This study shows that there is a relationship between age and the incidence of hypertension after surgery with general anesthesia (p, 0.05). There were 67 subjects experiencing postoperative hypertension (54.5%) and the majority of subjects (66.66%) in the age range 46-80 years, had postoperative hypertension and the most minor incidence (29%) was in the age range 17-25 year.

Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial

Emraclidine is a novel, brain-penetrant, highly selective M4 receptor positive allosteric modulator in development for the treatment of schizophrenia. We aimed to evaluate the safety and tolerability of multiple ascending doses of emraclidine in patients with schizophrenia. We conducted a two-part, randomised, phase 1b trial in the USA. Eligible participants were aged 18-50 years (part A) or 18-55 years (part B) with a primary diagnosis of schizophrenia per the Diagnostic and Statistical Manual of Mental Disorders 5th edition, as confirmed by the Mini International Neuropsychiatric Interview, and extrapyramidal symptom assessments indicating normal to mild symptoms at screening. Part A evaluated the safety and tolerability of emraclidine in five cohorts of participants with stable schizophrenia who received ascending oral doses of emraclidine 5-40 mg (40 mg was administered as 20 mg twice daily) or placebo at a single US site. Part B was a double-blind, randomised, placebo-controlled study that enrolled adults with acute schizophrenia across five US sites; participants were randomly assigned (1:1:1) to receive emraclidine 30 mg once daily, emraclidine 20 mg twice daily, or placebo for 6 weeks (doses established in part A). The primary endpoint was safety and tolerability, assessed in the safety population (participants who received at least one dose of emraclidine or placebo). This trial is now complete and is registered with ClinicalTrials.gov, NCT04136873. Between Sept 23, 2019, and Sept 17, 2020, 118 patients were assessed for eligibility and 49 were randomly assigned across five cohorts in part A. 44 participants completed the study, with 36 participants receiving emraclidine and eight receiving placebo. The two highest doses tested were selected for part B. Between Oct 12, 2020, and May 7, 2021, 148 patients were assessed for eligibility and 81 were randomly assigned to emraclidine 30 mg once daily (n=27), emraclidine 20 mg twice daily (n=27), or placebo (n=27) in part B. Incidence of adverse events (14 [52%] of 27 participants in the emraclidine 30 mg once daily group, 15 [56%] of 27 in the emraclidine 20 mg twice daily group, and 14 [52%] of 27 in the placebo group), clinical assessments, and weight changes were similar across groups. The most common adverse event was headache (15 [28%] of 54 participants in the emraclidine groups, seven [26%] of 27 in the placebo group). Modest, transient increases in blood pressure and heart rate in emraclidine groups observed at treatment initiation diminished over time and were not considered clinically meaningful by week 6. These data support further investigation of emraclidine as a once-daily treatment for schizophrenia without need for titration and with a potentially favourable side-effect profile. Cerevel Therapeutics.

Temporal fluctuations of cardiovascular parameters after intravitreal injections.

Despite the effectiveness of intravitreal injection (IVI) of anti-vascular endothelial growth factor in treating retinal diseases, there remains a paucity of evidence on potential systemic risks associated with this procedure. This study aims to investigate cardiovascular parameters and the risk of hypertensive urgency after IVIs. Patients who received IVIs for retinal/macular diseases were enrolled retrospectively. Patients who received cataract surgeries were enrolled as controls. Systolic and diastolic blood pressure (BP) and heart rate were measured 10 minutes before, immediately after, and more than 30 minutes after IVIs and cataract surgery. Multivariate analysis was performed to evaluate risk factors for hypertensive urgency. Seventy patients who received IVIs and 95 patients who received cataract surgeries were enrolled. A higher preoperative systolic BP was found in the IVI groups than in the control group (147.0 ± 22.9 vs 136.3 ± 21.8 mmHg, respectively). The patients who received IVIs had a higher increase in perioperative systolic BP immediately after the procedure than the controls (17.43 ± 20.53 mmHg vs 9.11 ± 18.92 mmHg, p = 0.009). The IVI procedure (odds ratio [OR] 4.84, p = 0.008), preoperative systolic BP ≥160 mmHg (OR 17.891, p = 0.001, compared to preoperative systolic BP <140 mmHg), and underlying hypertension (OR 3.305, p = 0.041) were risk factors for hypertensive urgency immediately after the IVIs. We found a transient increase in BP after IVIs, which may have been associated with hypertensive urgency and related cardiovascular disorders in older patients and in those with relevant comorbidities. Clinicians should pay more attention to these patients before performing IVIs.

Cardiorespiratory adaptation to low-dose dexamethasone for lung disease in extremely preterm infants: A prospective echocardiographic study.

The cardiovascular impact of dexamethasone (Dex) is not well understood. Most data are obtained from a 6week, high-dose regimen, and are limited to findings of hypertension and cardiac hypertrophy. The present study ascertained the impact of low-dose Dex on cardiac indices when administered to extremely preterm infants for lung disease. A pre-post intervention prospective echocardiographic (Echo) study was undertaken, with cardiac assessments performed before and within 24h after completion of first course of therapy (10day regimen, cumulative 0.89mgkg-1 ). Thirty infants with a gestational age of 24.6±1.1weeks and birthweight of 612±125g, respectively, were studied. The age at Dex administration was 20±9days. Fractional inspired oxygen decreased from 0.7±0.23 to 0.35±0.14 (P<0.001). Patent ductus arteriosus was noted in 20 infants at Echo1. At Echo2, the ductal diameter decreased from 2.16±0.8 to 1.1±0.8mm (P= 0.0003), with complete closure in 7/20 (35%). A reduction in left pulmonary artery end-diastolic velocity was noted (17±12 to 9±10cms-1 , P<0.001). Pulmonary vascular resistance decreased (increased time to peak velocity/right ventricular ejection time, 0.2±0.03 to 0.23 ±0.03, P= 0.0001) and right ventricular systolic performance improved (tricuspid annular plane systolic excursion, 4.9±0.8 to 5.5±0.9mm, P= 0.02). No significant changes in fractional shortening and left ventricular mass were noted. A significant increase in blood pressure was noted. As a percentage of pre-treatment baseline, the mean increase for systolic blood pressure was 20.3% (95% confidence interval=14-26) on day 2 (P= 0.008). Low-dose Dex influenced cardiovascular parameters related to pulmonary circulation. KEY POINTS: Corticosteroid therapy is frequently used in preterm infants who are dependent on ventilator support. Echocardiographic studies in infants administered a 6week course of steroids have noted left ventricular hypertrophy, outlet obstruction and hypertension, but no information is available on right heart indices. The cardiopulmonary effects of the current, significantly lesser cumulative dose (10day regimen, commonly described as 'DART') have not been evaluated. The present study noted a significant influence on ductal and pulmonary circulation indices. Left heart architecture and function was maintained, whereas a significant but transient increase in blood pressure was noted.

Transvenous Radiofrequency Ablation of Adrenal Gland: Experimental Study.

The aim was to evaluate a flexible device for transvenous adrenal gland radiofrequency ablation in vitro and in an in vivo animal model. A flexible radiofrequency-tip catheter with an inner-cooling mechanism and a guidewire lumen was made. Then, using a polyvinyl alcohol gel model, the ablation diameter was evaluated and how much energy to deliver in vivo was determined. Finally, transvenous radiofrequency ablation of the left adrenal glands of two pigs was performed, delivering 5000 or 7000J in a single dose to each. The ablation effects were also assessed by histological examination of hematoxylin-eosin-stained sections. The mean ablation diameters in the gel model were 20.2 and 21.9mm in the short axis and 15 and 20mm in the long axis for 5000 or 7000J, respectively. The device was inserted into porcine left adrenal vein with no complications. The mean ablation diameters were 10mm in the shorter axis (whole thickness of porcine left adrenal gland) in the porcine model for 7000J. Transient increases in blood pressure and heart rate occurred during ablation. Histologically, the adrenal gland showed severe necrosis at ablated area. There was venous congestion upstream in a non-ablated area, and thermal damage to surrounding organs was not observed. A flexible radiofrequency-tip catheter could be inserted successfully into the left adrenal vein. The left adrenal gland was entirely ablated without any thermal damage to surrounding organs. We suggest transvenous adrenal ablation has potential as a therapeutic option for primary aldosteronism.

Comprehensive Nonclinical Safety Assessment of Nirmatrelvir Supporting Timely Development of the SARS-COV-2 Antiviral Therapeutic, Paxlovid™.

COVID-19 is a potentially fatal infection caused by the SARS-CoV-2 virus. The SARS-CoV-2 3CL protease (Mpro) is a viral enzyme essential for replication and is the target for nirmatrelvir. Paxlovid (nirmatrelvir co-administered with the pharmacokinetic enhancer ritonavir) showed efficacy in COVID-19 patients at high risk of progressing to hospitalization and/or death. Nonclinical safety studies with nirmatrelvir are essential in informing benefit-risk of Paxlovid and were conducted to support clinical development. In vivo safety pharmacology assessments included a nervous system/pulmonary study in rats and a cardiovascular study in telemetered monkeys. Potential toxicities were assessed in repeat dose studies of up to 1 month in rats and monkeys. Nirmatrelvir administration (1,000 mg/kg, p.o.) to male rats produced transient increases in locomotor activity and respiratory rate but did not affect behavioral endpoints in the functional observational battery. Cardiovascular effects in monkeys were limited to transient increases in blood pressure and decreases in heart rate, observed only at the highest dose tested (75 mg/kg per dose b.i.d; p.o.). Nirmatrelvir did not prolong QTc-interval or induce arrhythmias. There were no adverse findings in repeat dose toxicity studies up to 1 month in rats (up to 1,000 mg/kg daily, p.o.) or monkeys (up to 600 mg/kg daily, p.o.). Nonadverse, reversible clinical pathology findings without clinical or microscopic correlates included prolonged coagulation times at ≥60 mg/kg in rats and increases in transaminases at 600 mg/kg in monkeys. The safety pharmacology and nonclinical toxicity profiles of nirmatrelvir support clinical development and use of Paxlovid for treatment of COVID-19.

Morning hypertension for stroke and cardiovascular: clinical pearls for primary care

Hypertension is the world’s leading cause of mortality and morbidity. One of the phenomena that commonly occur in hypertensive as well as normotensive patients, is morning hypertension. Blood pressure (BP) follows a diurnal rhythm, reaching its highest level during the morning hours and dropping to the lowest level at midnight. Transient increases in BP in morning hypertension plus persistent stressors within 24 hours are thought to increase target organ damage and trigger cardiovascular events. Therefore, ambulatory BP monitoring or morning home BP monitoring is recommended as a strong predictor of cardiovascular events. There are two types of morning hypertension according to its underlying mechanisms; the first one is called nocturnal hypertensive morning hypertension, and the other one is morning-surge hypertension. Numerous studies have proved that this phenomenon often leads to several acute cardiovascular events, such as stroke, coronary artery disease, and peripheral artery disease. To prevent these complications, cost-effective management is needed, especially for identifying accurate diagnostic tools, as well as creating specific regimens. Therefore, to achieve appropriate management of hypertension, including morning hypertension, long-acting antihypertensive drugs should be used, at full doses and in the form of combination therapy. The clinical usefulness of antihypertensive drugs with specific mechanisms for morning BP or split or timed dosing of long-acting drugs in controlling morning BP remains under investigation. More studies are needed, especially looking for other clinical evidence of the benefits of lowering BP in the morning. Home BP monitoring is recommended as a good choice for BP measurements, especially in the primary care setting.

Новые подходы к комбинированной терапии ирритативных симптомов нижних мочевыводящих путей пациентов с доброкачественной гиперплазией предстательной железы

Introduction Daytime and nighttime urinary frequency is a common complaint in patients with benign prostatic hyperplasia (BPH). The most common reason for seeking elective surgery is an ineffective treatment with alpha-blockers. The aim of the study was to evaluate the efficacy and safety of combination therapy with tamsulosin 0.4 mg and mirabegron 50 mg in patients with BPH and predominant irritative symptoms. Materials and methods from January 2018 to December 2019 in the outpatient department of the city clinical hospital named after D.D. Pletnev, a total of 64 patients with BPH with complains of frequent nighttime and daytime frequency and a desire to undergo surgery were followed. The patients underwent a comprehensive clinical and laboratory examination, according to which 10 patients had indications for surgery, and they were excluded from the study. In 6 patients, the prevalence of nocturnal over daytime diuresis was revealed and they were also excluded. Combination therapy with tamsulosin 0.4 mg and mirabegron 50 mg a day was prescribed to 48 patients. The average duration of therapy was 15.4 +/- 3.1 months. Patients underwent a follow-up examination to evaluate the efficiency and safety after 3, 6 and 12 months of therapy. Adverse events, possibly treatment-related, were recorded. Results there was an additional decrease in irritative complaints according to the I-PSS, namely 2 points after 3 months and 4 points after 6 and 12 months. In addition, a decrease in the number of nocturnal urinations by one, a decrease in daytime urination by one after 3 months and by two after 6 and 12 months, as well as an increase in the average voided volume from 150 +/- 33 to 240 +/- 40 ml after 12 months of therapy was seen. The change in other parameters was not significant. Two patients stopped taking the drug due to non-medical reasons. In other 2 patients, the development of sinus tachycardia and a transient increase in blood pressure were noted, which did not require discontinuation of the drug. Conclusions Combination therapy with tamsulosin 0.4 mg and mirabegron 50 mg reduces the frequency of daytime and night urination with the maximum effect after 6-12 months, improves the quality of life and has a good safety profile.

Effect of Ketamine on Cardiovascular Function During Procedural Sedation of Adults.

Introduction: Ketamine is commonly used in emergency department procedural sedation. Mild to moderate transient increases in blood pressure, heart rate, and cardiac output are common due to ketamine causing an increase in sympathetic activity. There is a concern that these physiological changes could result in an increased myocardial oxygen demand that may exacerbate underlying cardiac disease.Methods: Convenience sample of patients older than 50 years receiving ketamine for procedural sedation in the emergency department was used (n = 31). Patients were selected to receive ketamine based on provider discretion. Primary outcome was incidence of new myocardial ischemia apparent on an electrocardiogram (ECG). ECGs were obtained prior to sedation and during the sedation approximately one minute after administration of ketamine. ECGs were reviewed by a board-certified emergency medicine physician and a board-certified cardiologist.Results: New onset ischemia was found in 9.7% (3/31) of ECGs. Of these, one was in a patient who had previously received ketamine without evidence of ischemia on the repeat ECG. There were no statistically significant differences between the groups. Evidence of ischemia on ECG did not impact patient disposition.Conclusions: Ketamine is a useful medication in procedural sedation; however, careful attention should be made in patient selection when ketamine is the desired agent. Consideration might be made in using the lowest possible dose of ketamine to obtain adequate sedation in order to hopefully lessen the occurrence of ECG changes suggestive of myocardial ischemia. Based on this small sample, single-site study, no evidence of statistically or clinically significant ischemia was seen with the use of ketamine for procedural sedation. Ketamine remains a safe medication option in adults undergoing procedural sedation.

The impact of anti-CGRP monoclonal antibodies in resistant migraine patients: a real-world evidence observational study.

To evaluate the frequency and headache-related impact response to monoclonal antibodies against calcitonin gene-related peptide (CGRP) in a clinical sample of refractory migraine patients. We included migraine patients with ≥ 8 headache days/month that had failed at least three preventive medications. Demographic, medical and migraine history were collected. Patients completed an electronic headache diary including headache days/month, migraine days/month, headache pain intensity (0-3 numerical scale), use of analgesics and completed Patient-Reported Outcome questionnaires at baseline and after 12weeks. Patients were classified into ≥ 50%, ≥ 75% and 100% responders according to the improvement in frequency. We included 155 patients (109 erenumab and 46 galcanezumab). After 12weeks, headache frequency decreased - 9.1 headache days/month and - 8.5 migraine days/month from baseline. A 39.5% had a ≥ 50% headache days/month reduction and a 51.6% ≥ 50% migraine days/month reduction. In the ≥ 50% migraine days/month-responders group, frequency reduction was - 13,9 migraine days/month from baseline and showed clear improvements for all patient-reported outcomes. A 14.2% and 26.5% had a ≥ 75% response in headache and migraine days/month, respectively, and 11.0% showed a 100% migraine days/month reduction. Patients who were not on other preventive medications had less severe disability and higher ratio of migraine over headache days/month were more likely of being a ≥ 50% migraine days/month-responder. We did not record any severe adverse events, being the most common constipation (20.0%), fatigue (7.1%) and a transient increase in blood pressure (5.2%). In real-world clinical practice, monoclonal antibodies against CGRP proved to be effective treatments in resistant migraine patients.

Acute glucose influx-induced mitochondrial hyperpolarization inactivates myosin phosphatase as a novel mechanism of vascular smooth muscle contraction

It is well-established that long-term exposure of the vasculature to metabolic disturbances leads to abnormal vascular tone, while the physiological regulation of vascular tone upon acute metabolic challenge remains unknown. Here, we found that acute glucose challenge induced transient increases in blood pressure and vascular constriction in humans and mice. Ex vivo study in isolated thoracic aortas from mice showed that glucose-induced vascular constriction is dependent on glucose oxidation in vascular smooth muscle cells. Specifically, mitochondrial membrane potential (ΔΨm), an essential component in glucose oxidation, was increased along with glucose influx and positively regulated vascular smooth muscle tone. Mechanistically, mitochondrial hyperpolarization inhibited the activity of myosin light chain phosphatase (MLCP) in a Ca2+-independent manner through activation of Rho-associated kinase, leading to cell contraction. However, ΔΨm regulated smooth muscle tone independently of the small G protein RhoA, a major regulator of Rho-associated kinase signaling. Furthermore, myosin phosphatase target subunit 1 (MYPT1) was found to be a key molecule in mediating MLCP activity regulated by ΔΨm. ΔΨm positively phosphorylated MYPT1, and either knockdown or knockout of MYPT1 abolished the effects of glucose in stimulating smooth muscle contraction. In addition, smooth muscle-specific Mypt1 knockout mice displayed blunted response to glucose challenge in blood pressure and vascular constriction and impaired clearance rate of circulating metabolites. These results suggested that glucose influx stimulates vascular smooth muscle contraction via mitochondrial hyperpolarization-inactivated myosin phosphatase, which represents a novel mechanism underlying vascular constriction and circulating metabolite clearance.

A Systematic Review on the Efficacy of Intravenous Racemic Ketamine for Bipolar Depression.

Ketamine, a glutamate N-methyl-d-aspartate receptor antagonist, has shown rapid antidepressant effects in treatment-resistant depression. We conducted a systematic review of studies evaluating the efficacy of intravenous ketamine augmentation in treatment-resistant depression patients with bipolar disorder. Major databases were searched for open-label and randomized controlled trials (RCT). Two independent reviewers screened and selected the studies that met the inclusion criteria. Studies were selected following the standard Cochrane methodology, and the findings are reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Methodological quality of the included studies was assessed using standardized measures. A total of 1442 articles were screened. Five studies were included in the systematic review (3 RCTs and 2 open-label studies) enrolling 110 subjects (mean age, 45.54 ± 12.65 years; 68.18% female). All the RCTs and open-label studies showed improvement in depressions symptoms after receiving a single infusion of ketamine. Included studies also suggested improvement in suicidal ideation and anhedonia after ketamine infusion. Dissociation and transient increase in blood pressure were the most common reported adverse effects with ketamine. Ketamine infusions did not increase mania symptoms. Limited data show efficacy and feasibility of intravenous racemic ketamine in treatment-resistant bipolar depression. Further studies with larger sample size are required to strengthen the evidence.

Pharmacokinetics and pharmacodynamics of l-methadone in isoflurane-anaesthetized and mechanically ventilated ponies

ObjectiveTo evaluate the pharmacokinetics and selected pharmacodynamic effects of a commercially available l-methadone/fenpipramide combination administered to isoflurane anaesthetized ponies. Study designProspective single-group interventional study. AnimalsA group of six healthy adult research ponies (four mares, two geldings). MethodsPonies were sedated with intravenous (IV) detomidine (0.02 mg kg–1) and butorphanol (0.01 mg kg–1) for an unrelated study. Additional IV detomidine (0.004 mg kg–1) was administered 85 minutes later, followed by induction of anaesthesia using IV diazepam (0.05 mg kg–1) and ketamine (2.2 mg kg–1). Anaesthesia was maintained with isoflurane in oxygen. Baseline readings were taken after 15 minutes of stable isoflurane anaesthesia. l-Methadone (0.25 mg kg–1) with fenpipramide (0.0125 mg kg–1) was then administered IV. Selected cardiorespiratory variables were recorded every 10 minutes and compared to baseline using the Wilcoxon signed-rank test. Adverse events were recorded. Arterial plasma samples for analysis of plasma concentrations and pharmacokinetics of l-methadone were collected throughout anaesthesia at predetermined time points. Data are shown as mean ± standard deviation or median and interquartile range (p < 0.05). ResultsPlasma concentrations of l-methadone showed a rapid initial distribution phase followed by a slower elimination phase which is best described with a two-compartment model. The terminal half-life was 44.3 ± 18.0 minutes, volume of distribution 0.43 ± 0.12 L kg–1 and plasma clearance 7.77 ± 1.98 mL minute–1 kg–1. Mean arterial blood pressure increased from 85 (±16) at baseline to 100 (±26) 10 minutes after l-methadone/fenpipramide administration (p = 0.031). Heart rate remained constant. In two ponies fasciculations occurred at different time points after l-methadone administration. Conclusions and clinical relevanceAdministration of a l-methadone/fenpipramide combination to isoflurane anaesthetized ponies led to a transient increase in blood pressure without concurrent increases in heart rate. Pharmacokinetics of l-methadone were similar to those reported for conscious horses administered racemic methadone.

Habitual cigarette smoking raises pressor responses to spontaneous bursts of muscle sympathetic nerve activity.

Smoking is a risk factor for cardiovascular diseases. Prior reports showed a transient increase in blood pressure (BP) following a spontaneous burst of muscle sympathetic nerve activity (MSNA). We hypothesized that this pressor response would be accentuated in smokers. Using signal-averaging techniques, we examined the BP (Finometer) response to MSNA in 18 otherwise healthy smokers and 42 healthy nonsmokers during resting conditions. The sensitivities of baroreflex control of MSNA and heart rate were also assessed. The mean resting MSNA, heart rate, and mean arterial pressure (MAP) were higher in smokers than nonsmokers. The MAP increase following a burst of MSNA was significantly greater in smokers than nonsmokers (Δ3.4 ± 0.3 vs. Δ1.6 ± 0.1 mmHg, P < 0.001). The baroreflex sensitivity (BRS) of burst incidence, burst area, or total activity was not different between the two groups. However, cardiac BRS was lower in smokers than nonsmokers (14.6 ± 1.7 vs. 24.6 ± 1.5 ms/mmHg, P < 0.001). Moreover, the MAP increase following a burst was negatively correlated with the cardiac BRS. These observations suggest that habitual smoking in otherwise healthy individuals raises the MAP increase following spontaneous MSNA and that the attenuated cardiac BRS in the smokers was a contributing factor. We speculate that the accentuated pressor increase in response to spontaneous MSNA may contribute to the elevated resting BP in the smokers.

His-Leu, an angiotensin I-derived peptide, does not affect haemodynamics in rats.

Introduction:The dipeptide histidine-leucine (His-Leu) is formed in the process of converting angiotensin I into angiotensin II. Several studies show that short peptides containing His-Leu may produce significant haemodynamic effects; however, to the best of our knowledge, data on haemodynamic effects of His-Leu are not available in medical databases.Materials and methods:We evaluated acute haemodynamic effects of intravenous administration of either 0.9% NaCl (vehicle) or His-Leu at a dose of 3–15 mg/kg body weight in anaesthetized 15–16-week-old, male, normotensive Wistar Kyoto and spontaneously hypertensive rats. Chronic effects of treatment with either the vehicle or His-Leu at a dose of 15 mg/kg body weight given subcutaneously daily were determined during continuous telemetry recordings in freely moving rats.Results:In anaesthetized rats both the vehicle and His-Leu produced a mild and transient increase in blood pressure and no change in plasma renin activity. There was no significant difference in haemodynamics between the rats infused with the vehicle and the rats infused with His-Leu. In chronic studies, seven-day treatment with vehicle and with His-Leu did not affect arterial blood pressure in freely moving rats.Conclusion:His-Leu does not produce either acute or chronic changes in arterial blood pressure in normotensive and hypertensive rats.

Abstract 378: Predilection of Low Protein C-induced Spontaneous Atherothrombosis for the Right Coronary Sinus in Apolipoprotein E-deficient mice

Atherothrombosis is the cause of death of over 14 million people per year worldwide and murine models to replicate this process in vivo are mostly lacking. Previously we demonstrated that silencing of anticoagulant protein C using RNA interference ( siProc ) induces spontaneous atherothrombosis in the aortic root of apolipoprotein E-deficient ( Apoe -/- ) mice, albeit at a low incidence rate. Here we aim to determine if plaque susceptibility for rupture can be linked to plaque characteristics and/or blood composition, and moreover, we attempt to boost incidence through a transient increase in blood pressure as well as to localize atherothrombosis to an additional predefined vascular site by means of a semi-constrictive collar around the carotid artery. In the current study, si Proc -driven spontaneous atherothrombosis in the aortic root of Apoe-/- mice was reproduced and occurred at an incidence of 23% (9 out of 39 mice), while the incidence of collar-induced atherothrombosis in the carotid artery was 2.6% (1 out of 39 mice). Treatment with phenylephrine, to transiently increase blood pressure, did not increase atherothrombosis in the aortic root of the Apoe -/- mice nor in the carotid arteries with collars. Plaques in the aortic root with an associated thrombus were lower in collagen and macrophage content, and mice with atherothrombosis had significantly more circulating platelets. Plasma protein C, white blood cell counts, total cholesterol, fibrinogen, and serum amyloid A were not different amongst si Proc -treated mice with or without thrombosis. Remarkably, our data revealed that thrombus formation preferably occurred on plaques in the right coronary sinus of the aortic root. In conclusion, there is a predilection of low protein C-induced spontaneous atherothrombosis in Apoe -/- mice for the right coronary sinus, a process that is associated with an increase in platelets and plaques lower in collagen and macrophage content.