Antihypertensive treatment during pregnancy induces long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring.

The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.

Cerebral Blood Flow Assessed with Phase-contrast Magnetic Resonance Imaging during Blood Pressure Changes with Noradrenaline and Labetalol: A Trial in Healthy Volunteers.

BACKGROUND: Adequate cerebral perfusion is central during general anesthesia. However, perfusion is not readily measured bedside. Clinicians currently rely mainly on mean arterial pressure (MAP) as a surrogate, even though the relationship between blood pressure and cerebral blood flow is not well understood. The aim of this study was to apply phase-contrast magnetic resonance imaging to characterize blood flow responses in healthy volunteers to commonly used pharmacologic agents that increase or decrease arterial blood pressure. METHODS: Eighteen healthy volunteers aged 30 to 50 yr were investigated with phase-contrast magnetic resonance imaging. Intra-arterial blood pressure monitoring was used. First, intravenous noradrenaline was administered to a target MAP of 20% above baseline. After a wash-out period, intravenous labetalol was given to a target MAP of 15% below baseline. Cerebral blood flow was measured using phase-contrast magnetic resonance imaging and defined as the sum of flow in the internal carotid arteries and vertebral arteries. Cardiac output (CO) was defined as the flow in the ascending aorta. RESULTS: Baseline median cerebral blood flow was 772 ml/min (interquartile range, 674 to 871), and CO was 5,874 ml/min (5,199 to 6,355). The median dose of noradrenaline was 0.17 µg · kg-1 · h-1 (0.14 to 0.22). During noradrenaline infusion, cerebral blood flow decreased to 705 ml/min (606 to 748; P = 0.001), and CO decreased to 4,995 ml/min (4,705 to 5,635; P = 0.01). A median dose of labetalol was 120 mg (118 to 150). After labetalol boluses, cerebral blood flow was unchanged at 769 ml/min (734 to 900; P = 0.68). CO increased to 6,413 ml/min (6,056 to 7,464; P = 0.03). CONCLUSIONS: In healthy, awake subjects, increasing MAP using intravenous noradrenaline decreased cerebral blood flow and CO. These data do not support inducing hypertension with noradrenaline to increase cerebral blood flow. Cerebral blood flow was unchanged when decreasing MAP using labetalol.

Haemodynamic effects of labetalol in isoflurane-anaesthetized dogs that received dexmedetomidine: A randomized clinical trial.

OBJECTIVE: To test whether labetalol improved cardiovascular function in anaesthetized dogs injected with dexmedetomidine. STUDY DESIGN: Prospective, randomized, blinded, clinical trial. ANIMALS: A group of 20 healthy client-owned dogs undergoing ovariohysterectomy. METHODS: Each dog received dexmedetomidine (5 µg kg-1) and methadone (0.2 mg kg-1) intramuscularly. General anaesthesia was induced with propofol and maintained with isoflurane in oxygen. All dogs were mechanically ventilated, and epidural anaesthesia with lidocaine was performed. Standard anaesthetic monitoring, invasive blood pressure, oesophageal Doppler and near-infrared tissue perfusion/oxygenation were applied. Peak velocity (PV), mean acceleration and stroke distance (SD) from the oesophageal Doppler were recorded. Arterial elastance (Ea) was calculated. Tissue oxygenation (rStO2) was also recorded. Prior to surgery, animals received either 0.1 mg kg-1 of labetalol intravenously (IV) over 60 seconds or the equivalent volume of saline. Data were recorded for 20 minutes. Age, weight and propofol dose were compared with a Wilcoxon rank-sum test. The effects of time, treatment and their interaction with haemodynamic and perfusion variables were analysed with mixed-effect models and Tukey's post hoc tests. RESULTS: Significant effects of the interaction between treatment and time were observed whereby heart rate (HR) was higher in dogs given labetalol (p = 0.01), whereas arterial blood pressure and Ea were lower (p < 0.01). Similarly, PV, SD and rStO2 were higher in the labetalol group, and significant effects were detected for the interaction between treatment and time (p < 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Labetalol at a dose of 0.1 mg kg-1 IV in dogs under general anaesthesia and administered a pre-anaesthetic medication of dexmedetomidine produced mild vasodilation (reduction of Ea), resulting in an increase in HR and left ventricular outflow. Although labetalol could be an effective option to achieve haemodynamic optimization after dexmedetomidine-induced vasoconstriction, future studies are needed to assess long-term effects.

Identifying Targets to Improve the Management of Severe Hypertension in Pregnancy and Postpartum.

OBJECTIVES: To (1) define quality indicators, (2) describe care gaps, and (3) identify process issues in severe hypertension (sustained systolic blood pressure [BP] ≥160 mm Hg or diastolic BP ≥110 mm Hg) management at our tertiary care centre. METHODS: Pregnant and postpartum persons diagnosed with a hypertensive disorder of pregnancy from 2018 to 2019 were identified. A retrospective cohort of patients with severe hypertension was constructed, and data were collected through chart review. Severe hypertension management was assessed according to defined quality indicators. Clinical characteristics were compared between participants with and without time-to-target BP within 60 minutes. Process issues were examined for each severe hypertension occurrence. RESULTS: Of 608 participants with a hypertensive disorder of pregnancy, 90 (15%) experienced severe hypertension. Median time-to-target BP was 76 minutes (interquartile range 47-123 minutes), and target BP (<155/105 mm Hg) was achieved within 60 minutes in 31/90 (34%) participants. Appropriate antihypertensives for severe hypertension were used in 55/90 (61%), and time-to-treatment initiation was within 30 minutes in 42/54 (78%). Chronic hypertension and oral labetalol use were associated with delays in achieving target BP. Process issues related to severe hypertension management included inappropriate treatment (n = 35/90; 39%), failure to recognize severe hypertension as an emergency (n = 21/90; 23%), and delayed treatment initiation (n = 12/54; 22%). CONCLUSION: We defined quality indicators for severe hypertension management. Time-to-target BP within 60 minutes was achieved in a minority of patients, and chronic hypertension was associated with delayed severe hypertension resolution. Process issues in severe hypertension management were described.

Evaluation of intravenous infusion of labetalol versus magnesium sulfate on cerebral hemodynamics of preeclampsia patients with severe features using transcranial doppler.

PURPOSE: It is essential to understand the underlying pathophysiological mechanisms of preeclampsia cerebral complications. This study aimed to compare the cerebral hemodynamic effects of magnesium sulfate (MgSO4) and labetalol in pre-eclampsia patients with severe features. METHODS: Singleton pregnant women who suffered from late onset preeclampsia with severe features were enrolled and subjected to baseline Transcranial doppler (TCD) evaluation and then randomly assigned to either the magnesium sulfate group or labetalol group. TCD to measure middle cerebral artery (MCA) blood flow indices including mean flow velocity (cm/s), mean end-diastolic velocity (DIAS), and pulsatility index (PI) and to estimate CPP and MCA velocity were performed as basal measurements before study drug administration and at post-treatment one and six hours after administration. The occurrence of seizures and any adverse effects were recorded for each group. RESULTS: Sixty preeclampsia patients with severe features were included and randomly allocated into two equal groups. In group M the PI was 0.77 ± 0.04 at baseline versus 0.66 ± 0.05 at 1hour and 0.66 ± 0.05 at 6 hours after MgSO4 administration (p value < 0.001) also the calculated CPP was significantly decreased from 103.3 ± 12.7mmHg to 87.8 ± 10.6mmHg and 89.8 ± 10.9mmHg (p value < 0.001) at 1 and 6 hours respectively. Similarly, in group L the PI was significantly decreased from 0.77 ± 0.05 at baseline to 0.67 ± 0.05 and 0.67 ± 0.06 at 1 and 6 hours (p value < 0.001) after labetalol administration. Moreover, the calculated CPP was significantly decreased from 103.6 ± 12.6 mmHg to 86.2 ± 13.02mmHg at 1 hour and to 83.7 ± 14.6mmHg at 6 hours (p value < 0.001). In terms of changes in blood pressure and the heart rate, they were significantly lower in the labetalol group. CONCLUSION: Both magnesium sulfate and labetalol reduce CPP while maintaining cerebral blood flow (CBF) in preeclampsia patients with severe features. TRIAL REGISTRATION: The institutional review board of the Faculty of Medicine, Zagazig University approved this study with the reference number (ZU-IRB#: 6353-23-3-2020) and it was registered at clinicaltrials.gov (NCT04539379).

Comparison of Intravenous Antihypertensives on Blood Pressure Control in Acute Neurovascular Emergencies: A Systematic Review.

BACKGROUND: Acute blood pressure (BP) management in neurologic patients is paramount. Different neurologic emergencies dictate various BP goals. There remains a lack of literature determining the optimal BP regimen regarding safety and efficacy. The objective of this study was to identify which intravenous antihypertensive is the most effective and safest for acute BP management in neurologic emergencies. METHODS: Ovid EBM (Evidence Based Medicine) Reviews, Ovid Embase, Ovid Medline, Scopus, and Web of Science Core Collection were searched from inception to August 2020. Randomized controlled trials or comparative observational studies that evaluated clevidipine, nicardipine, labetalol, esmolol, or nitroprusside for acute neurologic emergencies were included. Outcomes of interest included mortality, functional outcome, BP variability, time to goal BP, time within goal BP, incidence of hypotension, and need for rescue antihypertensives. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to evaluate the degree of certainty in the evidence available. RESULTS: A total of 3878 titles and abstracts were screened, and 183 articles were selected for full-text review. Ten studies met the inclusion criteria; however, the significant heterogeneity and very low quality of studies precluded a meta-analysis. All studies included nicardipine. Five studies compared nicardipine with labetalol, three studies compared nicardipine with clevidipine, and two studies compared nicardipine with nitroprusside. Compared with labetalol, nicardipine appears to reach goal BP faster, have less BP variability, and need less rescue antihypertensives. Compared with clevidipine, nicardipine appears to reach goal BP goal slower. Lastly, nicardipine appears to be similar for BP-related outcomes when compared with nitroprusside; however, nitroprusside may be associated with increased mortality. The confidence in the evidence available for all the outcomes was deemed very low. CONCLUSIONS: Because of the very low quality of evidence, an optimal BP agent for the treatment of patients with neurologic emergencies was unable to be determined. Future randomized controlled trials are needed to compare the most promising agents.

In Vitro Toxicological Profile of Labetalol-Folic Acid/Folate Co-Administration in H9c2(2-1) and HepaRG Cells.

Background and Objectives: The consumption of dietary supplements has increased over the last decades among pregnant women, becoming an efficient resource of micronutrients able to satisfy their nutritional needs during pregnancy. Furthermore, gestational drug administration might be necessary to treat several pregnancy complications such as hypertension. Folic acid (FA) and folate (FT) supplementation is highly recommended by clinicians during pregnancy, especially for preventing neural tube birth defects, while labetalol (LB) is a ß-blocker commonly administered as a safe option for the treatment of pregnancy-related hypertension. Currently, the possible toxicity resulting from the co-administration of FA/FT and LB has not been fully evaluated. In light of these considerations, the current study was aimed at investigating the possible in vitro cardio- and hepato-toxicity of LB-FA and LB-FT associations. Materials and Methods: Five different concentrations of LB, FA, FT, and their combination were used in myoblasts and hepatocytes in order to assess cell viability, cell morphology, and wound regeneration. Results: The results indicate no significant alterations in terms of cell viability and morphology in myoblasts (H9c2(2-1)) and hepatocytes (HepaRG) following a 72-h treatment, apart from a decrease in the percentage of viable H9c2(2-1) cells (~67%) treated with LB 150 nM−FT 50 nM. Additionally, LB (50 and 150 nM)−FA (0.2 nM) exerted an efficient wound regenerating potential in H9c2(2-1) myoblasts (wound healing rates were >80%, compared to the control at 66%), while LB-FT (at all tested concentrations) induced no significant impairment to their migration. Conclusions: Overall, our findings indicate that LB-FA and LB-FT combinations lack cytotoxicity in vitro. Moreover, beneficial effects were noticed on H9c2(2-1) cell viability and migration from LB-FA/FT administration, which should be further explored.

Metabolic Activation and Cytotoxicity of Labetalol Hydrochloride Mediated by Sulfotransferases.

Labetalol hydrochloride (LHCl), an α- and ß-adrenoreceptor blocker, is widely used for the treatment of hypertension as well as angina pectoris. Previous reports have demonstrated the adverse events during clinical application of LHCl, such as liver injury and acute renal failure. The present study aimed to investigate metabolic activation of LHCl to initiate the elucidation of the mechanisms of its liver toxicity. One glutathione (GSH) conjugate was detected in rat and human primary hepatocytes as well as bile of rats after exposure to LHCl. The GSH conjugate was chemically synthesized and characterized by Q-TOF and 1H NMR. Pretreatment of 2,6-dichloro-4-nitrophenol (DCNP), a broad-spectrum sulfotransferase (SULT) inhibitor, significantly attenuated the formation of the GSH conjugate in LHCl-treated hepatocytes and animals, indicating the participation of SULTs in metabolic activation of LHCl. Moreover, pretreatment with DCNP displayed significant protection against the observed cytotoxicity in rat primary hepatocytes, which suggests a correlation of the bioactivation of LHCl mediated by SULTs with LHCl-induced hepatotoxicity.

Intravenous labetalol versus oral nifedipine for acute hypertension in pregnancy: effects on cerebral perfusion pressure.

BACKGROUND: Pregnant women with preeclampsia have been found to have elevated cerebral perfusion pressure and impaired cerebral autoregulation compared with normal pregnant women. Transcranial Doppler is a noninvasive technique used to estimate cerebral perfusion pressure. The effects of different antihypertensive medications on cerebral perfusion pressure in preeclampsia are unknown. OBJECTIVE: To compare the change in cerebral perfusion pressure before and after intravenous labetalol vs oral nifedipine in the setting of acute severe hypertension in pregnancy. STUDY DESIGN: This is a prospective cohort study of pregnant women between 24 and 42 weeks' gestation with severe hypertension (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥110 mm Hg). Women who consented to the study and received either intravenous labetalol or oral nifedipine were included. Exclusion criteria included active labor or receipt of any antihypertensive medication within 2 hours of initial cerebral perfusion pressure measurement. Peripheral blood pressure and transcranial Doppler studies for middle cerebral artery hemodynamics were performed prior to the administration of antihypertensive medications and repeated 30 minutes after medication administration. RESULTS: A total of 16 women with acute severe hypertension were enrolled; 8 received intravenous labetalol and 8 received oral nifedipine. There were no significant differences between the labetalol and nifedipine groups in baseline characteristics such as maternal age, race and ethnicity, payment, hospital site, body mass index, nulliparity, gestational age, preexisting diabetes mellitus or chronic hypertension, fetal growth restriction, magnesium sulfate administration, and symptomatology (P>.05). When examined 30 minutes after the administration of either intravenous labetalol or oral nifedipine, there was a significantly greater decrease in systolic blood pressure (-9.8 mm Hg vs -39 mm Hg; P=.003), mean arterial pressure (-7.1 mm Hg vs -22.3 mm Hg; P=.02), and cerebral perfusion pressure (-2.5 mm Hg vs -27.7 mm Hg; P=.01) in the nifedipine group. There was no statistically significant decrease in diastolic blood pressure (-12.9 mm Hg vs -5.4 mm Hg; P=.15). The change in middle cerebral artery velocity by transcranial Doppler was compared between the groups and was not different (0.07 cm/s vs 0.16 cm/s; P=.64). CONCLUSION: Oral nifedipine resulted in a significant decrease in cerebral perfusion pressure, whereas labetalol did not, after administration for acute severe hypertension among women with preeclampsia. This decrease seems to be driven by a decrease in peripheral arterial blood pressure rather than a direct change in cerebral blood flow.

Effects of nitroglycerin versus labetalol on peripheral perfusion during deliberate hypotension for sinus endoscopic surgery: a randomized, controlled, double-blinded trial.

BACKGROUND: Deliberate hypotension is used to provide a bloodless field during functional endoscopic sinus surgery; however, the impact of controlled hypotension during anesthesia on peripheral tissue perfusion has not been extensively evaluated. The aim of this study was to compare the impact of nitroglycerin- versus labetalol-induced hypotension on peripheral perfusion. METHODS: The present randomized, double-blinded, controlled trial included adult patients undergoing endoscopic sinus surgery. Patients were allocated to one of two groups according to the drug received for induction of deliberate hypotension: nitroglycerin (n = 20) or labetalol (n = 20). Mean arterial pressure was maintained at 55-65 mmHg in both groups. Both study groups were compared according to pulse oximeter-derived peripheral perfusion index (primary outcome), serum lactate level, mean arterial pressure, heart rate, surgical field score, and intraoperative blood loss. RESULTS: Forty patients were included in the final analysis. The nitroglycerin group exhibited a higher peripheral perfusion index at nearly all records (p < 0.0001) and lower postoperative serum lactate levels (1.3 ± 0.2 mmol/L vs. 1.7 ± 0.4 mmol/L; p = 0.001) than the labetalol group. The peripheral perfusion index was higher in the nitroglycerin group than at baseline at most intraoperative readings. The median surgical field score was modestly lower in the labetalol group than in the nitroglycerin group in the first 20 min (2 [interquartile range (IQR) 2-2.5] versus 1.5 [IQR 1-2]; p = 0.001). Both groups demonstrated comparable and acceptable surgical field scores in all subsequent readings. CONCLUSION: Nitroglycerin-induced deliberate hypotension was accompanied by higher peripheral perfusion index and lower serum lactate levels than labetalol-induced deliberate hypotension during sinus endoscopic surgery. TRIAL REGISTRATION: The study was registered at clinicaltrials registry system with trial number: NCT03809065. Registered at 19 January 2019. This study adheres to CONSORT guidelines.

Nicardipine Reduces Blood Pressure Variability After Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Blood pressure variability (BPV) is an independent predictor for early hematoma expansion, neurologic deterioration, and mortality. There are no studies on the effect of intravenous (IV) antihypertensive drugs on BPV. We sought to determine whether patients have more BPV with certain antihypertensive agents, in particular the effect of IV nicardipine. METHODS: We conducted a single-center, retrospective chart review of individuals diagnosed with spontaneous intracerebral hemorrhage (ICH) receiving labetalol, hydralazine, and/or nicardipine within 24 h of hospital admission to assess the primary endpoint of BPV, defined as the standard deviation of systolic BP, with labetalol and/or hydralazine compared to nicardipine ± labetalol and/or hydralazine. Repeated measures linear regression was performed to compare BPV over 24 h between regimens, and Cox proportional hazards regression was used to compare the time to goal SBP between regimens. RESULTS: Of the 1330 patients screened, 272 were included in our analysis; those included had a mean age of 69 years with 87.9% of Caucasian race. A total of 164 patients received IV bolus antihypertensives alone (labetalol, hydralazine or both), and 108 patients received IV nicardipine with or without additional IV boluses (labetalol, hydralazine, or both). Those who had IV nicardipine had significantly less BPV (p = 0.04) and was more likely to attain an SBP goal < 140 mmHg (p < 0.01). CONCLUSION: Our study suggests patients with ICH who do not receive a nicardipine-based antihypertensive regimen have more BPV, which has been associated with poor clinical outcomes. Prospective, randomized, controlled trials are needed to determine the impact of specific antihypertensive regimens on clinical outcomes.

Comparing the effect of dexmedetomidine and labetalol on hemodynamic variables in patients undergoing microlaryngoscopy.

INTRODUCTION: This study was conducted to compare the effect of dexmedetomidine and labetalol on hemodynamic variables in patients undergoing microlaryngoscopy. MATERIAL AND METHODS: In this randomized clinical trial study 70 patients undergoing microlaryngoscopy were involved. The patients were randomly assigned into two groups. Patients in dexmedetomidine group received 0.5 µg/kg of dexmedetomidine diluted in 100 ml of saline solution and the patients in the second group received 0.25 mg/kg of labetalol before anesthesia induction. At the beginning of the surgery, dexmedetomidine was infused at the dose of 0.4 µg/kg/h in the dexmedetomidine group, and labetalol at the dose of 1.8 mg/kg/h in the labetalol group. Patients' systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and heart rate at different times and anesthesia and surgery duration, recovery time and dose of prescribed propofol were recorded and compared between two groups. RESULTS: There was a significant difference in mean systolic blood pressure, mean diastolic blood pressure, mean arterial blood pressure and mean heart rate between two groups at different times (p value < 0.05). CONCLUSION: The results of this study indicated that dexmedetomidine had higher efficacy, compared to labetalol, in reducing diastolic blood pressure, systolic blood pressure, heart rate, and mean arterial blood pressure following microlaryngoscopy.

α1-and ß-adrenergic antagonist labetalol induces morphological changes in human erythrocytes.

Labetalol is one of the most used drugs for the treatment of hypertension. This molecule is able to bind to both alpha-1 (α1) and beta (ß) adrenergic receptors present in vascular smooth muscle among other tissues. It has been determined that human erythrocytes possess both alpha receptors and beta-adrenergic receptors expressed on their surface. The objective of this work was to study the effect of labetalol on the morphology of human erythrocytes. To accomplish this goal, human erythrocytes and model membranes built of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) were used. These lipid species are present in the outer and inner monolayers of the red blood cell membrane, respectively. Our findings obtained by X-ray diffraction and differential scanning calorimetry (DSC) indicate that labetalol interacted with both lipids in a process dependent on concentration. In fact, at low concentrations labetalol preferentially interacted with DMPE. On the other hand, results obtained by scanning electron microscopy (SEM) showed that labetalol alters the normal biconcave form of erythrocytes to stomatocytes and knizocytes (cells with one or more cavities, respectively). According to the bilayers couple hypothesis, this result implied that the drug inserted in the inner monolayer of the human erythrocyte membrane.

Outcomes of "diabetes-friendly" vs "diabetes-unfriendly" ß-blockers in older nursing home residents with diabetes after acute myocardial infarction.

AIMS: To assess whether nursing home (NH) residents with type 2 diabetes mellitus (T2D) preferentially received "T2D-friendly" (vs "T2D-unfriendly") ß-blockers after acute myocardial infarction (AMI), and to evaluate the comparative effects of the two groups of ß-blockers. MATERIALS AND METHODS: This new-user retrospective cohort study of NH residents with AMI from May 2007 to March 2010 used national data from the Minimum Data Set and Medicare system. T2D-friendly ß-blockers were those hypothesized to increase peripheral glucose uptake through vasodilation: carvedilol, nebivolol and labetalol. Primary outcomes were hospitalizations for hypoglycaemia and hyperglycaemia in the 90 days after AMI. Secondary outcomes were functional decline, death, all-cause re-hospitalization and fracture hospitalization. We compared outcomes using binomial and multinomial logistic regression models after propensity score matching. RESULTS: Of 2855 NH residents with T2D, 29% initiated a T2D-friendly ß-blocker vs 24% of 6098 without T2D (P < 0.001). For primary outcomes among residents with T2D, T2D-friendly vs T2D-unfriendly ß-blockers were associated with a reduction in hospitalized hyperglycaemia (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.21-0.97), but unassociated with hypoglycaemia (OR 2.05, 95% CI 0.82-5.10). For secondary outcomes, T2D-friendly ß-blockers were associated with a greater rate of re-hospitalization (OR 1.26, 95% CI 1.01-1.57), but not death (OR 1.06, 95% CI 0.85-1.32), functional decline (OR 0.91, 95% CI 0.70-1.19), or fracture (OR 1.69, 95% CI 0.40-7.08). CONCLUSIONS: In older NH residents with T2D, T2D-friendly ß-blocker use was associated with a lower rate of hospitalization for hyperglycaemia, but a higher rate of all-cause re-hospitalization.

Associations of polymorphisms of CYP2D6 and CYP2C9 with early onset severe pre-eclampsia and response to labetalol therapy.

PURPOSE: Early onset preeclampsia (PPE) contributes to life-threatening maternal complications and fetal demise. Pharmacogenomics is a precision medicine, and metabolizing enzymes responsive to antihypertensive remains understudied. The aim of this study was to evaluate the associations of polymorphisms of cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) and cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) with PPE and the relationship among CYP2D6, CYP2C9 polymorphisms and response to labetalol therapy. METHODS: Totally 105 gravidas diagnosed with PPE (case) and 103 healthy gravidas (control) were recruited between August 2013 and July 2016. Labetalol was given to control blood pressures (BP) with PPE. If labetalol administration alone did not exceed the mean dose and effectively controlled the BP, it would be considered to be valid (n = 75). Genotype and allele frequencies of CYP2C9 gene (rs1057910 and rs4918758) and CYP2D6 gene (rs1065852, rs28371725, rs35742686, and rs3892097) were analyzed by TaqMan PCR. Differences in the genotype and allele frequencies were compared between case-control groups, and the responsive and nonresponsive to labetalol in PPE. RESULTS: Out of six variants, only CC and CT genotypes of the CYP2D6 variants (rs28371725) in PPE were significantly higher than those in the control group [18.1% (19/105) vs 14.6% (15/103); 56.2% (59/105) vs 42.7% (44/103); χ2 = 6.707]. However, there were no differences in maternal age, diastolic pressure, BMI, BW, serum triglyceride, and creatinine were observed among women with CC, CT, or TT genotype of CYP2D6 gene rs28371725 in the experimental group (all P > 0.05). Compared with the gravidas with CT or TT genotype of CYP2D6 gene rs28371725, those with CC genotype had longer gestational age [(32.5 ± 2.1) vs (29.5 ± 1.8) and (29.8 ± 2.2) weeks] and higher plasma albumin [(27.2 ± 9.3) vs (20.3 ± 10.4) and (22.5 ± 7.4) g/L], but lower systolic pressure and 24 h urine protein (LSD test, all P < 0.05). The G allele frequency in CYP2D6 gene rs1065852 nonresponsive to labetalol group was higher than that in responsive labetalol group [93.3% (56/60) vs 76.0% (114/150), χ2 = 8.351, P = 0.004]. CONCLUSIONS: The polymorphism of CYP2D6 gene rs28371725 may be associated with PPE, and the allele of G in CYP2D6 gene rs1065852 may be associated with the efficacy of labetalol in treatment of PPE.

Chemical Sympathectomy, but not Adrenergic Blockade, Improves Stroke Outcome.

BACKGROUND: A robust adrenergic response following stroke impairs lymphocyte function, which may prevent the development of autoimmune responses to brain antigens. We tested whether inhibition of the sympathetic response after stroke would increase the propensity for developing autoimmune responses to brain antigens. METHODS: Male Lewis rats were treated with 6-hydroxydopamine (OHDA) prior to middle cerebral artery occlusion (MCAO), labetalol after MCAO, or appropriate controls. Behavior was assessed weekly and animals survived to 1 month at which time ELISPOT assays were done on lymphocytes from spleen and brain to determine the Th1 and Th17 responses to myelin basic protein (MBP), ovalbumin (OVA), and concanavalin A. A subset of animals was sacrificed 72 hours after MCAO for evaluation of infarct volume and lymphocyte responsiveness. Plasma C-reactive protein (CRP) was measured as a biomarker of systemic inflammation. RESULTS: Despite similar initial stroke severity and infarct volumes, 6-OHDA-treated animals lost less weight and experienced less hyperthermia after stroke. 6-OHDA-treated animals also had decreased CRP in circulation early after stroke and experienced better neurological outcomes at 1 month. The Th1 and Th17 responses to MBP did not differ among treatment groups at 1 month, but the Th1 response to OVA in spleen was more robust in labetalol and less robust in 6-OHDA-treated animals. CONCLUSIONS: Chemical sympathectomy with 6-OHDA, but not treatment with labetalol, decreased systemic markers of inflammation early after stroke and improved long-term outcome. An increase in Th1 and Th17 responses to MBP was not seen with inhibition of the sympathetic response.

Antihypertensive methyldopa, labetalol, hydralazine, and clonidine reversed tumour necrosis factor-α inhibited endothelial nitric oxide synthase expression in endothelial-trophoblast cellular networks.

Medications used to control hypertension in pregnancy also improve trophoblast and endothelial cellular interaction in vitro. Tumour necrosis factor-α (TNF-α) inhibits trophoblast and endothelial cellular interactions and simultaneously decreases endothelial nitric oxide synthase (eNOS) expression. This study investigated whether antihypertensive medications improved these cellular interactions by modulating eNOS and inducible nitric oxide synthase (iNOS) expression. Human uterine myometrial microvascular endothelial cells (UtMVECs) were pre-incubated with (or without) low dose TNF-α (0.5 ng/mL) or TNF-α plus soluble fms-like tyrosine kinase-1 (sFlt-1) (100 ng/mL). The endothelial cells were cultured on Matrigel. After endothelial cellular networks appeared, trophoblast derived HTR-8/SVneo cells were co-cultured in the presence of clinically relevant doses of methyldopa, labetalol, hydralazine or clonidine for 24 hours. Cells were retrieved from the Matrigel to extract mRNA and eNOS and iNOS expression were examined by quantitative PCR. Methyldopa, labetalol, hydralazine and clonidine reversed the inhibitory effect of TNF-α on eNOS mRNA expression. After pre-incubating endothelial cells with TNF-α and sFlt-1, all the medications except methyldopa lost their effect on eNOS mRNA expression. In the absence of TNF-α, antihypertensive medications did not change eNOS expression. The mRNA expression of iNOS was not affected by TNF-α or any medications. This study shows that selected antihypertensive medications used in the treatment of hypertension in pregnancy increase eNOS expression in vitro when induced by the inflammatory TNF-α. The anti-angiogenic molecule sFlt-1 may antagonise the potential benefit of these medications by interfering with the NOS pathway.

Acute Toxicity from Topical Cocaine for Epistaxis: Treatment with Labetalol.

BACKGROUND: Topical cocaine is sometimes used for the treatment of epistaxis, as it has both potent anesthetic and vasoconstrictive properties. Cocaine has unpredictable cardiovascular effects, such as sudden hypertension, tachycardia, coronary arterial vasoconstriction, and dysrhythmia. CASE REPORT: We report a case of acute iatrogenic cardiovascular toxicity from the use of topical cocaine in a 56-year-old man presenting to the Emergency Department with profound epistaxis. To prepare for cauterization and nasal packing, the patient received 4% topical cocaine-soaked nasal pledgets. He became hypertensive, tachypneic, tachycardic, and dysphoric immediately after administration. To directly counter these adverse hyperadrenergic effects, the patient was given 10 mg intravenous labetalol, a mixed ß- and α-blocker. This instantly normalized his vital signs and adverse subjective effects. His epistaxis was successfully treated, and he was discharged 1 h later. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We believe that emergency physicians should be aware of the unpredictable acute cardiovascular toxicity of topical cocaine. Labetalol represents an effective first-line treatment, which, unlike benzodiazepines, directly counters the pharmacologic effects of cocaine and has no respiratory or sedative side effects. Labetalol, with its mixed ß/α-blocking properties, also mitigates the potential for "unopposed α-stimulation."

The sympathetic nervous system is controlled by transient receptor potential vanilloid 1 in the regulation of body temperature.

Transient receptor potential vanilloid 1 (TRPV1) is involved in sensory nerve nociceptive signaling. Recently, it has been discovered that TRPV1 receptors also regulate basal body temperature in multiple species from mice to humans. In the present study, we investigated whether TRPV1 modulates basal sympathetic nervous system (SNS) activity. C57BL6/J wild-type (WT) mice and TRPV1 knockout (KO) mice were implanted with radiotelemetry probes for measurement of core body temperature. AMG9810 (50 mg/kg) or vehicle (2% DMSO/5% Tween 80/10 ml/kg saline) was injected intraperitoneally. Adrenoceptor antagonists or vehicle (5 ml/kg saline) was injected subcutaneously. In WT mice, the TRPV1 antagonist, AMG9810, caused significant hyperthermia, associated with increased noradrenaline concentrations in brown adipose tissue. The hyperthermia was significantly attenuated by the ß-adrenoceptor antagonist propranolol, the mixed α-/ß-adrenoceptor antagonist labetalol, and the α1-adrenoceptor antagonist prazosin. TRPV1 KO mice have a normal basal body temperature, indicative of developmental compensation. d-Amphetamine (potent sympathomimetic) caused hyperthermia in WT mice, which was reduced in TRPV1 KO mice, suggesting a decreased sympathetic drive in KOs. This study provides new evidence that TRPV1 controls thermoregulation upstream of the SNS, providing a potential therapeutic target for sympathetic hyperactivity thermoregulatory disorders.

Olfactory perceptual learning requires action of noradrenaline in the olfactory bulb: comparison with olfactory associative learning.

Noradrenaline contributes to olfactory-guided behaviors but its role in olfactory learning during adulthood is poorly documented. We investigated its implication in olfactory associative and perceptual learning using local infusion of mixed α1-ß adrenergic receptor antagonist (labetalol) in the adult mouse olfactory bulb. We reported that associative learning, as opposed to perceptual learning, was not affected by labetalol infusions in the olfactory bulb. Accordingly, this treatment during associative learning did not affect the survival of bulbar adult-born neurons. Altogether, our results suggest that the noradrenergic system plays different parts in specific olfactory learning tasks and their neurogenic correlates.