Repurposing old drugs as novel inhibitors of human MIF from structural and functional analysis.

Human macrophage migration inhibitory factor (MIF) is an important pro-inflammatory cytokine that plays multiple pleiotropic functions. It is considered as a promising therapeutic target for the infectious, autoimmune, and cardiovascular diseases and cancers. The development of MIF inhibitors has not been translated into clinical success despite decades of research. Given the time and cost of developing new drugs, existing drugs with clarified safety and pharmacokinetics are explored for their potential as novel MIF inhibitors. This study identified five known drugs that could inhibit MIF's tautomerase activity and MIF-mediated cell chemotaxis in RAW264.7 cells. It was found that compounds D2 (histamine), D5 (metaraminol), and D8 (nebivolol) exhibited micromolar-range inhibition potency close to the positive control ISO-1. Kinetics and the mechanism for inhibition were subsequently determined. Moreover, the detailed inhibitor-binding patterns were investigated by X-ray crystallography, computational molecular docking, and structure-based analysis. Therefore, this study elucidates the molecular mechanism of repurposed drugs acting on MIF and provides a structural foundation for lead optimization to promote the clinical development of MIF-targeted drugs.

Metaraminol use during spinal anaesthesia for caesarean section: a meta-analysis of randomised controlled trials.

INTRODUCTION: During caesarean section, the use of a vasopressor is often required to achieve haemodynamic stability of the parturient. Metaraminol is a vasopressor used in this context in some countries. However, the differences between metaraminol and other vasopressors remain unclear. METHODS: A search of the PubMed, Cochrane Library, and Embase databases was performed to identify randomised controlled trials comparing the use of metaraminol with other vasopressors during spinal anaesthesia at caesarean section. The selected studies were subjected to meta-analysis and risk-of-bias assessment. RESULTS: Four randomised, controlled trials met the selection criteria and 409 parturients who underwent an elective caesarean section were included in this meta-analysis. The quality of these trials was good. Metaraminol was associated with higher umbilical arterial pH (standardised mean difference [SMD] 0.82, 95% CI 0.01 to 1.62, P=0.05); a lower incidence of fetal acidosis (RR 0.08, 95% CI 0.01 to 0.63, P=0.02); and a lower incidence of nausea or vomiting (RR 0.16, 95% CI 0.04 to 0.57, P=0.0005) than was ephedrine. Metaraminol resulted in higher umbilical arterial pH (SMD 0.42, 95% CI 0.15 to 0.68, P=0.002) but a higher incidence of reactive hypertension (RR 1.80, 95% CI 1.32 to 2.46, P=0.0002) than did phenylephrine. CONCLUSION: The results of this study showed that for spinal anaesthesia at elective caesarean section, metaraminol may be a more suitable vasopressor than ephedrine and its effects are at least not inferior to those of phenylephrine.

GABAergic modulation of noradrenaline release caused by blood pressure changes in the rat median preoptic area.

Experiments using in-vivo microdialysis methods were conducted to investigate whether blood pressure changes cause an alteration in the release of noradrenaline (NA) in the median preoptic nucleus (MnPO) and whether the γ-aminobutyric acid (GABA) receptor mechanism is involved in the modulation of the pressure response-induced alteration in the NA release. In urethane-anesthetized male rats, intravenous administration of metaraminol, an α-agonist, significantly produced an increase in dialysate NA concentration in the MnPO area accompanied by an elevation in the mean arterial pressure (MAP). Perfusion with GABA (10 µM) through the dialysis probe elicited a significant decrease in either MAP or the NA concentration in the MnPO area. Similar perfusion with either the GABAA receptor antagonist bicuculline (10 µM) or the GABAB receptor antagonist phaclofen (10 µM) caused a significant increase in both MAP and the NA release in the MnPO area. Either bicuculline or phaclofen administered together with the metaraminol further enhanced the metaraminol-induced MAP and NA release in the MnPO area. The degree of increases in the both MAP of the NA release was significantly greater in the bicuculline-treated group than in the phaclofen-treated group. These results suggest that the NA release in the MnPO area may be potentiated during an elevation in arterial pressure caused by the metaraminol injection and imply that the NA release may be mediated through GABAA receptors rather than GABAB receptors in the MnPO area.

Chronic stress accelerates the development of endometriosis in mouse through adrenergic receptor ß2.

STUDY QUESTION: Does chronic stress in mice accelerate the development of endometriosis, and, if so, through what mechanism? SUMMARY ANSWER: Exposure to chronic stress accelerates the development of endometriosis and exacerbates the endometriosis-associated generalized hyperalgesia, most likely through activation of the adrenoceptor ß2 (ADRB2) and cAMP responsive element-binding protein (CREB). WHAT IS KNOWN ALREADY: Women with endometriosis tend to have higher levels of psychological stress, which is known to impact negatively on health in general and to promote tumor growth and metastasis in particular. Exposure to chronic stress before and after the induction of endometriosis is reported to increase lesion sizes in rodents, but it is unclear whether adrenoceptors are involved or not in the stress-promoted development of endometriosis. STUDY DESIGN, SIZE, DURATION: Three independent, prospective, randomized mouse experimentations. A total of 184 virgin female Balb/C mice were used. PARTICIPANTS/MATERIALS, SETTING, METHODS: In Experiment 1, the mice were randomly divided into four groups: the control group, which received no stress; the before, after and both groups, which received immobilization stress before, after and both before and after the induction of endometriosis, respectively. In Experiment 2, mice were randomly divided into four groups one day after the induction of endometriosis: phosphate buffer saline (PBS) and propranolol (PROP) groups, which received the mini-pump containing, respectively, PBS only and propranolol (a non-selective ADRB antagonist) but no stress, STR+PROP and STR+PBS groups, which received stress and the mini-pump containing, respectively, propranolol and PBS. The immobilization stress started after the insertion of mini-pumps. In Experiment 3, mice were induced with endometriosis. Three days after the induction, they were randomly divided into four groups: control, ADRAa, ADRB2a, and ADRBa, which received the mini-pump containing solution only, metaraminol (a non-specific α adrenoceptor agonist), tebutaline (a specific ADRB2 agonist), or isoproterenol (a non-specific ADRB agonist), respectively. In all three experiments, the bodyweight and hotplate latency were evaluated before sacrifice 14 days after the induction. In all experimentations, the lesion weight was evaluated and the harvested ectopic endometrial tissue samples were subjected to immunohistochemistry analysis of vascular endothelial growth factor (VEGF), CD31-positive microvessels, proliferating cell nuclear antigen (PCNA), phosphorylated CREB, ADRB1, ADRB2, ADRB3, adrenergic receptor α1 (ADRA1) and ADRA2. MAIN RESULTS AND THE ROLE OF CHANCE: Exposure to chronic stress accelerated the development of endometriosis and exacerbated the endometriosis-associated generalized hyperalgesia. This promotional effect is likely to be mediated through the systemic activation of the sympatho-adreno-medullary (SAM) axis, which results in subsequent release of catecholamines. The surging catecholamines may activate ADRB2 and CREB, yielding increased angiogenesis and cellular proliferation in ectopic endometrium in mice with induced endometriosis. In addition, ß adrenergic receptor blockade completely abolished the promotional effect of chronic stress, likely through suppression of ADRB2 and CREB activation, thus suppressing angiogenesis and proliferation. Moreover, a non-specific adrenergic ß agonist and a specific adrenergic ß2 agonist, but not non-specific adrenergic α agonist, acted similarly to chronic stress, accelerating the development of endometriosis and exacerbating the generalized hyperalgesia in mice with pre-existing endometriosis. LARGE SCALE DATA: NA. LIMITATIONS, REASONS FOR CAUTION: This study is limited by the use of immunohistochemistry analyses only and the lack of molecular data. WIDER IMPLICATIONS OF THE FINDINGS: The present study provides the experimental evidence that chronic stress can promote the development of endometriosis through the activation of ADRB2. Given ADRB2 is also expressed in human endometriosis and appears to be functional, and in light of recent awareness that adrenergic signaling plays critical roles in tumorigenesis, it is likely that adrenergic signaling may play important roles in the development of endometriosis and is potentially a target for intervention. STUDY FUNDING/COMPETING INTERESTS: This research was supported in part by grants (81270676,  81471434 and 81530040  to S.W.G.;  81370695 and 81671436  to X.S.L.) from the National Natural Science Foundation of China, and grant (2013ZYJB0019 to X.S.L.) from Shanghai Municipal Commission of Health and Family Planning. None of the authors has anything to disclose.

In silico drug re-purposing against African sleeping sickness using GlcNAc-PI de-N-acetylase as an experimental target.

Trypanosoma brucei is a protozoan that causes African sleeping sickness in humans. Many glycoconjugate compounds are present on the entire cell surface of Trypanosoma brucei to control the infectivity and survival of this pathogen. These gycoconjugates are anchored to the plasma membrane with the help of glycosyl phosphatidyl inositol (GPI) anchors. This type of anchor is much more common in protozoans than in other eukaryotes. The second step of glycosyl phosphatidyl inositol (GPI) anchor biosynthesis is catalyzed by an enzyme, which is GlcNAc-PI de-N-acetylase. GlcNAc-PI de-N-acetylase has a conserved GPI domain, which is responsible for the functionality of this enzyme. In this study, the three-dimensional structure of the target is modelled by I-TASSER and the ligand is modelled by PRODRG server. It is found that the predicted active site residues of the GPI domain are ultra-conserved for the Trypanosomatidae family. The predicted active site residues are His41, Pro42, Asp43, Asp44, Met47, Phe48, Ser74, Arg80, His103, Val144, Ser145, His147 and His150. Two hydrogen bond acceptors and four hydrogen bond donors are found in the modelled pharmacophore. All compounds of the Drugbank database and twenty three known inhibitors have been considered for structure based virtual screening. This work is focused on approved drugs because they are already tested for safety and effectiveness in humans. After the structure-based virtual screening, seventeen approved drugs and two inhibitors are found, which interact with the ligand on the basis of the designed pharmacophore. The docking has been performed for the resultant seventeen approved drugs and two known inhibitors. Two approved drugs have negative binding energy and their pKa values are similar to the selected known inhibitors. The result of this study suggests that the approved drugs Ethambutol (DB00330) and Metaraminol (DB00610) may prove useful in the treatment of African sleeping sickness.

Endotoxaemic myocardial dysfunction: the role of coronary driving pressure in subendocardial perfusion.

OBJECTIVE: To investigate the role of coronary driving pressure (CDP) in myocardial microcirculatory blood flow during sepsis. We hypothesised that in septic shock there is an impaired autoregulation of microcirculation, and blood flow is totally dependent on CDP. We analysed the effect of lipopolysaccharide (LPS)-induced shock on myocardial microcirculation, separating subendocardial and epicardial areas. We then studied the effect of CDP increases using noradrenaline (NOR) or metaraminol (Aramine [ARA]) on myocardial microcirculation and function, and we analysed the effect of volume infusion on CDP and myocardial function. DESIGN AND SETTING: Endotoxaemia was induced in male Wistar rats by an intraperitoneal injection of LPS 10 mg/kg. Animals were divided into a control (CT) group, an LPS-injected group, and an LPS-injected group treated with saline fluid, NOR or ARA. MAIN OUTCOME MEASURES: Ninety minutes later, a haemodynamic evaluation was performed. NOR or ARA were used to manage the mean arterial pressure (MAP) and CDP, and we inserted a catheter into the left ventricle to measure cardiac parameters. To measure blood flow in the myocardium and other organs, microspheres were introduced into the left ventricle using an infusion pump. RESULTS: After LPS treatment, left ventricular (LV) systolic function (dP/dt max) and diastolic function (dP/dt min) decreased by 34% and 15%, respectively, and load-independent indices (LV contractility in ejection phase and dP/dt max÷end-diastolic volume) were reduced. The CDP was also reduced (by 58%) in the endotoxaemic rats. Myocardial blood flow was reduced (by 80%) in animals with an MAP≤65 mmHg. NOR increased the CDP (LPS, 38 mmHg [SEM, 2 mmHg]; LPS+NOR, 59 mmHg [SEM, 3 mmHg]) and microcirculatory perfusion (LPS, 2 mL/min/g tissue [SEM, 0.6 mL/min/g]; LPS+NOR, 6.2 mL/min/g [SEM, 0.8 mL/min/g]). ARA was also effective in improve microcirculation but saline volume infusion was ineffective in improving CDP or myocardial function. CDP showed a significant correlation with subendocardial blood flow. CONCLUSIONS: Myocardial blood flow in the LV subendocardium and the right ventricle decreases in endotoxaemic rats. Increasing CDP improves myocardial blood flow and function. Thus, in endotoxaemia, microcirculatory blood flow is pressure dependent, suggesting that it may be beneficial to treat patients with sepsis using a higher CDP.

Multifractal analysis of hemodynamic behavior: intraoperative instability and its pharmacological manipulation.

BACKGROUND: Physiologic instability is a common clinical problem in the critically ill. Many natural feedback systems are nonlinear, and seemingly random fluctuations may result from the amplification of external perturbations or even arise de novo as a consequence of their underlying dynamics. Characterization of the underlying nonlinear state may be of clinical importance, providing a technique to monitor complex physiology in real-time, guiding patient care and improving outcomes. METHODS: We employ the wavelet modulus maxima technique to characterize the multifractal properties of heart rate and mean arterial pressure physiology retrospectively for four patients during open abdominal aortic aneurysm repair. We calculated point-estimates for the dominant Hölder exponent (hm, hm) and multifractal spectrum width-at-half-height for both heart rate and mean arterial pressure signals. We investigated how these parameters changed with the administration of an intravenous vasoconstrictor and examined how this varied with atropine pretreatment. RESULTS: Hypotensive patients showed lower values of hm, consistent with a more highly fluctuating and complex behavior. Treatment with a vasoconstrictor led to a transient increase in hm, revealing the appearance of longer-range correlations, but did not impact hm. On the other hand, prior treatment with atropine had no effect on hm behavior but did tend to increase hm. CONCLUSIONS: Hypotension leads to a reduction in dominant Hölder exponents for mean arterial pressure, demonstrating an increasing signal complexity consistent with the activation of important homeokinetic processes. Conversely, pharmacological interventions may also alter the underlying dynamics. Pharmacological restoration of homeostasis leads to system decomplexification, suggesting that homeokinetic mechanisms are derecruited as homeostasis is restored.

Numerical optimization studies of cardiovascular-rotary blood pump interaction.

A heart-pump interaction model has been developed based on animal experimental measurements obtained with a rotary blood pump in situ. Five canine experiments were performed to investigate the interaction between the cardiovascular system and the implantable rotary blood pump over a wide range of operating conditions, including variations in cardiac contractility and heart rate, systemic vascular resistance (SVR), and total blood volume (V(total) ). It was observed in our experiments that SVR decreased with increasing mean pump speed under the healthy condition, but was relatively constant during the speed ramp study under reduced cardiac contractility conditions. Furthermore, we also found a significant increase in pulmonary vascular resistance with increasing mean pump speed and decreasing total blood volume, despite a relatively constant SVR. Least squares parameter estimation methods were utilized to fit a subset of model parameters in order to achieve better agreement with the experimental data and to evaluate the robustness and validity of the model under various operating conditions. The fitted model produced reasonable agreement with the experimental measurements, both in terms of mean values and steady-state waveforms. In addition, all the optimized parameters were within physiological limits.

A comparison of three minimally invasive cardiac output devices with thermodilution in elective cardiac surgery.

This study compared the cardiac output responses to haemodynamic interventions as measured by three minimally invasive monitors (Oesophageal Doppler Monitor the VigileoFlotrac and the LiDCOrapid) to the responses measured concurrently using thermodilution, in cardiac surgical patients. The study also assessed the precision and bias of these monitors in relation to thermodilution measurements. After a fluid bolus of at least 250 ml, the measured change in cardiac output was different among the devices, showing an increase with thermodilution in 82% of measurements, Oesophageal Doppler Monitor 68%, VigileoFlotrac 57% and LiDCOrapid 41%. When comparing the test devices to thermodilution, the kappa statistic showed at best only fair agreement, Oesophageal Doppler Monitor 0.34, LiDCOrapid 0.28 and VigileoFlotrac -0.03. After vasopressor administration, there was also significant variation in the change in cardiac output measured by the devices. Using Bland-Altman analysis, the precision of the devices in comparison to thermodilution showed minimal bias, but wide limits of agreement with percentage errors of Oesophageal Doppler Monitor 64.5%, VigileoFlotrac 47.6% and LiDCOrapid 54.2%. These findings indicate that these three devices differ in their responses, do not always provide the same information as thermodilution and should not be used interchangeably to track cardiac output changes.

Molecular imaging of cardiac sympathetic innervation by 11C-mHED and PET: from man to mouse?

UNLABELLED: Dysfunction of the sympathetic nervous system underlies many cardiac diseases and can be assessed by molecular imaging using PET in humans. Small-animal PET should enable noninvasive quantitation of the sympathetic nervous system in mouse models of human disease. For mice, however, the radioactivity needed to give acceptable image quality may be associated with a mass of unlabeled compound sufficient to block the binding of radioligand to its target. The present study assesses the feasibility of using [N-methyl-(11)C]meta-hydroxyephedrine ((11)C-mHED) to measure norepinephrine reuptake in humans, to determine cardiac innervation in mice. METHODS: Anesthetized mice were placed in a small-animal PET scanner. (11)C-mHED (containing 18% precursor metaraminol) was injected via a tail vein into each animal simultaneously. Fifteen minutes later, animals were injected with saline or metaraminol which competes with mHED for norepinephrine reuptake. (18)F-FDG was injected at 60 min to identify heart regions. After reconstruction of the list-mode data, radioactivity in myocardial regions was computed using in-house software, and time-activity curves were plotted. RESULTS: Hearts were clearly visualized after injection of (11)C-mHED. Injection of metaraminol at doses less than 50 nmol x kg(-1) had no effect, whereas doses greater than 100 nmol x kg(-1) caused a dose-dependent loss of specifically bound radioactivity. CONCLUSION: (11)C-mHED was successfully used to visualize and assess myocardial innervation in mice. Uptake of (11)C-mHED is displaceable by the false transmitter metaraminol. The total molar dose of metaraminol and (11)C-mHED must be considered in the analysis of PET data.

A prospective comparison of vasopressor requirement and hemodynamic changes during spinal anesthesia for cesarean delivery in patients with multiple gestation versus singleton pregnancy.

BACKGROUND: It is commonly taught that patients with multiple gestation pregnancy are prone to more severe hypotension during spinal and epidural anesthesia compared to those with singleton pregnancy. However, few quantitative data are available to support this claim. In this study, we prospectively compared vasopressor requirement and hemodynamic changes in patients with multiple gestation versus singleton pregnancy during spinal anesthesia for elective cesarean delivery. METHODS: Forty parturients with multiple gestation and 60 singleton controls who had identical anesthetic management during spinal anesthesia for elective cesarean delivery were enrolled. After IV prehydration, patients received intrathecal bupivacaine-fentanyl and were tilted to the left. A metaraminol infusion was titrated with the target of maintaining systolic blood pressure at 90%-100% of baseline. Vasopressor dose, minimum and maximum values for systolic blood pressure and the incidences of hypotension, hypertension, and nausea/vomiting were compared. RESULTS: All outcome variables were similar between groups. The total dose of metaraminol required until uterine incision was similar in multiple gestation pregnancy (median 2.9 [interquartile range 2.0-3.7] mg) when compared with singleton pregnancy (median 3.1 [interquartile range 2.3-3.9] mg, P = 0.25; median difference 0.30 mg, 95% confidence interval of difference -0.20 to 0.90 mg). Neonatal outcome was similar between groups. CONCLUSION: Patients with multiple gestation pregnancy do not exhibit greater hemodynamic instability during spinal anesthesia for cesarean delivery compared to those with singleton pregnancy.

Growth of Staphylococcus epidermidis in anaesthetic resuscitative drugs: implications for potential contamination.

This controlled laboratory study investigated the survival of Staphylococcus epidermidis (S. epidermidis) over a 24 hour period in four commonly drawn-up anaesthetic resuscitative drugs: suxamethonium, atropine, metaraminol and ephedrine. These drugs were prepared in typical therapeutic concentrations and then inoculated with S. epidermidis. Samples of the inoculated drug preparations were cultured on horse blood agar plates at 0, 2, 6, 12 and 24 hourly intervals and incubated for 24 hours. Colony counts were performed at the end of the incubation period. Suxamethonium, atropine and metaraminol all showed an inhibitory effect on colony counts within the first six hours. There was a more gradual decline of colony counts over a 24 hour period in the ephedrine solution. This decline was similar to that occurring in the normal saline. It is concluded that suxamethonium, atropine and metaraminol do not support the survival of the common skin contaminant, S. epidermidis over a 24 hour period.

Norepinephrine and metaraminol in septic shock: a comparison of the hemodynamic effects.

OBJECTIVE: To compare the effects of norepinephrine and metaraminol on hemodynamics in septic shock patients. DESIGN AND SETTING: Open-label, controlled clinical trial in the general intensive care unit of a university-affiliated hospital. PATIENTS AND PARTICIPANTS: Ten consecutive septic shock patients receiving norepinephrine to maintain the mean arterial pressure higher than 65 mmHg. INTERVENTIONS: Patients were monitored with pulmonary artery catheter and indirect calorimetry. At the baseline hemodynamic variables were obtained during norepinephrine infusion. Subsequently norepinephrine was replaced by metaraminol infusion in a dose sufficient to keep mean arterial pressure constant. After 20 min of stable arterial pressure a new set of measurement was repeated. MEASUREMENTS AND RESULTS: Mean arterial pressure did not differ significantly with norepinephrine or metaraminol; there was no relationship between the norepinephrine and metaraminol doses. Replacement norepinephrine with metaraminol did not modify hemodynamic variables; in particular there were no changes in heart rate, stroke volume index, pulmonary artery occlusion pressure, or oxygen consumption index. CONCLUSIONS: This study shows that metaraminol increases arterial pressure as does norepinephrine in septic shock patients. Despite similar effects of norepinephrine and metaraminol, there was no relationship between the dose of the two drugs.

Cerebellar interpositus nuclear inputs impinge on paraventricular neurons of the hypothalamus in rats.

Several reports have indicated that the cerebellum is involved in regulation of some non-somatic activities through the cerebellohypothalamic projections. Therefore, the modulatory effects of the cerebellar interpositus nucleus (IN) on neuronal activity of the paraventricular nucleus of the hypothalamus (PVN) was investigated in this study by using in vivo extracellular recording technique in rats. We recorded from 115 PVN neurons, 51 (44.3%) responded to the cerebellar IN stimulation. Of the responsive PVN neurons tested for their sensitivity to hypertensive and/or hyperosmotic stimulations, 66.7% (6/9) and 75.0% (6/8) responded to intravenous metaraminol and hypertonic saline administration, respectively. These results demonstrate that the cerebellar IN afferent inputs impinge on the PVN neurons, including those baroreflex-sensitive and osmoresponsive neurons, suggesting that the cerebellum may actively participate in the cardiovascular regulation and osmoregulation through the cerebellohypothalamic projections.

Drinking attenuates the noradrenaline release in the lateral hypothalamic area induced by angiotensin II activation of the subfornical organ in rats.

Experiments were conducted to investigate the role of noradrenergic systems in the lateral hypothalamus area (LHA) in the water intake caused by injection of angiotensin II (ANG II) into the subfornical organ (SFO) in rats. Intracerebral microdialysis techniques were utilized to quantify the extracellular content of noradrenaline (NA) in the LHA. Microinjection of ANG II into the SFO significantly increased NA release in the LHA when water was not available for drinking. The increase in the release of NA in the LHA was significantly attenuated by water intake. In urethane-anesthetized rats, injections of ANG II into the SFO significantly enhanced the release of NA in the LHA that accompanied an elevation in mean arterial pressure (MAP). Intravenous administration of the alpha-agonist metaraminol, on the other hand, significantly decreased the NA release in the LHA that accompanied an increase in MAP, suggesting that the enhanced NA release in the LHA caused by ANG II into the SFO may be not mediated by increasing in arterial pressure. These results show the involvement of the noradrenergic systems in the LHA in the dipsogenic response induced by angiotensinergic activation of the SFO.

Comparison of metaraminol and ephedrine infusions for maintaining arterial pressure during spinal anesthesia for elective cesarean section.

BACKGROUND: Although ephedrine is usually recommended as the first-line vasopressor in obstetrics, its superiority over other vasopressors has not been proven in humans. METHODS: In a double-blind study, the authors randomized women having elective cesarean section with spinal anesthesia to receive an intravenous infusion of ephedrine, starting at 5 mg/min (n = 25), or metaraminol, starting at 0.25 mg/min (n = 25), titrated to maintain systolic arterial pressure in the target range 90-100% of baseline. Umbilical cord gases, maternal hemodynamics, uterine artery puLsatility index, and Apgar scores were compared. RESULTS: Systolic arterial pressure was maintained more closely in the target range in the metaraminol group compared with the ephedrine group. In the metaraminol group, umbilical arterial pH was greater (median and interquartile range, 7.31 and 7.31-7.33 vs. 7.24 and 7.14-7.29; P < 0.0001), and umbilical venous pH was greater (7.36 and 7.35-7.38 vs. 7.33 and 7.26-7.34; P < 0.0001) compared with the ephedrine group. No patient in the metaraminol group had umbilical arterial pH less than 7.2, compared with nine patients (39%) in the ephedrine group (P = 0.0005). Apgar scores were similar between groups. Changes in uterine artery pulsatility index were similar between groups. CONCLUSIONS: When used by infusion to maintain arterial pressure during spinal anesthesia for cesarean section, metaraminol was associated with less neonatal acidosis and more closely controlled titration of arterial pressure compared with ephedrine.

Metaraminol infusion for maintenance of arterial blood pressure during spinal anesthesia for cesarean delivery: the effect of a crystalloid bolus.

We randomly allocated women having elective cesarean delivery to receive either no bolus (Control Group, n = 31) or 20 mL/kg lactated Ringer's solution (Bolus Group, n = 35) IV before spinal anesthesia. An infusion of metaraminol started at 0.25 mg/min was titrated to maintain systolic arterial blood pressure in the target range 90%-100% of baseline. The total dose of metaraminol required up to the time of uterine incision was similar between the Control Group and the Bolus Group (3.62 +/- 1.20 vs 3.27 +/- 1.39 mg, P = 0.3). However, the Control Group required more metaraminol in the first 5 min (1.29 +/- 0.60 vs 0.96 +/- 0.58 mg, P = 0.025) and a faster maximum infusion rate (0.45 +/- 0.20 vs 0.32 +/- 0.13 mg/min, P = 0.002) compared with the Bolus Group. There was no difference between groups in regards to changes in systolic arterial blood pressure or heart rate over time, or maternal or neonatal outcome. We conclude that when metaraminol is used to maintain arterial pressure during spinal anesthesia for cesarean delivery, crystalloid bolus is not essential provided that sufficient vasopressor is given in the immediate postspinal period.

Comparative anorectic effects of metaraminol and phenylephrine in rats.

Structure-anorectic activity relationship of two substituted amphetamines has been investigated in this study. Literature reports showed conflicting results in their anorectic activities in spite of the similarity in chemical structures of metaraminol and phenylephrine. Hence, the effects of alpha-carbon atom substitution and primary (metaraminol) and secondary amine (phenylephrine) moieties of these substituted amphetamines on the anorexia of rats were investigated in this study in nonfood- and food-deprived rats. Food intake at 1, 3, 14, and 24 h intervals, water intake at a 24-h interval, and body weight alteration for 10 days were monitored after daily drug administration for 3 consecutive days. Both metaraminol and phenylephrine were found to be potent anorectic. The relative anorectic potencies of phenylephrine were 0.54 and 0.81 of that of metaraminol at 1- and 3-h intervals, respectively. Body weight of rats treated with metaraminol (5.0 mg/kg) and phenylephrine (10 mg/kg) decreased significantly from Days 1 to 9.

Noradrenaline release in the rat subfornical organ area to blood pressure changes.

To verify whether noradrenergic inputs to the subfornical organ (SFO) are involved in the control system of arterial pressure, we investigated the effects of blood pressure changes on noradrealine (NA) release in the SFO and its surrounding sites using microdialysis techniques in rats. Hemorrhage (5 or 10 ml/kg) significantly increased the NA concentration in the region of the SFO, but did not cause significant changes in the sites away from the SFO. An elevation in arterial pressure following intravenous administration of the alpha-agonist metaraminol slightly decreased the NA level in the region of the SFO. These results imply that the noradrenergic neural inputs to the SFO area may be involved in the control of cardiovascular function.