Phenylephrine Infusion Research Articles

The medial amygdaloid nucleus modulates the baroreflex activity in conscious rats.

The medial amygdaloid nucleus (MeA) is involved in cardiovascular control. In the present study we report the effect of MeA pharmacological ablations caused by bilateral microinjections of the nonselective synaptic blocker CoCl2 on cardiac baroreflex responses in rats. MeA synaptic inhibition evoked by local bilateral microinjection of 100 nL of CoCl2 (1 mM) did not affect blood pressure or heart rate baseline, suggesting no tonic MeA influence on resting cardiovascular parameters. However, 10 min after CoCl2 microinjection into the MeA of male Wistar rats, the reflex bradycardic response evoked by intravenous infusion of phenylephrine was significantly enhanced when compared with the reflex bradycardic response observed before CoCl2. The treatment did not affect the tachycardic responses to the intravenous infusion of sodium nitroprusside (SNP). Baroreflex activity returned to control values 60 min after CoCl2 microinjections, confirming a reversible blockade. The present results indicate an involvement of the MeA in baroreflex modulation, suggesting that synapses in the MeA have an inhibitory influence on the bradycardic component of the baroreflex in conscious rats.

Hypotensive and diuretic effect of the butanolic soluble fraction of the hydroethanolic extract of bark of Scutia buxifolia Reissek in rats

Ethnopharmacological relevanceScutia buxifolia, a native tree popularly known as “coronilha”, is widely used in Brazilian folk medicine for diuretic and anti-hypertensive purposes. Aim of the studyWe investigated the effects of a butanolic (BuOH) soluble fraction of the hydroethanolic extract (HESB) of bark of Scutia buxifolia on both blood pressure and urinary excretion of rats. The involvement of the nitric oxide/guanylate cyclase pathway in the hypotensive effect found was also explored. Material and methodsWe tested the effect of the BuOH soluble fraction of HESB on the mean arterial pressure (MAP) of anesthetized rats. The fraction was administered at doses of 1, 3 and 10mg/kg (i.v.) in normotensive rats during continuous infusion of vehicle (10μl/min), or phenylephrine (4μg/kg/min), or l-NAME (7mg/kg/min), two approaches able to induce a sustained hypertensive state. In some experiments, a bolus injection of ODQ (2mg/kg) was administered in animals infused with phenylephrine before the administration of the BuOH soluble fraction of HESB. We also measured the effects of the BuOH soluble fraction on the MAP of spontaneously hypertensive rats (SHR). Separate groups of rats were treated orally with either HESB (10, 30 or 100mg/kg), or its BuOH soluble fraction (3, 10 or 30mg/kg), and were subjected to measurement of diuresis and blood pressure. ResultsThe BuOH soluble fraction of HESB (10mg/kg, i.v.) reduced the MAP of both phenylephrine-infused and SHR rats by 20.6±6.0 and 41.8±8.3mmHg, respectively. However, no hypotensive effect was found in normotensive animals infused with l-NAME, a non-selective inhibitor of nitric oxide synthase, or animals previously treated with the soluble guanylate cyclase inhibitor ODQ. The urinary excretion was increased by 70% at 6–8h after a single oral administration of the BuOH soluble fraction of HESB (10mg/kg), without change in urinary density, pH, or Na+ and K+ concentrations. In addition, MAP was lower 3h after the acute oral treatment with the BuOH soluble fraction (82.1±3.8mmHg), compared with MAP of animals from the control group (97±3.2mmHg). ConclusionThis study demonstrates that the BuOH soluble fraction of the hydroethanolic bark of Scutia buxifolia, which has its bark used in folk medicine for the treatment of hypertension mainly by its presumed diuretic properties, possesses both diuretic and hypotensive effects in rats, and that at least the hypotensive effect is fully dependent on activation of the nitric oxide/guanylate cyclase pathway.

ATF3-dependent cross-talk between cardiomyocytes and macrophages promotes cardiac maladaptive remodeling

RationalePressure overload induces adaptive remodeling processes in the heart. However, when pressure overload persists, adaptive changes turn into maladaptive alterations leading to cardiac hypertrophy and heart failure. ATF3 is a stress inducible transcription factor that is transiently expressed following neuroendocrine stimulation. However, its role in chronic pressure overload dependent cardiac hypertrophy is currently unknown. ObjectiveThe objective of the study was to study the role of ATF3 in chronic pressure overload dependent cardiac remodeling processes. Methods and resultsPressure overload was induced by phenylephrine (PE) mini-osmotic pumps in various mice models of whole body, cardiac specific, bone marrow (BM) specific and macrophage specific ATF3 ablations. We show that ATF3-KO mice exhibit a significantly reduced expression of cardiac remodeling markers following chronic pressure overload. Consistently, the lack of ATF3 specifically in either cardiomyocytes or BM derived cells blunts the hypertrophic response to PE infusion. A unique cross-talk between cardiomyocytes and macrophages was identified. Cardiomyocytes induce an ATF3 dependent induction of an inflammatory response leading to macrophage recruitment to the heart. Adoptive transfer of wild type macrophages, but not ATF3-KO derived macrophages, into wild type mice potentiates maladaptive response to PE infusion. ConclusionsCollectively, this study places ATF3 as a key regulator in promoting pressure overload induced cardiac hypertrophy through a cross-talk between cardiomyocytes and macrophages. Inhibiting this cross-talk may serve as a useful approach to blunt maladaptive remodeling processes in the heart.

Is there a place for intra-aortic balloon counterpulsation support in acute right ventricular failure by pressure-overload?

BackgroundMost therapeutic strategies for acute right ventricular failure (RVF) by pressure-overload are directed to improve cardiac output and coronary perfusion pressure by vasopressive agents. The eventual role of intra-aortic balloon counterpulsation (IABP) support remains questionable. This study investigates the contribution of IABP for acute RVF by pressure-overload, in comparison with phenylephrine (PE) and norepinephrine (NOR). MethodsAcute RVF is induced by fixed pulmonary artery constriction in 6 pigs, pursuing a 50% reduction of cardiac output. Assessment of the treatment interventions included biventricular PV-loop analysis, and continuous measurement of aortic and right coronary artery flow. ResultsRestoration of baseline cardiac output was only observed by administration of NOR (Baseline=3.82±1.52ml/min — RVF=2.03±0.59ml/min — IABP=2.45±0.62ml/min — PE=2.98±0.63ml/min — NOR=3.95±0.73ml/min, p<0.001). NOR had most effect on biventricular contractility (PRSW-slope-RV: IABP +24% — PE +59% — NOR +208%, p<0.001 and PRSW-slope-LV: IABP +36% — PE +53% — NOR +196%, p<0.001), heart rate acceleration (IABP +7% — PE +12% — NOR +51%, p<0.001), and RCA flow (IABP +31% — PE +58% — NOR +180%, p<0.001), concomitant to a higher increase of LV-to-RV pressure ratio (IABP: +7% versus −3%, PE: +36% versus +8%, NOR: +101% versus 42%). The hemodynamic contribution of IABP was limited, unless a modest improvement of LV compliance during PE and NOR infusion. ConclusionIn a model of acute pressure-overload RV failure, IABP appears to offer limited hemodynamic benefit. The administration of norepinephrine is most effective to correct systemic output and myocardial perfusion through adding an inotropic and chronotropic effect to systemic vasopression.

Pressure changes within the sac of human cerebral aneurysms in response to artificially induced transient increases in systemic blood pressure.

Formation and rupture of cerebral aneurysms have been associated with chronic hypertension. The effect of transient increase in blood pressure and its effect on intra-aneurysmal hemodynamics have not been studied. We examined the effects of controlled increases in blood pressure on different pressure parameters inside the sac of human cerebral aneurysms and corresponding parent arteries using invasive technology. Twelve patients (10 female, 2 male, age 54±15 years) with unruptured cerebral aneurysms undergoing endovascular coiling were recruited. Dual-sensor microwires with the capacity to simultaneously measure flow velocity and pressure were used to measure systolic, diastolic, and mean pressure inside the aneurysm sac and to measure both pressures and flow velocities in the feeder vessel just outside the aneurysm. These pressures were recorded simultaneously with pressures from a radial arterial catheter. Measurements were taken at baseline and then during a gradual increase in systemic systolic blood pressure to a target value of ≈25 mm Hg above baseline, using a phenylephrine infusion. The dose needed to achieve the required increase in radial arterial systolic blood pressure was 0.8±0.2 μg/kg/min. There was a clear linear relationship between changes in radial and aneurysmal pressures with substantial patient-by-patient variation in the slopes of those relationships. The overall increases in systolic and mean pressures in both radial artery and in the aneurysms were similar. Pressures in the aneurysm and in the parent vessels were similar. Peak and mean flow velocities in the parent arteries did not change significantly with phenylephrine infusion, nor did vessel diameters as measured angiographically.

The Effect of β2-Adrenoceptor Genotype on Phenylephrine Dose Administered During Spinal Anesthesia for Cesarean Delivery.

The β2-adrenoceptor (ADRB2 gene) possesses several polymorphic sites that have physiologic and/or pharmacologic significance. Previous work has demonstrated that the ADRB2 genotype affects the amount of ephedrine administered to maintain blood pressure during cesarean delivery with spinal anesthesia. This study investigated whether the ADRB2 genotype affected phenylephrine dose requirements during cesarean delivery. Our hypothesis was that the ADRB2 genotype altered the ephedrine dose-response and that we would not see this effect if phenylephrine was the vasopressor used to maintain blood pressure because phenylephrine does not act via the β2-adrenoceptor. Women undergoing elective cesarean delivery were studied. Baseline systolic blood pressure (SBP) was determined, and spinal anesthesia was initiated with hyperbaric bupivacaine 12 mg, fentanyl 20 μg, and morphine 200 μg. Hypotension was treated with a phenylephrine infusion using a standardized algorithm (50 μg/min if SBP was 90%-99% of baseline, 100 μg/min for SBP 80%-89% baseline, and 200 μg/min plus boluses for SBP <80% baseline) for 15 minutes after the administration of spinal anesthesia. ADRB2 genotype at codons 16 and 27 was determined. The effect of genotype on administered phenylephrine was compared by analysis of variance and linear regression. Ninety-six women completed the protocol with full data available for analysis. In the unadjusted analysis, there were no significant differences in phenylephrine dose administered among different genotypes at codons 16 and 27. When adjusted for covariates (maternal body mass index, baseline systolic and diastolic blood pressure, neonatal weight, and ethnicity), there was an increase of 200 μg (95% confidence interval, 4-396; P = 0.04) in phenylephrine administered to Arg16 homozygous genotype subjects compared with Gly16 homozygous genotype subjects. Phenylephrine dose requirements to maintain SBP after spinal anesthesia are affected by ADRB2 genotype but to a lesser extent than ephedrine. This suggests that previous work demonstrating a large effect of ADRB2 genotype on ephedrine dose requirements may be explained, at least in part, by a differential response to ephedrine based on ADRB2 genotype. It also suggests that there may be ADRB2-mediated differences in the physiologic response to spinal anesthesia.

The Effects of Ephedrine and Phenylephrine on Placental Vascular Resistance During Cesarean Section Under Epidual Anesthesia.

The purpose of this article is to study the effect of ephedrine and phenylephrine on placental vascular resistance during cesarean section under epidural anesthesia via Doppler ultrasonography. Sixty female subjects, scheduled for elective cesarean section and had an intrathecal injection of bupivacaine, were randomly divided into two groups to receive phenylephrine (50μg/min) or ephedrine (4mg/min) via titration to maintain systolic blood pressure at baseline. Doppler ultrasonography was used to measure baseline vascular resistance values prior to administration of anesthesia, and resistance index (RI) and systolic peak velocity/diastolic velocity (S/D) values of umbilical artery and uterine artery were measured at each time point within first 20min following intrathecal injection. Blood samples were collected from umbilical artery and umbilical vein during delivery to assess the blood gas values. No significant differences in RI and S/D values of umbilical artery and uterine artery after intrathecal injection were found between two groups. RI and S/D values of uterine artery slightly increased in both groups at each time point after anesthesia, but remained within the normal range. No significant differences were observed in blood gas values and the total amount of vasoconstriction drugs between two groups. In contrast to previous reports that used animal models, our study did not show increased placental vascular resistance in patients following phenylephrine (50μg/min) or ephedrine (4mg/min) infusion, as well as no significant differences in the effect of either of these two. The discrepancy between the results of human and animal studies may be related to species differences and the mechanism of human placental vascular remodeling.

Contracting human skeletal muscle maintains the ability to blunt α1‐adrenergic vasoconstriction during KIR channel and Na+/K+‐ATPase inhibition

During exercise there is a balance between vasoactive factors that facilitate increases in blood flow and oxygen delivery to the active tissue and the sympathetic nervous system, which acts to limit muscle blood flow for the purpose of blood pressure regulation. Functional sympatholysis describes the ability of contracting skeletal muscle to blunt the stimulus for vasoconstriction, yet the underlying signalling of this response in humans is not well understood. We tested the hypothesis that activation of inwardly rectifying potassium channels and the sodium-potassium ATPase pump, two potential vasodilator pathways within blood vessels, contributes to the ability to blunt α1 -adrenergic vasoconstriction. Our results show preserved blunting of α1 -adrenergic vasconstriction despite blockade of these vasoactive factors. Understanding this complex phenomenon is important as it is impaired in a variety of clinical populations. Sympathetic vasoconstriction in contracting skeletal muscle is blunted relative to that which occurs in resting tissue; however, the mechanisms underlying this 'functional sympatholysis' remain unclear in humans. We tested the hypothesis that α1 -adrenergic vasoconstriction is augmented during exercise following inhibition of inwardly rectifying potassium (KIR ) channels and Na(+) /K(+) -ATPase (BaCl2 +ouabain). In young healthy humans, we measured forearm blood flow (Doppler ultrasound) and calculated forearm vascular conductance (FVC) at rest, during steady-state stimulus conditions (pre-phenylephrine), and after 2min of phenylephrine (PE; an α1 -adrenoceptor agonist) infusion via brachial artery catheter in response to two different stimuli: moderate (15% maximal voluntary contraction) rhythmic handgrip exercise or adenosine infusion. In Protocol1 (n=11 subjects) a total of six trials were performed in three conditions: control (saline), combined enzymatic inhibition of nitric oxide (NO) and prostaglandin (PG) synthesis (l-NMMA+ketorolac) and combined inhibition of NO, PGs, KIR channels and Na(+) /K(+) -ATPase (l-NMMA+ketorolac+BaCl2 +ouabain). In Protocol2 (n=6) a total of four trials were performed in two conditions: control (saline), and combined KIR channel and Na(+) /K(+) -ATPase inhibition. All trials occurred after local β-adrenoceptor blockade (propranolol). PE-mediated vasoconstriction was calculated (%ΔFVC) in each condition. Contrary to our hypothesis, despite attenuated exercise hyperaemia of ∼30%, inhibition of KIR channels and Na(+) /K(+) -ATPase, combined with inhibition of NO and PGs (Protocol1) or alone (Protocol2) did not enhance α1 -mediated vasoconstriction during exercise (Protocol1: -27±3%; P=0.2vs. control, P=0.4vs. l-NMMA+ketorolac; Protocol2: -21±7%; P=0.9vs. control). Thus, contracting human skeletal muscle maintains the ability to blunt α1 -adrenergic vasoconstriction during combined KIR channel and Na(+) /K(+) -ATPase inhibition.

Continuous minimally invasive cardiac output monitoring with the COstatus in a neonatal swine model: recalibration is necessary during vasoconstriction and vasodilation.

The COstatus monitor measures cardiac output via the transpulmonary ultrasound dilution method (COTPUD ) after injection of normal saline, and can calculate continuous cardiac output (CCO) from the arterial pressure waveform. The relationship between arterial waveform and COTPUD however, might be degraded during vasoconstriction/vasodilation. To examine if recalibration of arterial waveform-derived CCO is required during mild vasoconstriction/vasodilation. In 10 anesthetized piglets (6.6-10.1kg), two COstatus monitors calculated the CCO from the same femoral arterial waveform before and during infusions of phenylephrine (PE; 1 or 3mg·kg(-1) ·min(-1) ) and sodium nitroprusside (SNP; 1 or 5mg·kg(-1) ·min(-1) ), administered in random order. One monitor was recalibrated (CCORecal ) after each intervention, while the other monitor was not (CCONon-Recal ). Recalibration was performed with COTPUD with 1ml·kg(-1) normal saline as indicator. The effects of each infusion on hemodynamic parameters were compared with baseline using paired t-tests. The bias, limits of agreement (LOA), and percentage error between simultaneous measurements (CCORecal and CCONon-Recal ) were examined with Bland-Altman plots. Infusion of PE significantly increased COTPUD , heart rate (HR), and arterial pressures but not systemic vascular resistance (SVR). Infusion of SNP decreased arterial pressures without affecting COTPUD , HR, and SVR. There was no bias between CCORecal and CCONon-Recal at the baseline, but a small bias was observed during PE and SNP infusions. The LOA increased approximately 10 fold during vasoconstriction and vasodilation. Thepercentage error increased from ≤ 5% to 32% and 27% during PE and SNP infusions, respectively. Continuous cardiac output (CO) measured with the COstatus monitor requires recalibration during vasoconstriction and vasodilation, even if changes in COTPUD or SVR are not substantial.

Vasopressin decreases pulmonary-to-systemic vascular resistance ratio in a porcine model of severe hemorrhagic shock.

Vasopressors are gaining renewed interest as treatment adjuncts in hemorrhagic shock. The ideal vasoconstrictor will increase systemic blood pressure without increasing pulmonary vascular resistance (PVR), which hinders pulmonary perfusion and exacerbates hypoxemia. However, the selectivity of pressors for pulmonary versus systemic vasoconstriction during hemorrhage has not been characterized. The purpose of this study was to test the hypothesis that vasopressin (VP) has distinct effects on pulmonary versus systemic hemodynamics, unlike the catecholamine vasopressors norepinephrine (NE) and phenylephrine (PE). Anesthetized and ventilated pigs were assigned to resuscitation with saline only (n = 7) or saline with VP (n = 6), NE (n = 6), or PE (n = 6). Animals were hemorrhaged to a target volume of 30 mL/kg and a mean arterial pressure of 35 mmHg. One hour after the start of hemorrhage, animals were resuscitated with saline up to one shed blood volume, followed by either additional saline or a vasopressor. Hemodynamics and oxygenation were measured hourly for 4 h after the start of hemorrhage. Vasopressin increased systemic vascular resistance (SVR) while sparing the pulmonary vasculature, leading to a 45% decrease in the PVR/SVR ratio compared with treatment with PE. Conversely, NE induced pulmonary hypertension and led to an increased PVR/SVR ratio associated with decreased oxygen saturation. Phenylephrine and crystalloid had no significant effect on the PVR/SVR ratio. Sparing of pulmonary vasoconstriction occurs only with VP, not with administration of crystalloid or catecholamine pressors. The ability of VP to maintain blood oxygenation indicates that VP may prevent hypoxemia in the management of hemorrhagic shock.

Myocardial Hypertrophic Preconditioning Attenuates Cardiomyocyte Hypertrophy and Slows Progression to Heart Failure Through Upregulation of S100A8/A9.

Transient preceding brief ischemia provides potent cardioprotection against subsequent long ischemia, termed ischemic preconditioning. Here, we hypothesized that transient short-term hypertrophic stimulation would induce the expression of hypertrophy regression genes and render the heart resistant to subsequent hypertrophic stress, and slow the progression to heart failure, as well. Cardiomyocyte hypertrophy was induced in mice by either transverse aortic constriction or an infusion of phenylephrine, and in neonatal rat ventricular cardiomyocytes by norepinephrine exposures. In the preconditioning groups, hypertrophic stimulation was provided for 1 to 7 days and then withdrawn for several days by either aortic debanding or discontinuing phenylephrine or norepinephrine treatment, followed by subsequent reexposure to the hypertrophic stimulus for the same period as in the control group. One or 6 weeks after transverse aortic constriction, the heart weight/body weight ratio was lower in the preconditioning group than in the control group, whereas the lung weight/body weight ratio was significantly decreased 6 weeks after transverse aortic constriction. Similar results were obtained in mice receiving phenylephrine infusion and neonatal rat ventricular cardiomyocytes stimulated with norepinephrine. Both mRNA and protein expression of S100A8 and S100A9 showed significant upregulation after the removal of hypertrophic stimulation and persisted for 6 weeks in response to reimposition of transverse aortic constriction. The treatment with recombinant S100A8/A9 inhibited norepinephrine-induced myocyte hypertrophy and reduced the expression of calcineurin and NFATc3, but the silencing of S100A8/A9 prevented such changes. Preconditioning with prohypertrophic factors exerts an antihypertrophic effect and slows the progression of heart failure, indicating the existence of the phenomenon for hypertrophic preconditioning.

Augmentation of Functional Sympatholysis via Endothelial Signaling Is Independent of Nitric Oxide and Prostaglandins in Humans

Sympathetic vasoconstriction is blunted in contracting skeletal muscle in an intensity dependent manner, and increasing endothelium‐dependent vasodilatory signaling during mild exercise can augment this “sympatholysis” similar to that observed during moderate exercise. Here, we determine the role of nitric oxide (NO) and vasodilating prostaglandins (PGs) to the endothelium‐dependent augmentation of sympatholysis during mild exercise. In 10 young subjects we measured forearm blood flow (Doppler ultrasound) and calculated vascular conductance (FVC) responses to local intra‐arterial infusion of phenylephrine (PE; α1‐agonist) during 1) infusion of the endothelium‐dependent dilator acetylcholine (ACH), 2) moderate (15% maximum voluntary contraction; MVC) handgrip exercise and 3) mild (5% MVC) exercise + ACH infusion. Trials were repeated after combined local blockade of NO/PGs (L‐NMMA/Ketorolac, respectively). Vasoconstriction to PE was blunted during 15% exercise compared to control ACH infusion (ΔFVC: ‐14±3% vs ‐30±3%, P&lt;0.05). Augmenting endothelium‐dependent signaling during 5% exercise blunted vasoconstriction similar to 15% exercise (ΔFVC: ‐8±4%). After blockade of NO/PGs, vasoconstriction to PE was blunted in all conditions (ΔFVC: ACH: ‐20±5%; 15% MVC: ‐15±5%; 5%MVC + ACH: ‐7±4%; all P&lt;0.05) relative to control ACH infusion. These data demonstrate that increasing endothelial vasodilatory signaling limits sympathetic vasoconstriction independent of NO/PGs, implicating a role for endothelial hyperpolarization in sympatholysis in humans. Support: HL102720

Baroreflex impairment in a rat model of Parkinson's disease

Parkinson's disease (PD) exhibit motor and non‐motor symptoms. Among non‐motor symptoms, the cardiovascular autonomic dysfunction is frequently. The aim of this work was to evaluate whether in a model of PD induced by injection of the toxin 6‐hydroxy‐dopamine (6‐OHDA) into the striatum was able to produce changes in the baroreflex as well as in neurons in brainstem areas enrolled in cardiovascular control. Wistar rats (300‐320 g, n = 5) received bilateral injections of 6‐OHDA or vehicle into the striatum. After 60 days,baroreflex was assessed by determining the heart rate (HR) responses to ramped infusions of phenylephrine (PE) and sodium nitroprusside (SNP)induced mean arterial pressure (MAP) changes. After, the rats were anesthetized for brain perfusion and processed for tyrosine hydroxylase (TH) and the transcription factor Phox2b immunoreactive. PE produced a similar increased in MAP in 6‐OHDA and control groups. However, the bradycardia was blunted in 6‐OHDA (D = ‐7.5±0.5 to ‐62±6 vs. vehicle: ‐29.5±1.2 to ‐148.5±9.8 bpm). In 6‐OHDA, the SNP produced a smaller decrease in MAP (Δ = ‐18±2.6 to ‐24.5±0.8 vs. vehicle: ‐60.3±2 to ‐96.5±1.9 mmHg) and a smaller increase in HR (Δ = 34.75±3.4 to 59.5±7.8 vs. vehicle: 61±7.8 to 101.3±6 bpm). Ocurred a reduction in TH neurons in the substantia nigra (85%), in the C1 regions (70%) and in the Phox2b+ neurons in the NTS (48%). We observed an impairment of baroreflex sensitivity in the 6‐OHDA model of PD, which could be correlated with a reduction in the neuronal cytoarchitecture of brainstem regions involved in cardiovascular controlFinancial support: FAPESP, CNPq, CAPES/PROEX

Intralipid Reverses Propofol‐Mediated Hypotension in Rats

IntroductionPropofol is a commonly used anesthetic. Despite its favourable safety profile, propofol causes hypotension which can result in end‐organ hypoperfusion. Intralipid is a lipid emulsion that has been shown to reverse the vasodilatory effects of propofol in isolated vessels; however, whether these effects are recapitulated in vivo is not known. The objectives of this study were to determine if intralipid reverses the hypotensive and anesthetic effects of propofol in rats.MethodsUnder isoflurane anesthesia, male Sprague Dawley rats were instrumented with indwelling catheters for mean arterial pressure (MAP) assessments as well as subdural electrodes for cortical activity assessments by electroencephalography (EEG).ResultsPropofol (10 mg/kg IV) caused hypotension (55±2% drop in MAP, P&lt;0.001) and intralipid (4mL/kg IV) caused greater reversal (80±9%) of blood pressures compared to saline (19±1%; P&lt;0.001). Blockade of the autonomic nervous system with chlorisondamine (2.5 mg/kg IV) caused marked hypotension (56±3% lowering of MAP, P&lt;0.001) which could be reversed with a constant infusion of phenylephrine (300 μg/kg/hr); under these conditions, propofol nevertheless caused hypotension (12±4% lowering of MAP) which was completely reversed by intralipid. Propofol‐induced cortical burst suppression was not affected by intralipid (2±3%), saline (‐4%) or 20% BSA (‐2±1%; P=0.27).ConclusionThese results demonstrate that intralipid reverses propofol‐mediated hypotension with minimal effects on its anesthetic profile. Intralipid could be particularly useful as a rescue against propofol in patients prone to hemodynamic instability such as the elderly.This work was funded by a grant from the University Hospital Foundation.

SOD1 Overexpression Alters Aortic Depressor Nerve Function but Does not Protect Against Impairment of Baroreflex Heart Rate Control in Chronic Intermittent Hypoxia Exposed Mice

Mice overexpressing Cu/Zn Superoxide Dismutase (SOD1) have been used as a model for investigating effects of increased antioxidant activity in pathologies in which reactive oxygen species (ROS) play a role. Our objective in this study is to determine if human SOD1 overexpression can protect against dysfunction of aortic depressor nerve and baroreflex control of heart rate in chronic intermittent hypoxia (CIH) exposed mice. We used the transgenic mouse line C57B6SJL‐Tg (SOD1)2 Gur/J overexpressing human SOD1 and the non‐transgenic C57BL/6J mice (control). Mice (male, 4 months old, n=8‐9/group) were either maintained in room air (RA), or subjected to 6 minutes cycles of 21% and 5.7% O2 during 12‐h light cycles for 40‐50 days (CIH). Mice were anesthetized with isoflurane. Arterial blood pressure (ABP) and heart rate (HR) were measured from the femoral artery. Sodium nitroprusside (SNP) and phenylephrine (PE) were infused sequentially into the femoral vein to decrease and then increase ABP. Aortic depressor nerve activity (ADNA) was recorded. We found that: HR and mean arterial blood pressure (MABP) were similar between groups. Baroreflex control of HR in response to infusion of PE or SNP was not different in SOD1‐RA animals vs. C57‐RA, and it was decreased to a comparable extent in SOD1‐CIH and C57‐CIH. Recordings of ADNA in response to sequential SNP and PE injection‐induced blood pressure ramps revealed a significantly greater baroreceptor gain in SOD1‐RA compared to C57‐RA (p &lt; 0.01), but CIH exposure significantly decreased ADN baroreceptor gain in SOD1‐CIH compared to SOD1‐RA (P&lt;0.01). Our data suggests that SOD1 overexpression alters ADN function, but does not protect against CIH‐induced baroreflex impairment.

Deletion of Protein Tyrosine Phosphatase 1b (Ptp1b) in Proopiomelanocortin (POMC) Neurons Reduces Sympathetic Tone and Protects Mice from Leptin‐Induced High Blood Pressure

Ptp1b is a negative regulator of leptin signaling. Deletion of Ptp1b in POMC neurons increases energy expenditure and protects mice from obesity and type 2 diabetes. However, whether POMC‐Ptp1b deletion sensitizes the cardiovascular system to leptin is unknown. We addressed this question by analyzing the cardiovascular phenotype of flox/flox (WT) and POMC‐Ptp1b KO mice (KO), at baseline and after 7 days of chronic leptin infusion. Conscious blood pressure (BP) and heart rate recordings revealed that POMC‐Ptp1b deletion did not affect baseline BP [WT: 118.3±4.1 vs KO: 117.9± 4.2 mmHg]. However KO mice exhibit a lower BP response to ganglionic blockade [WT: ‐30±4 vs KO: ‐15±6 % drop, P&lt;0.05] that suggests a decreased neurogenic control of BP. Reduced sympathetic tone was further confirmed by showing that KO mice exhibit low plasma catecholamine levels [WT: 3765±483 vs KO: 2113±521 pg/mL, P&lt;0.05, HPLC] compared to WT mice and a compensatory increase in vascular adrenergic tone (increased vascular constriction to phenylephrine) and a1 adrenergic receptors expression (qRT‐PCR). Furthermore chronic sympatho‐activation for 7 days via phenylephrine infusion restored vascular adrenergic tone in KO mice. POMC‐Ptp1b deletion abolished leptin‐induced increase in BP [WT: +13±2.5 mmHg, P&lt;0.05 vs baseline; KO: +4±1.9 mmHg, NS]. However chronic leptin infusion restored vascular adrenergic tone in POMC‐Ptp1b KO mice by increasing vascular sympathoactivation. These data suggests that deletion of Ptp1b in POMC neurons protects from leptin‐induced high BP by reducing neurogenic control of blood pressure.

Targeted inhibition of ANKRD1 disrupts sarcomeric ERK-GATA4 signal transduction and abrogates phenylephrine-induced cardiomyocyte hypertrophy.

Accumulating evidence suggest that sarcomere signalling complexes play a pivotal role in cardiomyocyte hypertrophy by communicating stress signals to the nucleus to induce gene expression. Ankyrin repeat domain 1 (ANKRD1) is a transcriptional regulatory protein that also associates with sarcomeric titin; however, the exact role of ANKRD1 in the heart remains to be elucidated. We therefore aimed to examine the role of ANKRD1 in cardiomyocyte hypertrophic signalling. In neonatal rat ventricular myocytes, we found that ANKRD1 is part of a sarcomeric signalling complex that includes ERK1/2 and cardiac transcription factor GATA4. Treatment with hypertrophic agonist phenylephrine (PE) resulted in phosphorylation of ERK1/2 and GATA4 followed by nuclear translocation of the ANKRD1/ERK/GATA4 complex. Knockdown of Ankrd1 attenuated PE-induced phosphorylation of ERK1/2 and GATA4, inhibited nuclear translocation of the ANKRD1 complex, and prevented cardiomyocyte growth. Mice lacking Ankrd1 are viable with normal cardiac function. Chronic PE infusion in wild-type mice induced significant cardiac hypertrophy with reactivation of the cardiac fetal gene program which was completely abrogated in Ankrd1 null mice. In contrast, ANKRD1 does not play a role in haemodynamic overload as Ankrd1 null mice subjected to transverse aortic constriction developed cardiac hypertrophy comparable to wild-type mice. Our study reveals a novel role for ANKRD1 as a selective regulator of PE-induced signalling whereby ANKRD1 recruits and localizes GATA4 and ERK1/2 in a sarcomeric macro-molecular complex to enhance GATA4 phosphorylation with subsequent nuclear translocation of the ANKRD1 complex to induce hypertrophic gene expression.

A Randomized Controlled Trial of Variable Rate Phenylephrine Infusion With Rescue Phenylephrine Boluses Versus Rescue Boluses Alone on Physician Interventions During Spinal Anesthesia for Elective Cesarean Delivery

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Phenylephrine Infusions for Maintaining Blood Pressure During Spinal Anesthesia for Cesarean Delivery

Phenylephrine Infusions for Maintaining Blood Pressure During Spinal Anesthesia for Cesarean Delivery

A Randomized Controlled Trial of Variable Rate Phenylephrine Infusion With Rescue Phenylephrine Boluses Versus Rescue Boluses Alone on Physician Interventions During Spinal Anesthesia for Elective Cesarean Delivery

Siddik-Sayyid, Sahar M.; Taha, Samar K.; Kanazi, Ghassan E.; Aouad, Marie T. Author Information