Phenylephrine Infusion Research Articles

Intraoperative TTE inferior vena cava monitoring in elderly orthopaedic patients with cardiac disease and spinal-induced hypotension.

Objective To address the role of transthoracic echocardiography in inferior vena cava (IVC) monitoring in the management of haemodynamically unstable elderly patients subjected to lower limb orthopaedic surgery under spinal anesthesia. Possible implications in the postoperative care unit (PACU) length of stay (LOS) are investigated. Methods 41 elderly patients with cardiac diseases were recruited. Patients experiencing intraoperative haemodynamic instability (diastolic blood pressure≤60mmHg) were divided into two groups according to right atrial pressure (RAP), (RAP<5mmHg and RAP between 5 and 10mmHg) as measured by inferior vena cava collapsibility index (IVCCI). Haemodynamic instability was treated with normal saline infused at a constant rate supplemented by phenylephrine (PHE) infusions titrated to normal blood pressure values. Intraoperatively comparisons of peak PHE infusion rates and all episodes of hypotension, including in the PACU, were recorded among groups. The patients' PACU LOS and associated factors were assessed. Results The intraoperative peak PHE infusion rate and the incidence of haemodynamic instability in the postoperative period were significantly higher in patients with RAP<5mmHg. The total PHE consumption was also higher in patients with RAP<5mmHg postoperatively. The primary risk factor for a prolonged stay in PACU, as determined by multiple regression analysis was RAP. Conclusions Patients with high dynamic collapsibility of the IVC may require aggressive treatment to restore their haemodynamic status. Additionally, intraoperative levels of RAP, as measured by IVCCI, can act as a predictor for increased LOS in the PACU.

Prophylactic phenylephrine infusion for the prevention of hypotension after spinal anesthesia in the elderly: a randomized controlled clinical trial

Study objectiveHypotension frequently occurs during spinal anesthesia (SA), especially in the elderly. Phenylephrine is effective to prevent SA-induced hypotension during cesarean delivery. The objective of this study was to evaluate the efficacy and safety of prophylactic infusion of phenylephrine after SA for orthopedic surgery in the elderly. DesignThis prospective, randomized, double-blind, and placebo-controlled study included 54 patients older than 60 years undergoing elective lower limb surgery under SA (injection of 10 mg of isobaric bupivacaine with 5 μg of sufentanyl). InterventionPatients were randomized to group P (100-μg/mL solution of phenylephrine solution at 1 mL/min after placement of SA) or the control group C (0.9% isotonic sodium chloride solution). The flow of the infusion was stopped if the mean arterial blood pressure (MAP) was higher than the baseline MAP and maintained or restarted at 1 mL/min if MAP was equal to or lower than the baseline MAP. Heart rate and MAP were collected throughout the case. MeasurementsHypotension was defined by a 20% decrease and hypertension as a 20% increase from baseline MAP. Bradycardia was defined as a heart rate lower than 50 beats per minute. Main resultsTwenty-eight patients were randomized to group P and 26 patients to group C. MAP was higher in group P than in group C (92 ± 2 vs 82 ± 2 mm Hg, mean ± SD, P< .001). The number of hypotensive episodes per patient was higher in group C compared with group P (9 [0-39] vs 1 [0-10], median [extremes], P< .01), but the number of hypotensive patients was similar between groups (19 [73%] vs 20 [71%], P= 1). The time to onset of the first hypotension was shorter in group C (3 [1-13] vs 15 [1-95] minutes, P= .004). The proportion of patients without hypotension (cumulative survival) was better in group P (P= .04). The number of hypertensive episodes per patient and the number of bradycardic episodes per patient were similar between groups (P= not significant). ConclusionProphylactic phenylephrine infusion is an effective method of reducing SA-induced hypotension in the elderly. Compared with a control group, it delays the time to onset of hypotension and decreases the number of hypotensive episodes per patient. More data are needed to evaluate clinical outcomes of such a strategy.

Optimal dose of phenylephrine infusion for management of maternal hypotension under spinal anaesthesia during caesarean delivery

Phenylephrine is the drug presently recommended for prevention of maternal hypotension during caesarean section. The optimal infusion dose is still undetermined. We tried to determine the optimal infusion dose of phenylephrine to prevent maternal hypotension. After Institutional Ethical committee approval, consenting one hundred ASA physical status I or II parturients for elective caesarean delivery were included randomized into 4 groups of 25 each by picking lots. Group P25, P50, P75 and P100 received phenylephrine infusion in concentrations of 25, 50, 75 and 100µg/ min respectively. After administering spinal anaesthesia a infusion was started as per group allocation. 20% change in baseline mean blood pressure was taken for intervention. Hypotension was treated with 50µg phenylephrine bolus, bradycardia treated with atropine 0.6 mg. Hypertension treated by stopping the infusion. Neonatal Apgar at 1 and 5 minutes and base deficit in cord blood was assessed. Demographic, anaesthetic and surgical characteristics were comparable. 25% of patients in group P25 had hypotension requiring bolus phenylephrine dose. 40% in group P75 and 55% in group P100 had hypertension requiring infusion to be stopped. 6 patients in group P75 and 9 patients in group P100 required atropine to treat bradycardia. Neonatal outcome were comparable in 4 groups. Conclusions: Phenylephrine in an infusion dose of 50µg/min gives stable haemodynamics with good neonatal outcome.

A randomized trial comparing prophylactic phenylephrine and ephedrine infusion during spinal anesthesia for emergency cesarean delivery in cases of acute fetal compromise

BackgroundPrevious evidence showed that use of phenylephrine was associated with higher umbilical artery pH (UA pH) than ephedrine after elective cesarean delivery (CD). However, the best choice of vasopressor and its effect on funic gases in cases of acute fetal compromise require additional studies. MethodsNinety parturients showing acute fetal compromise during intrapartum period and taken up for CD (category II) under spinal anesthesia were randomized to receive prophylactic infusion of ephedrine 2.5mg/min or phenylephrine 30μg/min. Systolic blood pressure was targeted between 90% and 110% of baseline. Incidence of fetal acidosis (UA pH <7.2 and/or base deficit >12mmol/L) was recorded. Other parameters of cord gases, Apgar score, need for immediate resuscitation, maternal hemodynamics, and adverse events were also compared. ResultsNumber of neonates showing acidosis with ephedrine or phenylephrine was comparable (P=.22). Of these, newborns with base deficit >12mmol had low 1-minute Apgar scores (n=15/23). The ephedrine group had higher oxygen content in UA (P=.03). There was no adverse neonatal outcome during the period of observation. Incidence of maternal nausea and vomiting was higher with ephedrine than with phenylephrine (22.2% vs 4.4%; P=.02). Maternal bradycardia was observed with phenylephrine (P=.02). ConclusionOur data report similar fetal acidosis with either phenylephrine or ephedrine administered during spinal anesthesia for treating maternal hypotension in cases of emergency CD.

Effect of adrenergic agonists on coronary blood flow: a laboratory study in healthy volunteers.

Myocardial oxygen supply and demand mismatch is fundamental to the pathophysiology of ischemia and infarction. The sympathetic nervous system, through α‐adrenergic receptors and β‐adrenergic receptors, influences both myocardial oxygen supply and demand. In animal models, mechanistic studies have established that adrenergic receptors contribute to coronary vascular tone. The purpose of this laboratory study was to noninvasively quantify coronary responses to adrenergic receptor stimulation in humans. Fourteen healthy volunteers (11 men and 3 women) performed isometric handgrip exercise to fatigue followed by intravenous infusion of isoproterenol. A subset of individuals also received infusions of phenylephrine (n = 6), terbutaline (n = 10), and epinephrine (n = 4); all dosages were based on fat‐free mass and were infused slowly to achieve steady‐state. The left anterior descending coronary artery was visualized using Doppler echocardiography. Beat‐by‐beat heart rate (HR), blood pressure (BP), peak diastolic coronary velocity (CBVpeak), and coronary velocity time integral were calculated. Data are presented as M ± SD. Isometric handgrip elicited significant increases in BP, HR, and CBVpeak (from 23.3 ± 5.3 to 34.5 ± 9.9 cm/sec). Isoproterenol raised HR and CBVpeak (from 22.6 ± 4.8 to 43.9 ± 12.4 cm/sec). Terbutaline and epinephrine evoked coronary hyperemia whereas phenylephrine did not significantly alter CBVpeak. Different indices of coronary hyperemia (changes in CBVpeak and velocity time integral) were significantly correlated (R = 0.803). The current data indicate that coronary hyperemia occurs in healthy humans in response to isometric handgrip exercise and low‐dose, steady‐state infusions of isoproterenol, terbutaline, and epinephrine. The contribution of β1 versus β2 receptors to coronary hyperemia remains to be determined. In this echocardiographic study, we demonstrate that coronary blood flow increases when β‐adrenergic receptors are stimulated (i.e., during exercise and different intravenous infusions). Our infusion paradigms and beat‐by‐beat imaging methodologies can be used in future studies to evaluate age‐, sex‐, and disease‐ differences in adrenergic control of coronary blood flow.

Adaptive Parameter Estimation of Blood Pressure Dynamics Subject to Vasoactive Drug Infusion

Dynamic modeling of arterial blood pressure change subject to vasoactive drug infusion can be a valuable tool for computerized decision support of drug administration as well as for automated closed-loop drug delivery to treat hypotension in emergency trauma care. A time-varying time-delayed first-order dynamic model is considered to describe blood pressure response due to continuous injection of the vasorestrictive drug phenylephrine (PHP). The patient-to-patient as well as intrapatient variability of the dynamic response is taken into account by online identification of the varying model parameters. A multiple-model extended Kalman filter (MMEKF) structure is developed for the real-time estimation of mean arterial pressure and the dynamic blood pressure response model to PHP infusion to assist treatment. Convergence analysis is carried out, along with comparison with offline identification methods. Static drug-response curves for dosage recommendation are obtained from the estimation of the model sensitivity parameter. Finally, a detection algorithm is proposed to identify abrupt model variations caused by sudden physiological changes, such as hemorrhage. The proposed MMEKF parameter estimation method and the hemorrhage detection algorithm are tested and validated using data from animal experiments on anesthetized healthy and hemorrhagic swine that are subject to PHP infusion.

Anesthetic management for cesarean section in a patient with uncorrected double-outlet right ventricle.

BackgroundWe describe the anesthetic management for cesarean section in a pregnant woman with uncorrected double-outlet right ventricle. The anesthetic method, treatment of complications and lessons are discussed.Case presentationA 28-year-old woman visited our emergency room for progressive dyspnea and recurrent hemoptysis at 30 weeks’ gestation. Her New York Heart Association functional class was III–IV. Echocardiography indicated that she had congenital heart disease of double-outlet right ventricle. She hadn’t received any treatment. The obstetrician decided to terminate the pregnancy by cesarean section. We chose epidural anesthesia and pumped phenylephrine at the same time to minimize hemodynamic fluctuation. Just in the process of changing position to supine position with uterus displaced to the left, the patient coughed badly and complained about dyspnea. At the same time, the oxygen saturation decreased quickly. The symptoms were ameliorated soon by treating as heart failure. But the symptoms reappeared after oxytocin administration. At the end of surgery, the baby was sent to the Neonatal Intensive Care Unit for premature birth. The mother recovered successfully and discharged 7 days later.Discussion and EvaluationDouble-outlet right ventricle is a seldom disease and pregnancy with uncorrected double-outlet right ventricle is rare. In this case, the patient belonged to the type of ventricular septal defect characterized by subaortic ventricular septal defect without pulmonary stenosis. Most of the aorta arises from the right ventricle, the volume of venous blood was injected from the right ventricle into the aorta, which decided the oxygen saturations. Compared to general anesthesia, epidural anesthesia reduces venous return and alleviates the cardiac burden. So, we pumped phenylephrine along with epidural anesthesia in case of critical cyanosis following significant blood pressure decrease. In the process of anesthesia, dyspnea, cough and cyanosis attacked the patient for two times. The most probable reason was heart failure which induced by the sudden increasing of returned blood. As a result of severe cough, pulmonary artery pressure increased rapidly. Then a great amount of venous blood was injected into the aorta and cyanosis became more serious as well as oxygen saturation declined quickly. ConclusionEpidural anesthesia with continuous phenylephrine infusion is a preferable choice for parturient women with uncorrected double-outlet right ventricle for cesarean section. It is not the optimal choice for this type of patients to lie on the left. The dose of oxytocin should be reduced to avoid potential cardiovascular complications.

Reduced function of the RhoA/Rho‐Kinase pathway contributes for the vascular refractoriness to phenylephrine in septic mice

Hypotension and reduced vascular responses to vasoconstrictors are two hallmarks of septic shock. Activation of the RhoA/Rho‐Kinase pathway plays an important role in the vascular effects of ligands able to increase blood pressure. We have investigated the hypothesis that a reduced functionality of this pathway plays a role in the hyporesponsiveness to alpha‐1 adrenergic agonists in experimental sepsis induced by bacterial lipopolysaccharide (LPS) or Klebsiella pneumonia (KP). Male Swiss mice (3–4 months; n = 6 each group) were used in this study. For the LPS model, animals received an intraperitoneal injection of LPS (011‐B4; 7.5 mg/kg), or sterile saline (0.1 ml/10 g). For the KP model, the mice were anesthetized with ketamine/xylazine (80 and 20 mg/kg i.p.) and were inoculated with a sub‐lethal dose of KP (4 × 108 CFU), or sterile saline (0.05 ml), which were administered directly into their trachea. At 6 h or 18 h after LPS injection, and 6 h or 24 h after inoculation of KP, the animals were anesthetized with ketamine/xylazine (100 and 20 mg/kg, i.m.), and had their femoral vein and carotid artery cannulated for intravenous administration of drugs and direct measurement of the mean arterial pressure (MAP), respectively. After stabilization of MAP all groups received the selective Rho‐kinase inhibitor Y‐27632 (0.1 mg/kg, i.v.), or vehicle (10 μl/10 g, i.v.), followed by bolus infusions of phenylephrine (PE, 3, 10 and 30 nmol/kg). Each subsequent drug was administered only when the MAP returned to basal values. After the recording of MAP, blood samples were collected and used for Griess reaction, the animals were euthanized with anesthetic overdose and had the aorta collected and subjected to Western blotting detection of Rho‐A, ROCK I and ROCK II. Animals from both LPS and KP groups presented systemic hypotension, reduced reactivity to PE, and increased plasma levels of nitrate+nitrite, as detected at early (6 h) or late (18 h and 24 h, respectively) periods. Administration of 0.1 mg/kg Y‐27632 was unable to alter PE‐increased MAP in control animals, but resulted in further reduction in the hypertensive effect of PE at 18 h after LPS, as well as at 6 h and 24 h after inoculation of KP. For instance, the increase in MAP induced by 30 nmol/kg PE before and after Y‐2763, respectively, was 46.1 ± 4.8 and 38.5 ± 5.5 mmHg in control animals, and 27.5 ± 5.2 and 10.7 ± 2.3 mmHg at 18 h after LPS injection. In spite of the lack of significant changes in the levels of RhoA, ROCK I and ROCK II in the aortas from KP‐treated animals, the Western blotting analysis revealed that both RhoA and Rock II were significantly increased at 6 h after LPS, compared with samples from control animals. However, the levels of RhoA were reduced by 53% in the LPS 18 h groups. Our results reveal that the pressor effect of PE is more sensitivity to inhibition of ROCK in animals subjected to experimental models of sepsis, and suggest that changes in the expression or function of components of the Rho‐A/Rho‐ kinase pathway may contribute to the cardiovascular failure that takes place in septic shock.Support or Funding InformationFAPESC, SC, Brazil (TR2012000367) and CNPq, Brazil (448738/2014)

Individual variability of cerebral autoregulation, posterior cerebral circulation and white matter hyperintensity.

Cerebral autoregulation (CA) is a key mechanism to protect brain perfusion in the face of changes in arterial blood pressure, but little is known about individual variability of CA and its relationship to the presence of brain white matter hyperintensity (WMH) in older adults, a type of white matter lesion related to cerebral small vessel disease (SVD). This study demonstrated the presence of large individual variability of CA in healthy older adults during vasoactive drug-induced changes in arterial pressure assessed at the internal carotid and vertebral arteries. We also observed, unexpectedly, that it was the 'over-' rather than the 'less-reactive' CA measured at the vertebral artery that was associated with WMH severity. These findings challenge the traditional concept of CA and suggest that the presence of cerebral SVD, manifested as WMH, is associated with posterior brain hypoperfusion during acute increase in arterial pressure. This study measured the individual variability of static cerebral autoregulation (CA) and determined its associations with brain white matter hyperintensity (WMH) in older adults. Twenty-seven healthy older adults (13 females, 66±6years) underwent assessment of CA during steady-state changes in mean arterial pressure (MAP) induced by intravenous infusion of sodium nitroprusside (SNP) and phenylephrine. Cerebral blood flow (CBF) was measured using colour-coded duplex ultrasonography at the internal carotid (ICA) and vertebral arteries (VA). CA was quantified by a linear regression slope (CA slope) between percentage changes in cerebrovascular resistance (CVR=MAP/CBF) and MAP relative to baseline values. Periventricular and deep WMH volumes were measured with T2-weighted magnetic resonance imaging. MAP was reduced by -11±7% during SNP, and increased by 21±8% during phenylephrine infusion. CA demonstrated large individual variability with the CA slopes ranging from 0.37 to 2.20 at the ICA and from 0.17 to 3.18 at the VA; no differences in CA were found between the ICA and VA. CA slopes measured at the VA had positive correlations with the total and periventricular WMH volume (r=0.55 and 0.59, P<0.01). Collectively, these findings demonstrated the presence of large individual variability of CA in older adults, and that, when measured in the posterior cerebral circulation, it is the higher rather than lower CA reactivity that is associated with WMH severity.

Effect of Intraoperative Phenylephrine Infusion on Redistribution Hypothermia During Cesarean Delivery Under Spinal Anesthesia*

SummaryAn observational clinical study to evaluate the effect of phenylephrine infusion on maternal temperatures during scheduled cesarean delivery under spinal anaesthesia was conducted in 40 ASA physical status II parturients. Following placement of spinal anesthesia, phenylephrine infusion was initiated at 40 μg/min and titrated to maintain mean arterial pressure within 20 percent of baseline. Maternal oral temperature, heart rate, and blood pressure were measured at baseline, spinal placement, every 10 minutes thereafter for 60 minutes. Phenylephrine dose received was documented every ten minutes. The range in maternal temperature change was 0.06–0.29°C. The lowest recorded temperature was 36.3°C. Decreased maternal temperature was associated with duration of anesthesia and cumulative phenylephrine dose in a univariate model (P<0.001 for all). The multivariable model showed an association between a greater decrease in maternal temperature with larger doses of phenylephrine being administered.

Exploring novel infusion regimens of phenylephrine during spinal anesthesia for caesarean delivery: The effects on hemodynamic control and fetal acid-base status

Background: A renewed interest has emerged in the use of bolus or intravenous (IV) infusion of phenylephrine for management of hypotension during spinal anesthesia (SA) for caesarean section to achieve optimal maternal and neonatal outcome. The aim of our study was to investigate the efficacy of using three different phenylephrine infusion regimens to maintain maternal baseline blood pressure during SA for caesarean delivery. Materials and Methods: Ninety parturients undergoing SA for elective caesarean delivery received an IV infusion of phenylephrine in one of three different concentration ratios. The groups contained a potency equivalent of 100 μg/min, 80μg/min, and 60 μg/min infusion doses. The infusions were adjusted to maintain systolic blood pressure (SBP) near the baseline until uterine incision. Hemodynamic changes in mother and umbilical cord blood gases were compared. Results: As concentration of phenylephrine increased, following significant trends were noticed: in group A, 10/29 (34.5%) patients had hypotension as compared to 2/28 (7.4%) patients in group B and 4/28 (14.3%) patients in group C. On the other hand, we found that the incidence of hypertension and bradycardia was higher in groups B (22/28; 4/28) and C (26/28; 10/28) as compared to those in group A (3/29; 2/29), respectively. Neonatal acid-base status in all three groups was favorable. Conclusions: As the concentration of phenylephrine increased, the tendency for SBP to be above the baseline increased, along with an incidence of bradycardia. Therefore, we conclude that low dose infusion regimens of phenylephrine, i.e. between 60 μg/min and 80 μg/min, will be more effective in prevention of hypotension during SA for caesarean delivery.

A Comparison of A Crystalloid Co-Load, with or without A Phenylephrine Infusion, for Prevention of Hypotension Following Subarachnoid Block for Caesarean Section

A Comparison of A Crystalloid Co-Load, with or without A Phenylephrine Infusion, for Prevention of Hypotension Following Subarachnoid Block for Caesarean Section

Phenylephrine infusion for spinal-induced hypotension in elective cesarean delivery: Does preload make a difference?

Background and Aims:Patients undergoing elective cesarean delivery (CD) have a high-risk of spinal-induced hypotension (SIH). We hypothesized that a colloid preload would further reduce SIH when compared with a crystalloid preload.Material and Methods:Eighty-two healthy parturients undergoing elective CD were included in the study. Patients were randomly assigned to two groups (41 patients in each group) to receive either Lactated Ringer's solution (1500 ml) or hydroxyethyl starch (6% in normal saline, 500 ml) 30 min prior to placement of spinal anesthesia. All patients were treated with a phenylephrine infusion (100 mcg/min), titrated during the study.Results:There was no statistical difference between groups with regards to the incidence of hypotension (10.8% in the colloid group vs. 27.0% in the crystalloid group, P = 0.12). There was also no difference between groups with respect to bradycardia, APGAR scores, and nausea and vomiting. Significantly less phenylephrine (1077.5 ± 514 mcg) was used in the colloid group than the crystalloid group (1477 ± 591 mcg, P = 0.003).Conclusion:The preload with 6% of hydroxyethyl starch before CD might be beneficial for the prevention of SIH.

Increase in sensitivity of the baroreceptor reflex following microinjection of carbachol into the posterior hypothalamic nucleus of awake rats.

In a rat model, the baroreceptor reflex can be assessed by graded infusions of either phenylephrine or sodium nitroprusside with continuous hemodynamic monitoring. Microinjection of the cholinergic agonist carbachol (CCh) into the posterior hypothalamic nucleus (PHN) evokes an increase in mean arterial pressure and a change in heart rate. Lower doses of CCh evoke only tachycardia, whereas middle and higher doses evoke a biphasic change in heart rate of tachycardia followed by bradycardia. The bradycardia following the microinjection of CCh into the PHN can be attenuated by the previous administration of the vasopressin V1 receptor antagonist [d(CH2 )5 Tyr(Me)] arginine vasopressin (AVPX). Circulating arginine vasopressin (AVP) has been shown to increase the sensitivity of the baroreceptor reflex by stimulating vasopressin V1 receptors in the area postrema. The attenuation by AVPX of the bradycardia that results following the high doses of CCh suggests that AVP is released into the circulation following stimulation of cholinergic systems within the PHN. Thus, microinjection of a high dose of CCh (11nmol) into the PHN alters the sensitivity of the baroreceptor reflex by increasing peripheral levels of AVP.

Antihypertensive effects of new dihydropyridine derivatives on phenylephrine-raised blood pressure in rats.

Changes in the substitutions at C-3 and C-5 positions of 4-(1-methyl-5-nitro-2-imidazolyl) dihydropyridine analogs of nifedipine have led to changes in potency of the compounds. The objective of the present study was to examine the hypotensive effects of 5 newly synthesized dihydropyridine derivatives of nifedipine in rats with phenylephrine-raised blood pressure. Anesthetized Sprague-Dawley rats were randomly assigned to 19 groups of 7 animals each. Control group received the vehicle dimethylsulfoxide (0.05 mL), 3 groups were given nifedipine at 100, 300, or 1000 μg/kg, and 5 other groups each composed of 3 subgroups administered one of the 5 new dihydropyridine compound at 100, 300, or 1000 μg/kg. All animals were initially infused with 20 µg/kg/min phenylephrine for 45 min, and were then given a bolus of either dimethylsulfoxide, nifedipine, or new dihydropyridine compounds 20 min after the commencement of phenylephrine infusion. Blood pressure and heart rate (HR) of the animals were measured before and at the end of phenylephrine infusion, or 25 min after injection of vehicle or compounds. Compared to dimethylsulfoxide, nifedipine, and new 1, 4-dihydropyridine derivatives caused significant reductions in MBP. Moreover, cyclohexyl propyl, phenyl butyl, and cyclohexyl methyl analogs of 1, 4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazoyl)-3,5-pyridinedicarboxylase at 100 μg/kg, phenyl butyl, and cyclohexyl methyl analogs at 300 μg/kg, and cyclohexyl methyl analogs at 1000 μg/kg reduced MBP similar to nifedipine. There was no significant difference between HR of all groups before and after administration of the compounds. The findings indicated that changes in substitution at C-3 and C-5 positions of 2-(1-methyl-5-nitro-2-imidazolyl) dihydropyridine analogs of nifedipine were associated with changes in hypotensive activity of the compounds.

The Protein Acyl Transferase ZDHHC21 Modulates α1 Adrenergic Receptor Function and Regulates Hemodynamics.

Palmitoylation, the reversible addition of the lipid palmitate to a cysteine, can alter protein localization, stability, and function. The ZDHHC family of protein acyl transferases catalyzes palmitoylation of numerous proteins. The role of ZDHHC enzymes in intact tissue and in vivo is largely unknown. Herein, we characterize vascular functions in a mouse that expresses a nonfunctional ZDHHC21 (F233Δ). Physiological studies of isolated aortae and mesenteric arteries from F233Δ mice revealed an unexpected defect in responsiveness to phenylephrine, an α1 adrenergic receptor agonist. In vivo, F233Δ mice displayed a blunted response to infusion of phenylephrine, and they were found to have elevated catecholamine levels and elevated vascular α1 adrenergic receptor gene expression. Telemetry studies showed that the F233Δ mice were tachycardic and hypotensive at baseline, consistent with diminished vascular tone. In biochemical studies, ZDHHC21 was shown to palmitoylate the α1D adrenoceptor and to interact with it in a molecular complex, thus suggesting a possible molecular mechanism by which the receptor can be regulated by ZDHHC21. Together, the data support a model in which ZDHHC21 F233Δ diminishes the function of vascular α1 adrenergic receptors, leading to reduced vascular tone, which manifests in vivo as hypotension and tachycardia. This is to our knowledge the first demonstration of a ZDHHC isoform affecting vascular function in vivo and identifies a novel molecular mode of regulation of vascular tone and blood pressure.

Time course of muscle sympathetic nerve activity to active muscle during mild isometric contractions in humans

Ethanol consumption is associated with several cardiovascular dysfunctions. Studies indicate that exercise and testosterone can alter the ethanol consumption. However, the influence of these factors in ethanol-evoked cardiovascular changes is unknown. Here we investigated the influence of physical training and testosterone treatment in changes on blood pressure, heart rate (HR), and baroreflex activity evoked by ethanol consumption. For this, sedentary and trained animals were randomly assigned to 4 experimental groups treated with etanol (20%) and/or testosterone (10 mg/kg, s.c.). The training protocol was performed on a treadmill and consisted of a continuous 60-min session 5 days/week for 6 weeks. Rats had free access to ethanol 20% and water bottles 3 times a week during the entire training protocol. During the last 2 weeks, testosteronewas administrated daily concurrentlywith exercise and ethanol access. Analysis of arterial pressure did not indicate effect of either physical training (P N 0.05) or treatments (P N 0.05). However, testosterone treatment (alone or in combination with ethanol) reduced HR (P b 0.05). Physical training did not affect HR (P N 0.05). Neither physical training nor ethanol/testosterone affected bradycardiac response to blood pressure increase evoked by intravenous phenylephrine infusion (P N 0,05) and tachycardiac responses to blood pressure decrease evoked by intravenous infusion of sodium nitroprusside (P N 0.05). These results did not indicate an impact of intermittent ethanol consumption in a free-choice model on cardiovascular function, contrasting with previous results using continuous access to ethanol solution as the sole fluid source. Nevertheless, testosterone treatment evoked resting bradycardia, which was not affected by either ethanol consumption or physical training. Financial support: FAPESP, PADC/FCF-UNESP.

Cardiopulmonary and arterial baroreceptor unloading during passive hyperthermia does not contribute to hyperthermia-induced hyperventilation.

What is the central question of this study? Does baroreceptor unloading during passive hyperthermia contribute to increases in ventilation and decreases in end-tidal carbon dioxide during that exposure? What is the main finding and its importance? Hyperthermic hyperventilation is not mitigated by expanding central blood volume and reloading the cardiopulmonary baroreceptors via rapid saline infusion or by reloading the arterial baroreceptors via phenylephrine administration. The absence of a reduction in ventilation upon reloading the baroreceptors to pre-hyperthermic levels indicates that cardiopulmonary and arterial baroreceptor unloading with hyperthermia is unlikely to contribute to hyperthermic hyperventilation in humans. This study tested the hypothesis that baroreceptor unloading during passive hyperthermia contributes to increases in ventilation and decreases in end-tidal partial pressure of carbon dioxide (P ET ,CO2) during that exposure. Two protocols were performed, in which healthy subjects underwent passive hyperthermia (increasing intestinal temperature by ∼1.8°C) to cause a sustained increase in ventilation and reduction in P ET ,CO2. Upon attaining hyperthermic hyperventilation, in protocol1 (n=10; three females) a bolus (19±2mlkg(-1) ) of warm (∼38°C) isotonic saline was rapidly (5-10min) infused intravenously to restore reductions in central venous pressure, whereas in protocol2 (n=11; five females) phenylephrine was infused intravenously (60-120μgmin(-1) ) to return mean arterial pressure to normothermic levels. In protocol1, hyperthermia increased ventilation (by 2.2±1.7lmin(-1) , P<0.01), while reducing P ET ,CO2 (by 4±3mmHg, P = 0.04) and central venous pressure (by 5±1mmHg, P <0.01). Saline infusion increased central venous pressure by 5±1 mmHg (P<0.01), restoring it to normothermic values, but did not change ventilation or P ET ,CO2 (P>0.05). In protocol2, hyperthermia increased ventilation (by 5.0±2.7lmin(-1) , P <0.01) and reduced P ET ,CO2 (by 5±2 mmHg, P<0.01) and mean arterial pressure (by 9±7mmHg, P <0.01). Phenylephrine infusion increased mean arterial pressure by 12±3mmHg (P<0.01), restoring it to normothermic values, but did not change ventilation or P ET ,CO2 (P>0.05). The absence of a reduction in ventilation upon reloading the cardiopulmonary and arterial baroreceptors to pre-hyperthermic levels indicates that baroreceptor unloading with hyperthermia is unlikely to contribute to hyperthermic hyperventilation in humans.

Hypertensive rat model induced by iv infusion of phenylephrine via programmable pump

Hypertensive rat model induced by iv infusion of phenylephrine via programmable pump

Response letter: “ATF3: A promoter or inhibitor of cardiac maladaptive remodeling”

We thankYang et al. for their important comments regarding our recent manuscript “ATF3-dependent cross-talk between cardiomyocytes and macrophages promotes cardiac maladaptive remodeling” by Koren et al. [1]. We completely agree with the authors that the discrepancy can be explained by the different models used in the studies. Our analysis is based on the phenylephrine (PE) infusion pressure overload model and ATF3 transgenic mice. The results from these studies are consistent with ATF3's role in promoting cardiac hypertrophy [1,2]. In contrast, studies using the transverse aortic constriction (TAC) model suggest a cardio-protective role for ATF3 [3–6]. The opposing functions of ATF3 observed in the two models may be explained by the timing and duration of ATF3 expression. In the PE model, ATF3 expression is induced transiently and involves the recruitment of macrophages to the heart in an ATF3 dependent manner [1]. In the TAC model, whereas the involvement of immune cells is yet to be determined, persistent ATF3 expression appears as cardioprotective [3]. However, prolonged adult cardiac ATF3 expression displays maladaptive cardiac remodeling [2]. So how can constitutive ATF3 expression lead to opposite outcome? Previously, we showed that ATF3 may switch between either an inhibition or an activation mode, depending on the cellular context and protein partner, i.e. ATF3 inhibits transcription as a homodimer from TPA response elements, but activates transcription as a heterodimer with CHOP10 [7]. Revealing whether ATF3 exhibits differential transcriptional activity in the TAC, ATF3-transgenic mice and PE models may provide an explanation for the resulting diverse outcomes. Collectively, in mice models, ATF3 can play either a promoting or an inhibiting role in cardiacmaladaptive remodeling processes. Significantly