Adrenergic Blockade Research Articles

En bloc resection of a pheochromocytoma metastatic to the spine for local tumor control and for treatment of chronic catecholamine release and related hypertension

Resection of metastatic pheochromocytomas may be complicated by transient postoperative neurological deficits due to hypotension. The authors report the first case of en bloc excision of a spinal pheochromocytoma with associated long-term hypertensive management off all medication. Interestingly, this is the first case of transient hypotension following en bloc resection of pheochromocytoma associated with temporary hypotension-associated neurological decline that resolved completely after correction of hypotension postoperatively. A 23-year-old man with a prior adrenalectomy for pheochromocytoma presented with focal thoracic pain. He had a known T-10 vertebral body lesion for which he received chemotherapy and radiation therapy. Imaging demonstrated increased destruction of the T-10 vertebral body, which was concerning for tumor growth. The patient underwent angiographic embolization followed by single-stage posterior en bloc vertebrectomy with placement of a cage and posterior instrumentation and fusion without event. However, approximately 24 hours after surgery, the patient's systolic blood pressure was consistently no higher than 70 mm Hg. During this time, he began suffering from severe bilateral lower-extremity weakness. His systolic blood pressure increased with dopamine, and his strength immediately improved. The patient's oral regimen of adrenergic blockade was stopped, and he recovered without event. Since that time, the patient has been symptom free and requires no antihypertensive medication. The role of en bloc resection for metastatic lesions of the spine is controversial but may be warranted in cases of metastatic pheochromocytoma. En bloc resection avoids intralesional tumor resection and thus may help prevent complications of hypertensive crisis associated with hormonal secretion and extensive blood loss, which are not uncommon with pheochromocytoma resection surgeries. Additionally, the role of en bloc spondylectomy in this setting may allow for metabolic treatment as patients with actively secreting tumors may no longer require antiadrenergic medications.

Elevated plasma norepinephrine inhibits insulin secretion, but adrenergic blockade reveals enhanced β-cell responsiveness in an ovine model of placental insufficiency at 0.7 of gestation

In pregnancies complicated by placental insufficiency (PI), fetal hypoglycemia and hypoxemia progressively worsen during the third trimester, which increases circulating norepinephrine (NE). Pharmacological adrenergic blockade (ADR-block) at 0.9 gestation revealed that NE inhibits insulin secretion and enhanced β-cell responsiveness in fetuses with PI-induced intrauterine growth restriction (IUGR). NE concentrations in PI fetuses at 0.7 gestation were threefold greater compared with age-matched controls, but the levels were similar to near-term controls. Therefore, our objective was to determine whether elevations in plasma NE concentrations inhibit insulin secretion and produce compensatory β-cell responsiveness in PI fetuses at 0.7 gestation. Fetal insulin was measured under basal, glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-stimulated insulin secretion (GPAIS) conditions in the absence and presence of an ADR-block. Placental weights were 38% lower (P < 0.05) in PI fetus than in controls, but fetal weights were not different. PI fetuses had lower (P < 0.05) basal blood oxygen content, plasma glucose, insulin-like growth factor-1 and insulin concentrations and greater plasma NE concentrations (891 ± 211 v. 292 ± 65 pg/ml; P < 0.05) than controls. GSIS was lower in PI fetuses than in controls (0.34 ± 0.03 v. 1.08 ± 0.06 ng/ml; P < 0.05). ADR-block increased GSIS in PI fetuses (1.19 ± 0.11 ng/ml; P < 0.05) but decreased GSIS in controls (0.86 ± 0.02 ng/ml; P < 0.05). Similarly, GPAIS was 44% lower (P < 0.05) in PI fetuses than in controls, and ADR-block increased (P < 0.05) GPAIS in PI fetuses but not in controls. Insulin content per islet was not different between treatments. We conclude that elevations in fetal plasma NE suppress insulin concentrations, and that compensatory β-cell stimulus-secretion responsiveness is present before IUGR.

Contribution of sympathetic activation to coronary vasodilatation during the cold pressor test in healthy men: effect of ageing

The sympathetic nervous system is an important regulator of coronary blood flow. The cold pressor test (CPT) is a powerful sympathoexcitatory stressor. We tested the hypotheses that: (1) CPT-induced sympathetic activation elicits coronary vasodilatation in young adults that is impaired with advancing age and (2) combined α- and β-adrenergic blockade diminishes/abolishes these age-related differences. Vascular responses of the left anterior descending artery to the CPT were determined by transthoracic Doppler echocardiography before (pre-blockade) and during (post-blockade) systemic co-administration of α- and β-adrenergic antagonists in young (n = 9; 26 ± 1 years old, mean ± SEM) and older healthy men (n = 9; 66 ± 2 years old). Coronary vascular resistance (CVR; mean arterial pressure/coronary blood velocity) was used as an index of vascular tone. CPT decreased CVR (i.e. coronary vasodilatation occurred) in young ( -33 ± 6%), but not older men ( -3 ± 4%; P < 0.05 vs. young) pre-blockade. Adrenergic blockade abolished CPT-induced coronary vasodilatation in young men ( -33 ± 6% vs. 0 ± 6%, pre-blockade vs. post-blockade, respectively; P < 0.05) such that responses post-blockade mirrored those of older men ( -3 ± 4% vs. 8 ± 9%; both P > 0.05 compared to young pre-blockade). Impaired CPT-induced coronary vasodilatation could not be explained by a reduced stimulus for vasodilatation as group and condition effects persisted when CVR responses were expressed relative to myocardial oxygen demand (rate-pressure product). These data indicate that the normal coronary vascular response to sympathetic activation in young men is pronounced vasodilatation and this effect is lost with age as the result of an adrenergic mechanism. These findings may help explain how acute sympathoexcitation may precipitate angina and coronary ischaemic events, particularly in older adults.

Plasticity of cardiovascular function in snapping turtle embryos (Chelydra serpentina): chronic hypoxia alters autonomic regulation and gene expression

Reptile embryos tolerate large decreases in the concentration of ambient oxygen. However, we do not fully understand the mechanisms that underlie embryonic cardiovascular short- or long-term responses to hypoxia in most species. We therefore measured cardiac growth and function in snapping turtle embryos incubated under normoxic (N21; 21% O₂) or chronic hypoxic conditions (H10; 10% O₂). We determined heart rate (fH) and mean arterial pressure (Pm) in acute normoxic (21% O₂) and acute hypoxic (10% O₂) conditions, as well as embryonic responses to cholinergic, adrenergic, and ganglionic pharmacological blockade. Compared with N21 embryos, chronic H10 embryos had smaller bodies and relatively larger hearts and were hypotensive, tachycardic, and following autonomic neural blockade showed reduced intrinsic fH at 90% of incubation. Unlike other reptile embryos, cholinergic and ganglionic receptor blockade both increased fH. β-Adrenergic receptor blockade with propranolol decreased fH, and α-adrenergic blockade with phentolamine decreased Pm. We also measured cardiac mRNA expression. Cholinergic tone was reduced in H10 embryos, but cholinergic receptor (Chrm2) mRNA levels were unchanged. However, expression of adrenergic receptor mRNA (Adrb1, Adra1a, Adra2c) and growth factor mRNA (Igf1, Igf2, Igf2r, Pdgfb) was lowered in H10 embryos. Hypoxia altered the balance between cholinergic receptors, α-adrenoreceptor and β-adrenoreceptor function, which was reflected in altered intrinsic fH and adrenergic receptor mRNA levels. This is the first study to link gene expression with morphological and cardioregulatory plasticity in a developing reptile embryo.

Angiotensin II and developmental cardiovascular‐renal interactions in embryonic chickens

The role of Angiotensin II (ANGII) in cardiovascular‐renal interactions during embryonic development of White Leghorn chickens (Gallus gallus domesticus) was examined. Captopril, an angiotensin‐converting enzyme (ACE) inhibitor, or control saline, was delivered via the egg air cell on days 5–18. Masses, fluid osmolality and mean arterial pressure (MAP) and heart rate (fH) were measured on day 19 (90% of incubation). Embryo and heart masses did not differ between control and captopril embryos, but kidney wet and dry masses were both 10% larger in captopril embryos. In addition, blood osmolality was significantly lower. Captopril embryos were significantly hypotensive, with a MAP 15% lower than controls, but fH did not differ. MAP and fH of captopril embryos did not respond to an injection of Angiotensin I (ANGI), confirming ACE inhibition. ANGII induced a stronger hypertensive response in captopril embryos, with adrenergic and ganglionic blockade indicating that this was due to peripheral catecholamines. Chronic removal of embryonic ANGII has both cardiovascular and renal effects, implying “crosstalk” between the developing systems. Funding from NSF (IOS‐1025823) to WB.

Effect of Beta Adrenergic Stimulation and Blockade on Intrapulmonary Arteriovenous Anastamoses Recruitment

Intrapulmonary arteriovenous anastomoses (IPAVs) are large diameter conduits that bypass the pulmonary circulation. IPAVs can be recruited in humans by catecholamines and it has been suggested that this occurs as a result of an elevated cardiac output. In contrast, we hypothesized that IPAVs recruitment occurs as a result of beta adrenergic‐mediated vasodilation. To test our hypothesis, we measured the transpulmonary passage of 2.5×105 venous‐injected microspheres (25–50 μm) in anesthetized, room air ventilated rats infused with either saline (n=6) or isoproterenol (n=6) and found substantial microsphere passage in the isoproterenol group (0.4±0.9% vs 10.5±15.2%, p=0.007). However, because the contributions of cardiac output and vasodilation cannot be isolated in the intact model, we also perfused isolated rat lungs with buffered hetastarch (n=6) or isoproterenol (n=9), taking care to match pulmonary artery pressure and flow between groups. Transpulmonary microsphere passage occurred only in isoproterenol perfused lungs (1±3 vs 200±278, p=0.001). This suggests that, contrary to previous conclusions, catecholamines recruit IPAVs independently of increases in cardiac output, through active vasodilation. In subsequent preliminary work, we hypothesized that catecholamines are necessary for full IPAVs recruitment by hypoxia. In rats ventilated with 10% O2, pre‐treatment with propranolol (n=4) decreased the passage of microspheres by 58% compared to controls (n=5) (14.7±25.0 vs 6.1±3.2, p=0.10) but did not abolish the response. This suggests that the response to hypoxia is multifactorial, but that catecholamines are important contributors to IPAVs recruitment in hypoxia.

Safety and curative effect analysis of bilateral simultaneous adrenalectomy for the treatment of the bilateral adrenal pheochromocytoma associated with multiple endocrine neoplasia type 2A

Objective To study the clinical features of the bilateral adrenal pheochromocytomas (PHEO) in patients associated with multiple endocrine neoplasia type 2A (MEN2A) and to evaluate the safety and feasibility of applying simultaneous bilateral adrenalectomy (SBA).Methods From November 2003 to April 2011,clinical data of 8 patients from 4 unrelated MEN2A families treated with SBA were analyzed.There were 6 males and 2 females.The mean age was 44 years (range,35 to 56 years).4 patients were asymptomatic and 4 had clinical features related to PHEO.The diagnosis of bilateral PHEO was made after the diagnosis of MTC in 4 cases,previous hypertension in 1 case,and family investigation found 3 MTC and all were found with hyperparathyroidism.Plasma catecholamines were substantially elevated in 4 patients.Ultrasound and computerized tomography (CT) examination showed bilateral adrenal masses,of which 6 were bilateral and multiple tumors,2 were single tumor in one side and multiple tumors in the other side.On contrast CT,the tumors displayed heterogeneous contrast enhancement and low density area in the center of the tumors observed in 3 cases;renal,splenic vessels displacement and deformation were observed;local lymph node enlargement was not found.The mean maximum diameter of PHEO was 4.4 cm (range,2.7 to 7.0 cm).RET screening showed a heterozygous nucleotide substitution on exon 11,c.G1901A (p.C634Y) in all patients.After adequate adrenergic blockade,the SBA was performed by a single surgeon,PHEO were extirpated by laparoscopic radical adrenalectomy in 2 patie.nts,while in other 6 patients,PHEO were removed by partial adrenalectomy or adrenal tumorectomy with at least one normal appearing adrenal tissue preserved (4 by laparoscopic approach and 2 by open approach).Results The procedures were successful carried out on 8 cases with bilateral PHEO.There were totally 43 pieces of tumor obtained.The average time of operation was 181 min (range,150 to 240 min).Mean blood loss was 171ml (range,100 to 300 ml).Blood pressure fluctuations happened in 2 cases during operation (maximum:230/110 vs minimum:70/40 mm Hg).Histopathology showed PHEO in all patients.During the follow-up of 35 months (range,3 to 90),local and/or distant metastatic recurrence was not found in all cases,while two treated by total bilateral adrenalectomy and one by adrenal-sparing surgery required corticosteroid replacement.Conclusions SBA for bilateral PHEO in MEN2A is technically safe and feasible.Transperitoneal laparoscopic partial adrenalectomy for the treatment of bilateral PHEO can be considered as preferential choice. Key words: Multiple endocrine neoplasia type 2A; Pheochromocytoma; Bilateral simultaneous adrenalectomy; RET gene; Laparoscopy

A Case of Functioning Paraganglioma Mimicking Anaphylactic Shock - A Case Report -

Paraganglioma is a tumor originating from the extra-adrenal chromaffin cells, and functional paraganglioma causes paroxysmal hypertension, headache and tachycardia, due to excess excretion of catecholamine. However, rarely, ARDS, acute myocardial infarction, heart failure, arrhythmia, and pulmonary edema are also seen in patients with paraganglioma and clinical manifestations are depending on the patient’s intravascular volume status. Seventy one-years-old male was presented with hypotension and pulmonary edema after intravenous midazolam injection during colonoscopy under conscious sedation. The patient was initially suspected with anaphylactic shock, due to midazolam injection. However, later, he was diagnosed with paraganglioma, and blood pressure was successfully controlled with alpha adrenergic blockade. We suggest that when we encounter heart failure, pulmonary edema and shock of unknown origin, pheochromocytoma must be taken into consideration.

Laparoscopic adrenal surgery: ten-year experience in a single institution

BackgroundMinimal invasive adrenalectomy has become the procedure of choice to treat adrenal tumors with a benign appearance, ≤ 6 cm in diameter and weighing < 100 g. Authors evaluated medium- and long-term outcomes of laparoscopic adrenalectomy (LA), performed for ten years in a single endocrine surgery unit.MethodsWe retrospectively reviewed 88 consecutive patients undergone LA for lesions of adrenal glands from 2003 to 2013. The first 30 operations were considered part of the learning curve. Doxazosin was preoperatively administered in case of pheochromocytoma (PCC), while spironolactone and potassium were employed to treat Conn's disease. Perioperative cardiovascular status modifications and surgical and medium- and long-term results were analyzed.ResultsForty nine (55.68%) functioning tumors, and one (1.13%) bilateral adrenal disease were identified. In 2 patients (2.27%) a supposed adrenal metastasis was postoperatively confirmed, while in no patients a diagnosis of incidental primitive malignancy was performed. There was no mortality or major post operative complication. The mean operative time was higher during the learning curve. Conversion and morbidity rates were respectively 1.13% and 5.7%. Intraoperative hypertensive crises (≥180/90 mmHg) were observed in 23.5% (4/17) of PCC patients and were treated pharmacologically with no aftermath. There was no influence of age, size and operative time on the occurrence of PCC intraoperative hypertensive episodes. Surgery determined a normalization of the endocrine profile. One single PCC persistence was observed, while in a Conn's patient, just undergone right LA, a left sparing adrenalectomy was performed for a contralateral metachronous aldosteronoma.ConclusionsLA, a safe, effective and well tolerated procedure for the treatment of adrenal neoplasms ≤ 6 cm, is feasible for larger lesions, with a similar low morbidity rate. Operative time has improved along with the increase of the experience and of the technological development. Preoperative adrenergic blockade did not prevent PCC intraoperative hypertensive crises, but facilitated the control of the hemodynamic stability.

Pheochromocytoma Anesthetic Management

Pheochromocytomas are catecholamine producing tumors and although uncommon present a great challenge to the anesthesiologist since it has nonspecific clinical symptoms and risk of critical events, including death when not previously diagnosed. Clinical manifestation is variable, unspecific and depends on the catecholamine production profile. The classic triad of headache, palpitation and diaphoresis is present in up to 70% of the cases and only 50% have sustained hypertension. The best approach for pheochromocytoma treatment is surgical excision of the affected adrenal gland. The introduction of alpha adrenergic blockade medication, such as phentolamine and phenoxybenzamine had the highest impact in perioperative mortality reduction due to inhibition of the deleterious effect of vasoconstriction. The majority of anesthetic techniques and drugs are considered safe. Post-operative care in intensive care unit is advisable since patients may present instability of blood pressure and hypoglycemia. Genetic testing should be done in first-degree relatives of confirmed cases or when a genetic syndrome is suspected.

Laparoscopic adrenalectomy, a safe procedure for pheochromocytoma. A retrospective review of clinical series

BackgroundMinimally invasive adrenalectomy for pheochromocytoma (PCC) is a complex surgical procedure especially because of the haemodynamic instability due to the excessive secretion of cathecolamines, which may result in a considerable risk of conversion and complications. AimBy a multicentric retrospective study, the authors reported the results of laparoscopic adrenalectomies in patients operated for adrenal pheochromocytomas with the aim of investigating the role of the laparoscopic approach in managing adrenal disease. MethodsSixty patients, preoperatively treated with a selective alpha1-blocker, underwent 61 laparoscopic adrenalectomies for PCC smaller or larger than 6 cm – group A (≤6 cm), group B (>6 cm). We compared the two groups of patients analyzing haemodynamic instability, operative time, conversion rate, incidence of complications, length of hospital stay and medium and long-term outcomes. ResultsIn 23 cases tumor was >6 cm in diameter. Average operative time was 165 min, with a 5% conversion rate. There was no mortality and morbidity rate was 8.3%. Intraoperative hypertensive crises were registered in 15% of patients, whereas 5/60 patients had hypotensive crises. After comparing the two groups of patients, no statistically significant differences in terms of haemodynamic instability, operative time, conversion rate, morbidity and length of hospital stay were observed. ConclusionsAs a surgical treatment of pheochromocytomas, laparoscopic adrenalectomy is an effective and safe approach, in selected cases even for PCCs >6 cm in diameter, although patients with such large tumors may have a higher conversion rate and more intraoperative hypertensive crises. Preoperative selective adrenergic blockade does not prevent intraoperative hypertensive crises, but by facilitating the pharmacological management of the perioperative haemodynamic instability, may avoid the onset of major adverse cardiovascular complications.

Abstract 71: A Novel Animal Model of Pulseless Electrical Activity Cardiac Arrest: Adrenergic Blockade and Coronary Occlusion

Introduction: The incidence of VF as the first documented rhythm in out-of-hospital cardiac arrest (OOHCA) has been declining, while the incidence of pulseless electrical activity (PEA) has been increasing. The increasing proportion of PEA as the initial rhythm for OOHCA has paralleled the increasing use of adrenergic antagonist therapy in the population most at risk for cardiac arrest. We hypothesized that PEA cardiac arrest can result from acute coronary occlusion in the setting of pre-arrest adrenergic blockade. Methods: Twenty-six anesthetized and instrumented immature male swine (mean weight 36 kg) were pre-treated with an infusion of labetalol, a β-1 and α-1 adrenergic blocker (mean dose 6 ± 3 mg/kg). Adequacy of adrenergic blockade was determined using an intravenous challenge of epinephrine 0.1 mg IV. After challenge and return to baseline, balloon occlusion of the left anterior descending (LAD) or proximal right coronary artery (RCA) was performed and the rhythm and hemodynamic response observed during sustained occlusion. Results: Occlusion of the RCA was followed by PEA or pseudo-PEA (defined as an organized rhythm with systolic arterial pressure &lt;50 mm Hg) in 10/13 animals (77%). During RCA occlusion, cooling of the vagus nerve (reversible thermal vagotomy) did not prevent the hypotensive hemodynamic response. LAD occlusion was followed by PEA in 6/13 animals (46%). Brief occlusion of the RCA followed by occlusion of the LAD was followed by PEA in 5/7 animals (71%). Conclusions: Adrenergic blockade followed by coronary occlusion may be followed by PEA. This combination may play a role in the declining incidence of VF as the initial cardiac arrest rhythm in out-of-hospital cardiac arrest.

α1‐Adrenergic receptor control of the cerebral vasculature in humans at rest and during exercise

We tested the hypothesis that pharmacological blockade of α(1)-adrenoreceptors (by prazosin), at rest and during steady-state dynamic exercise, would impair cerebral autoregulation and result in cerebral vasodilatation in healthy humans. In 10 subjects, beat-to-beat mean arterial pressure and mean middle cerebral artery blood velocity were determined at rest and during low (Ex90) and moderate workload (Ex130) on an upright bicycle ergometer without and with prazosin. Plasma noradrenaline concentrations increased significantly from rest to Ex130 during control conditions (from 1.8 ± 0.2 to 3.2 ± 0.3 pmol (ml plasma)(-1)). In the control conditions, the transfer function gain between mean arterial pressure and mean middle cerebral artery blood velocity in the low-frequency range was decreased at Ex90 (P = 0.035) and Ex130 (P = 0.027) from rest. A significant increase in critical closing pressure (CCP) was also observed in the control conditions from rest to Ex90 to Ex130 (from 18 ± 3 to 24 ± 4 to 31 ± 4 mmHg). An average of 74 ± 2% blockade of blood pressure response was achieved with oral prazosin. Following blockade, plasma noradrenaline concentrations further increased at rest and during Ex130 from the control value (from 2.6 ± 0.3 to 4.4 ± 0.5 pmol (ml plasma)(-1)). Prazosin also resulted in an increase in low-frequency gain (P < 0.003) compared with the control conditions. Prazosin blockade abolished the increases in CCP during Ex130 and increased the cerebrovascular conductance index (P = 0.018). These data indicate that in the control conditions a strengthening of cerebral autoregulation occurred with moderate dynamic exercise that is associated with an increase in CCP as a result of the exercise-mediated augmentation of sympathetic activity. Given that α(1)-adrenergic receptor blockade attenuated the increase in dynamic cerebral autoregulation and CCP, we conclude that increases in sympathetic activity have a role in establishing cerebral vascular tone in humans.

Preischemic Vagal Efferent Stimulation Increases Infarct Size in Rabbits

It has been shown that vagal stimulation induces cardioprotective effects and the administration of acetylcholine mimics ischemic preconditioning. However, there are no conclusive data about the effects of in vivo vagal stimulation on myocardial infarction. The objective of this study was to evaluate the effects of vagal stimulation on experimental myocardial infarction induced in rabbits subjected to 45 min of regional myocardial ischemia by ligation of a branch of the left coronary artery, followed by 4 hours of reperfusion (G1, n=14). In group 2 (G2, n=9) G1 protocol was repeated and, before inducing ischemia, right efferent vagal stimulation was performed during 10 min to an intensity enough to reduce heart rate by 10-20% followed by a recovery period of 5 min. In group 3 (G3, n=5) the G2 protocol was repeated, but atropine was administered during vagal stimulation. In other experimental groups the G2 protocol was repeated and short-acting b1-adrenergic blocker (esmolol, G4, n=7) or long-acting beta blocker (atenolol, G5, n=5) were administered during the stimulation. Preischemic vagal stimulation increased the infarct size from 45.2%±2.4% to 62.9%±3.1% (p <0.05). Atropine reverseed this effect reducing the infarct size to 44.8%±3.9% (p <0.05 vs. G2). The administration of esmolol or atenolol attenuated the increase in infarct size to 50.1%±4.2% and 50.0%±2.9%, respectively (p <0,05). Preischemic efferent vagal stimulation significantly increases the infarct size by a muscarinic cholinergic mechanism. This effect is reverseed by beta adrenergic blockade. Applying vagal stimulation to different clinical scenarios might cause deleterious secondary effects.

Inducibility of Atrial Fibrillation After GP Ablations and “Autonomic Blockade”: Evidence for the Pathophysiological Role of the Nonadrenergic and Noncholinergic Neurotransmitters

Recent clinical reports that used cholinergic and adrenergic blockade (CAB) as an alternative to ganglionated plexi (GP) ablation to terminate atrial fibrillation (AF) showed mixed results. We investigated the role of other neurotransmitters in AF inducibility. In 23 pentobarbital anesthetized dogs, a left and right thoracotomy allowed the attachment of electrode catheters to the left and right pulmonary veins and atrial appendages (AA). Programmed stimulation was used to determine the effective refractory periods (ERP) and AF inducibility, measured by the window of vulnerability (WOV). AF duration in response to acetylcholine (Ach; 100 mM) applied to the AA was measured before and after GP ablation + CAB and with vagus nerve stimulation (VNS). After GP ablation + CAB, Ach induced AF duration was determined in response to vasoactive intestinal peptide (VIP) and its specific antagonist ([Ac-Tyr1,D-phe2]-VIP). GP ablation + CAB significantly prolonged ERP, eliminated WOV, and suppressed the duration of Ach induced AF (P ≤ 0.01 for all). Also slowing of the heart rate by VNS was essentially blocked; however, with Ach 100 mM applied to the AA, VNS, and VIP applied to the AA markedly prolonged AF duration. This effect was blocked by the VIP antagonist. Neither GP ablation nor CAB can fully suppress AF inducibility arising from the atrial neural network. Our findings suggest that other neurotransmitters, such as VIP released during VNS, can promote sustained AF despite GP ablation and "autonomic blockade," which may further define the substrate for AF outside the pulmonary vein-atrial junctions.

Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial

BackgroundSevere TBI, defined as a Glasgow Coma Scale ≤ 8, increases intracranial pressure and activates the sympathetic nervous system. Sympathetic hyperactivity after TBI manifests as catecholamine excess, hypertension, abnormal heart rate variability, and agitation, and is associated with poor neuropsychological outcome. Propranolol and clonidine are centrally acting drugs that may decrease sympathetic outflow, brain edema, and agitation. However, there is no prospective randomized evidence available demonstrating the feasibility, outcome benefits, and safety for adrenergic blockade after TBI.Methods/DesignThe DASH after TBI study is an actively accruing, single-center, randomized, double-blinded, placebo-controlled, two-arm trial, where one group receives centrally acting sympatholytic drugs, propranolol (1 mg intravenously every 6 h for 7 days) and clonidine (0.1 mg per tube every 12 h for 7 days), and the other group, double placebo, within 48 h of severe TBI. The study uses a weighted adaptive minimization randomization with categories of age and Marshall head CT classification. Feasibility will be assessed by ability to provide a neuroradiology read for randomization, by treatment contamination, and by treatment compliance. The primary endpoint is reduction in plasma norepinephrine level as measured on day 8. Secondary endpoints include comprehensive plasma and urine catecholamine levels, heart rate variability, arrhythmia occurrence, infections, agitation measures using the Richmond Agitation-Sedation Scale and Agitated Behavior scale, medication use (anti-hypertensive, sedative, analgesic, and antipsychotic), coma-free days, ventilator-free days, length of stay, and mortality. Neuropsychological outcomes will be measured at hospital discharge and at 3 and 12 months. The domains tested will include global executive function, memory, processing speed, visual-spatial, and behavior. Other assessments include the Extended Glasgow Outcome Scale and Quality of Life after Brain Injury scale. Safety parameters evaluated will include cardiac complications.DiscussionThe DASH After TBI Study is the first randomized, double-blinded, placebo-controlled trial powered to determine feasibility and investigate safety and outcomes associated with adrenergic blockade in patients with severe TBI. If the study results in positive trends, this could provide pilot evidence for a larger multicenter randomized clinical trial. If there is no effect of therapy, this trial would still provide a robust prospective description of sympathetic hyperactivity after TBI.Trial registrationClinicalTrials.gov NCT01322048

Beta adrenergic blockade decreases the immunomodulatory effects of social disruption stress.

During physiological or psychological stress, catecholamines produced by the sympathetic nervous system (SNS) regulate the immune system. Previous studies report that the activation of β-adrenergic receptors (βARs) mediates the actions of catecholamines and increases pro-inflammatory cytokine production in a number of different cell types. The impact of the SNS on the immune modulation of social defeat has not been examined. The following studies were designed to determine whether SNS activation during social disruption stress (SDR) influences anxiety-like behavior as well as the activation, priming, and glucocorticoid resistance of splenocytes after social stress. CD-1 mice were exposed to one, three, or six cycles of SDR and HPLC analysis of the plasma and spleen revealed an increase in catecholamines. After six cycles of SDR the open field test was used to measure behaviors characteristic of anxiety and indicated that the social defeat induced increase in anxiety-like behavior was blocked by pre-treatment with the β-adrenergic antagonist propranolol. Pre-treatment with the β-adrenergic antagonist propranolol did not significantly alter corticosterone levels indicating no difference in activation of the hypothalamic-pituitary-adrenal axis. In addition to anxiety-like behavior the SDR induced splenomegaly and increase in plasma IL-6, TNFα, and MCP-1 were each reversed by pre-treatment with propranolol. Furthermore, flow cytometric analysis of cells from propranolol pretreated mice reduced the SDR-induced increase in the percentage of CD11b(+) splenic macrophages and significantly decreased the expression of TLR2, TLR4, and CD86 on the surface of these cells. In addition, supernatants from 18h LPS-stimulated ex vivo cultures of splenocytes from propranolol-treated SDR mice contained less IL-6. Likewise propranolol pre-treatment abrogated the glucocorticoid insensitivity of CD11b(+) cells ex vivo when compared to splenocytes from SDR vehicle-treated mice. Together, this study demonstrates that the immune activation and priming effects of SDR result, in part, as a consequence of SNS activation.

Authors' Reply

To the Editor: Akashi et al present interesting comments on the role of catecholamines in takotsubo cardiomyopathy patients. Combined α- and β-adrenergic blockade is an intriguing hypothesis; however, the only evidence we are aware of for any benefit is in a rat immobilization stress model. In addition, as the commentators note, several studies have shown that catecholamine levels are not consistently elevated in patients with takotsubo cardiomyopathy. Nevertheless, many patients in our practice are treated on diagnosis with carvedilol and angiotensin-converting enzyme (ACE) inhibitor as with any other nonischemic cardiomyopathy. The duration of treatment varies according to physician preference. None of the patients in our study were on combined α- and β-blockers on presentation. The role of higher doses of β-adrenergic blockers in attenuation or prevention of this syndrome remains to be studied. We have published a case of recurrent takotsubo cardiomyopathy,1 where the recurrence was precipitated by a higher level stressor (cerebrovascular accident) than the first episode, and the patient developed much higher cardiac enzyme levels despite being on low dose β-blocker therapy, suggesting that the severity of the syndrome may to a large extent depend on the level of stressor. Our study is by no means definitive with regard to the role of adrenergic blockade in the prevention or attenuation of takotsubo cardiomyopathy. Additional studies with higher doses of β-adrenergic blockade and combined α- and β-blockade (although difficult to carry out given the low recurrence rates), would certainly provide additional insight into this question.

Altered baroreflex and autonomic modulation in monosodium glutamate-induced hyperadipose rats

We aimed to examine the cardiovascular function by tonic and baroreflex alterations in obese rats induced by monosodium glutamate (MSG). Neonatal male Wistar rats were injected with MSG (4 mg/g body weight) or equimolar saline (control, C). At 90 days, all rats were anesthetized for catheterization of the femoral artery for mean arterial pressure (MAP) and heart rate (HR) recordings in the conscious state. After baseline, we performed IV treatment with hexamethonium (25 mg/kg), or atropine (1 mg/kg) or propranolol (3 mg/kg). We also performed the spectral analysis of heart rate variability (HRV) and baroreflex sensitivity. Baseline comparison showed that obese rats are hypertensive compared with control (C=110±2 mmHg; MSG=: 123±3 mmHg, P<0.05). After ganglionic blockade with hexamethonium the differences in MAP between control and obese rats disappeared. Beta adrenergic blockade with propranolol induced a greater decrease in heart rate compared with control. The analysis of HRV showed that obese rats have increased modulation by both components of the autonomic nervous system compared with control rats. The baroreflex gain showed increased sensitivity for the parasympathetic component in the obese rats (C=−2.41±0.25; MSG=−3.34±0.23 bpm/mmHg) compared with control. Our data suggest that both components of autonomic cardiac tonus and the parasympathetic component of the baroreflex sensitivity are increased in the MSG obese rat. It is possible that the parasympathetic alterations observed in these MSG obese rats may have originated from central areas of cardiovascular control.

Vasodilatory effects of ethanol extract of Radix Paeoniae Rubra and its mechanism of action in the rat aorta

Ethnopharmacological relevanceRadix Paeoniae Rubra (RPR) is an important traditional Chinese medicine (TCM) commonly used in clinic for a long history in China. RPR is the radix of either Paeonia lactiflora Pall. or Paeonia veitchii Lynch. RPR has a wide variety of pharmacological actions such as anti-thrombus, anti-coagulation, and anti-atherosclerotic properties, protecting heart and liver. However, the mechanisms involved are to be defined. Aim of the studyThe aim of the present study was to define the effect of Paeonia lactiflora Pall. extracts on vascular tension and responsible mechanisms in rat thoracic aortic rings. Materials and methodsEthanol extract of Paeonia lactiflora Pall. (EPL) was examined for their vascular relaxant effects in isolated phenylephrine-precontracted rat thoracic aorta. ResultsEPL induced relaxation of the phenylephrine-precontracted aortic rings in a concentration-dependent manner. Vascular relaxation induced by EPL was significantly inhibited by removal of the endothelium or pretreatment of the rings with NG-nitro-l-arginine methylester (l-NAME) or 1H-[1,2,4]-oxadiazolo-[4,3-α]-quinoxalin-1-one (ODQ). Extracellular Ca2+ depletion or diltiazem significantly attenuated EPL-induced vasorelaxation. Modulators of the store-operated Ca2+ entry (SOCE), thapsigargin, 2-aminoethyl diphenylborinate and Gd3+, and an inhibitor of Akt, wortmannin, markedly attenuated the EPL-induced vasorelaxation. Further, the EPL-induced vasorelaxation was significantly attenuated by pretreatment with tetraethylammonium, a non-selective KCa channels blocker, or glibenclamide, an ATP-sensitive K+ channels inhibitor, respectively. Inhibition of cyclooxygenases with indomethacin, and adrenergic and muscarinic receptors blockade had no effects on the EPL-induced vasorelaxation. ConclusionsThe present study suggests that EPL relaxes vascular smooth muscle via endothelium-dependent and Akt- and SOCE-eNOS-cGMP-mediated pathways through activation of both KCa and KATP channels and inhibition of L-type Ca2+ channels.