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1.  Arterial baroreflex control of muscle sympathetic nerve activity under orthostatic stress in humans 
The mechanisms by which blood pressure is maintained against the orthostatic stress caused by gravity's effect on the fluid distribution within the body are important issues in physiology, especially in humans who usually adopt an upright posture. Peripheral vasoconstriction and increased heart rate (HR) are major cardiovascular adjustments to orthostatic stress and comprise part of the reflex response elicited via the carotid sinus and aortic baroreceptors (arterial baroreflex: ABR) and cardiopulmonary stretch receptors (cardiopulmonary baroreflex). In a series of studies, we have been characterizing the ABR-mediated regulation of cardiovascular hemodynamics and muscle sympathetic nerve activity (MSNA) while applying orthostatic stress in humans. We have found that under orthostatic stress, dynamic carotid baroreflex responses are modulated as exemplified by the increases in the MSNA, blood pressure, and HR responses elicited by carotid baroreflex unloading and the shorter period of MSNA suppression, comparable reduction and faster recovery of mean arterial blood pressure (MAP) and greater HR response to carotid baroreflex stimulation. Our results also show that ABR-mediated beat-to-beat control over burst incidence, burst strength and total MSNA is progressively modulated as orthostatic stress is increased until induction of syncope, and that the sensitivity of ABR control over the aforementioned MSNA variables is substantially reduced during the development of syncope. We suggest that in humans, the modulation of ABR function under orthostatic stress may be one of the mechanisms by which blood pressure is maintained and orthostatic hypotension limited, and impairment of ABR control over sympathetic vasomotor activity leads to the severe hypotension associated with orthostatic syncope.
doi:10.3389/fphys.2012.00314
PMCID: PMC3429084  PMID: 22934064
sympathetic nervous system; lower body negative pressure; integrated circulatory regulation; blood pressure; peripheral reflexes
2.  Plasma Norepinephrine in Hypertensive Rats Reflects α2-Adrenoceptor Release Control Only When Re-Uptake is Inhibited 
α2-adrenoceptors (AR) lower central sympathetic output and peripheral catecholamine release, thereby protecting against sympathetic hyperactivity and hypertension. Norepinephrine re-uptake–transporter effectively (NET) removes norepinephrine from the synapse. Overflow to plasma will therefore not reflect release. Here we tested if inhibition of re-uptake allowed presynaptic α2AR release control to be reflected as differences in norepinephrine overflow in anesthetized hypertensive spontaneously hypertensive rats (SHR) and normotensive rats (WKY). We also tested if α2AR modulated the experiment-induced epinephrine secretion, and a phenylephrine-induced, α1-adrenergic vasoconstriction. Blood pressure was recorded through a femoral artery catheter, and cardiac output by ascending aorta flow. After pre-treatment with NET inhibitor (desipramine), and/or α2AR antagonist (yohimbine, L-659,066) or agonist (clonidine, ST-91), we injected phenylephrine. Arterial blood was sampled 15 min later. Plasma catecholamine concentrations were not influenced by phenylephrine, and therefore reflected effects of pre-treatment. Desipramine and α2AR antagonist separately had little effect on norepinephrine overflow. Combined, they increased norepinephrine overflow, particularly in SHR. Clonidine, but not ST-91, reduced, and pertussis toxin increased norepinephrine overflow in SHR and epinephrine secretion in both strains. L-659,066 + clonidine (central α2AR-stimulation) normalized the high blood pressure, heart rate, and vascular tension in SHR. α2AR antagonists reduced phenylephrine-induced vasoconstriction equally in WKY and SHR. Conclusions: α2AAR inhibition increased norepinephrine overflow only when re-uptake was blocked, and then with particular efficacy in SHR, possibly due to their high sympathetic tone. α2AAR inhibited epinephrine secretion, particularly in SHR. α2AAR supported α1AR-induced vasoconstriction equally in the two strains. α2AR malfunctions were therefore not detected in SHR under this basal condition.
doi:10.3389/fneur.2012.00160
PMCID: PMC3492874  PMID: 23162530
α2-adrenoceptors; norepinephrine re-uptake transporter; hypertension; sympathetic nervous system activity; norepinephrine; epinephrine; catecholamine release; plasma catecholamine concentrations
3.  Epinephrine, phenylephrine, and methoxamine induce infiltrative anesthesia via α1-adrenoceptors in rats 
Acta Pharmacologica Sinica  2009;30(9):1227-1236.
Aim:
To assess whether epinephrine, phenylephrine, and methoxamine act via certain subtypes of adrenoceptors to exert their local anesthetic activity.
Methods:
We investigated cutaneous anesthesia from adrenoceptor agonists and/or antagonists in conscious, unanesthetized Sprague-Dawley male rats (weight 200−250 g). Cutaneous anesthesia was evidenced by a block of the cutaneous trunci muscle reflex, which is characterized by reflex movement of the skin over the back produced by twitches of lateral thoracispinal muscles in response to local dorsal cutaneous noxious pinprick.
Results:
Local infiltration of epinephrine, L-phenylephrine, or methoxamine alone induces cutaneous anesthesia in rats in a dose-dependent way. Epinephrine is found to be 19 and 29 times more potent than those of methoxamine and L-phenylephrine, respectively. The cutaneous anesthesia induced by epinephrine, phenylephrine, or methoxamine can be significantly reduced by α1-adrenoceptor antagonists (eg, prazosin), α1, α2-adrenoceptor antagonist, α1A-adrenoceptor antagonist (eg, 5-methylurapdil), α1B-adrenoceptor antagonist (eg, chloroethylclonidine), or α1D-adrenoceptor antagonist (eg, BMY7873).
Conclusion:
Our results indicate that epinephrine, phenylephrine and methoxamine all act mainly via mixed subtypes of α1-adrenoceptors to induce cutaneous anesthesia in the rat.
doi:10.1038/aps.2009.129
PMCID: PMC4007178  PMID: 19730427
anesthesia; epinephrine; vasoconstriction; phenylephrine; methoxamine
4.  Effects of Anesthetics on the Renal Sympathetic Response to Anaphylactic Hypotension in Rats 
PLoS ONE  2014;9(11):e113945.
The autonomic nervous system plays an important role in rat anaphylactic hypotension. It is well known that sympathetic nerve activity and cardiovascular function are affected by anesthetics. However, the effects of different types of anesthesia on the efferent renal sympathetic nerve activity (RSNA) during anaphylactic hypotension remain unknown. Therefore, we determined the renal sympathetic responses to anaphylactic hypotension in anesthetized and conscious rats and the roles of baroreceptors in these responses. Sprague-Dawley rats were randomly allocated to anesthetic groups that were given pentobarbital, urethane, or ketamine-xylazine and to a conscious group. The rats were sensitized using subcutaneously injected ovalbumin. The systemic arterial pressure (SAP), RSNA and heart rate (HR) were measured. The effects of sinoaortic baroreceptor denervation on RSNA during anaphylaxis were determined in pentobarbital-anesthetized and conscious rats. In all of the sensitized rats, the RSNA increased and SAP decreased after antigen injection. At the early phase within 35 min of the antigen injection, the antigen-induced sympathoexcitation in the conscious rats was significantly greater than that in the anesthetized rats. Anaphylactic hypotension was attenuated in the conscious rats compared to the anesthetized rats. The anesthetic-induced suppression of SAP and RSNA was greater in the order ketamine-xylazine >urethane = pentobarbital. Indeed, in the rats treated with ketamine-xylazine, RSNA did not increase until 40 min, and SAP remained at low levels after the antigen injection. The baroreceptor reflex, as evaluated by increases in RSNA and HR in response to the decrease in SAP induced by sodium nitroprusside (SNP), was suppressed in the anesthetized rats compared with the conscious rats. Consistent with this finding, baroreceptor denervation attenuated the excitatory responses of RSNA to anaphylaxis in the conscious rats but not in the pentobarbital-anesthetized rats. RSNA was increased markedly in conscious rats during anaphylactic hypotension. Anesthetics attenuated this antigen-induced renal sympathoexcitation through the suppression of baroreceptor function.
doi:10.1371/journal.pone.0113945
PMCID: PMC4244183  PMID: 25423366
5.  Vasopressor choice for hypotension in elective Cesarean section: ephedrine or phenylephrine? 
Introduction
Hypotensive episodes are a common complication of spinal anesthesia during Cesarean section. The purpose of this study was to compare the effectiveness and the side effects of vasopressors, ephedrine and phenylephrine, administered for hypotension during elective Cesarean section under spinal anesthesia.
Material and methods
The study consisted of 100 selected ASA I/II females scheduled for elective Cesarean section under spinal anesthesia. Each patient was randomly assigned to one of the two double-blind study groups. Group E received 1 ml ephedrine (5 mg/ml) with normal saline if hypotension was present (n=50). Group P received 1 ml phenylephrine (100 µg/ml) with normal saline if hypotension developed (n=50). Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) were compared within and between groups to basal levels at time increments of 0, 2, 4, 6, 8, 10, 15, 20, 25, 30, 45, and 60 min from start of surgery. Incidence of side effects and neonatal outcomes were studied between groups.
Results
All patients required vasopressor therapy for hypotension. Administration of phenylephrine was associated with significant drop in HR. Changes in SBP, DBP, and MAP were similar in both groups for most observed times. The incidences of nausea/vomiting and tachycardia were significantly higher in the ephedrine group.
Conclusions
Phenylephrine and ephedrine are acceptable choices to combat maternal hypotension related to spinal anesthesia in elective Cesarean section. Complications of intra-operative nausea and vomiting, tachycardia and bradycardia should be considered when choosing a vasopressor, suggesting phenylephrine may be more appropriate when considering maternal well-being.
doi:10.5114/aoms.2010.13905
PMCID: PMC3281349  PMID: 22371756
ephedrine; phenylephrine; spinal anesthesia; Cesarean section
6.  Idiopathic orthostatic hypotension from failure of noradrenaline release in a patient with vasomotor innervation. 
A 26 year old man is described with life-long orthostatic hypotension unrelated to autonomic nerve degeneration and apparently due to failure of peripheral noradrenaline realese. Tests of parasympathetic and sympathetic cholinergic nerve function were normal, but sympathetic adrenergic activity was defective. Thus blood pressure regulation was abnoraml. There was no pressor response to tyramine, an indirect sympathomimetic drug, but a marked pressor response to the directly acting sympathomimetic drugs phenylephrine and noradrenaline. On standing there was a progressive fall rather than a rise in circulating noradrenaline concentrations, although adrenaline levels rose normally. The pupils showed diminished responses to ephedrine and cocaine, and a normal response to phenylephrine. Fluorescence microscopy of blood bessels showed that they were innervated with adrenergic nerves. His orthostatic hypotenstion responded well to oral phenylephrine (50 mg five times daily) but not to other forms of therapy. It is suggested that this patient's symptoms were due to failure of noradrenaline release even though sympathetic adrenergic nerves were present. We therfore wish to draw attention to a further cause of orthostatic hypotension, failure of peripheral noradrenaline release without autonomic neuropathy.
Images
PMCID: PMC492598  PMID: 191566
7.  Cannabinoid Receptor Activation in the Nucleus Tractus Solitaries Produces Baroreflex-Like Responses in the Rat 
The effects of cannabinoids on the baroreflex have been investigated in the nucleus tractus solitarii (NTS). In urethane-anesthetized rats, microinjection of the cannabinoid (CB) receptor agonist WIN 55212-2 (100 mM) into the NTS produced a short lasting decrease in arterial pressure (from 95.2 ± 2.9 to 76.2 ± 1.5, n=5, P<0.05) but no change in the heart rate. Another cannabinoid agonist, CP 55940 (100 mM) also caused hypotensive responses (from 90.2 ± 11.3 to 66.4 ± 12.3 mmHg, n=5, P<0.05). Simultaneous sympathetic nerve discharge recordings showed suppression prior to the arterial pressure lowering effect of these agonists. Microinjection of the cannabinoid receptor antagonist, AM 281 (70 mM) did not cause any significant change in arterial pressure (from 100.8 ± 12 mmHg to 108.1 ± 12.8 mmHg, n=5, P>0.05) though it inhibited the agonist-induced responses. The non-NMDA receptor antagonist, DNQX (4 mM) microinjections antagonized the actions of CB agonist WIN 55212-2. Furthermore, sinoaortic denervation attenuated the responses to CB agonists suggesting an intact baroreflex arc is necessary to elicit CB-mediated effects. Neither WIN 55212-2 nor AM 281, altered baroreceptor reflex activation by bolus phenylephrine (25 microg//kg) injections. These data suggest that cannabinoid receptors in the NTS are not involved in the tonic regulation of the arterial pressure but may have a modulatory role in the baroreceptor reflex integration.
PMCID: PMC3614708  PMID: 23675095
cannabinoids; arterial pressure; cardiovascular integration; glutamate; brain stem
8.  Postural Blood Pressure Changes and Associated Factors in Long-Term Type 1 Diabetes: Wisconsin Epidemiologic Study of Diabetic Retinopathy 
Purpose
To describe the frequency of orthostatic hypotension and hypertension and associations with risk factors in a cohort of persons with long term type 1 diabetes (n=440) participating in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR).
Methods
Evaluations included detailed medical history, electrocardiography (ECG), and laboratory tests. Blood pressure (BP) was measured in supine and standing positions. Standing decrease in systolic (SBP) or diastolic (DBP) BP of at least 20 mmHg or 10 mmHg, respectively, was defined as orthostatic hypotension; increase of SBP from <140 to ≥ 140mmHg or DBP from < 90 to ≥ 90mmHg was defined as orthostatic hypertension.
Results
Prevalence of orthostatic hypotension and orthostatic hypertension was 16.1% and 15.2%, respectively. Some ECG measurements of cardiac autonomic dysfunction were significantly associated with orthostatic hypotension. Association between SBP and orthostatic hypotension and orthostatic hypertension were significant (Odds Ratio (95% CI), 1.02 (1.01–1.05) and 1.02 (1.01–1.04), respectively) after adjusting for confounders. Interaction between SBP and age was observed. SBP was significantly associated with orthostatic hypotension and orthostatic hypertension in people ≤ 40 years old (1.35 (1.02–1.78) and 1.12 (1.05–1.18), respectively).
Conclusions
Results showed that measurements derived from the ECG can help describe an individual at increased risk of having postural BP changes. Moreover, SBP was associated with postural BP changes among individuals who were < 40 years of age with long-term type 1 diabetes.
doi:10.1016/j.jdiacomp.2008.01.002
PMCID: PMC2667332  PMID: 18413171
diabetes complications; hypertension; hypotension; prevalence; risk
9.  Orthostatic Dysregulation during Postural Change on the Dental Chair and Intraoperative Monitoring by Heart Rate Variability Analysis 
Case Reports in Dentistry  2014;2014:656045.
This is the first case report of orthostatic dysregulation (OD) manifested during postural change on the dental chair and intraoperatively monitored by heart rate variability (HRV) analysis. OD-associated autonomic dysfunction is induced by postural changes and easily leads to disturbance in circulatory dynamics; however, most dental practices have not yet realized the importance of managing OD. We measured autonomic activity in a patient with OD during dental therapy and assessed the clinical significance of HRV analysis for OD. The patient was a 17-year-old Japanese female. She was diagnosed with impacted wisdom teeth and had no previous history of a distinct systemic disease. A surgical procedure to extract the teeth was safely performed under both local anesthesia and sedation with nitrous oxide and midazolam. After the surgery, her postural change to sitting induced orthostatic hypotension. HRV variables showed parasympathetic dominance due to the upright position. Subsequently, her posture was returned to supine, and atropine sulfate administration for the immediate treatment of OD returned her blood pressure to normal levels. HRV variables showed relative sympathetic dominance due to an atropine-derived parasympathetic blockade. HRV analysis revealed OD-associated autonomic dysfunction and should become a standard tool for safe and secure dental management of OD.
doi:10.1155/2014/656045
PMCID: PMC4086516  PMID: 25045545
10.  The Effect of Maternal and Fetal β2-Adrenoceptor and Nitric Oxide Synthase Genotype on Vasopressor Requirement and Fetal Acid-Base Status During Spinal Anesthesia For Cesarean Delivery 
Anesthesia and analgesia  2011;112(6):1432-1437.
Background
Previous work demonstrated that maternal haplotypes of the β2-adrenoceptor gene (ADRB2) influence ephedrine requirements during cesarean delivery. The use of ephedrine versus a pure α-adrenergic agonist such as phenylephrine has been associated with lower umbilical artery (UA) pH, thought to be secondary to increased fetal metabolism. There are no data evaluating the effect of fetal/neonatal genotypes on the metabolic response to maternally administered vasopressors. We hypothesized that neonatal ADRB2 genotype would affect the extent of neonatal acidemia. We also examined the effect of maternal ADRB2 and the endothelial nitric oxide synthase gene (NOS3) on ephedrine and phenylephrine requirements for treatment of maternal hypotension.
Methods
The study was performed on 104 Chinese women scheduled for cesarean delivery under spinal anesthesia who were participating in a double-blinded randomized clinical trial evaluating the maternal and neonatal effects of ephedrine versus phenylephrine infusions. Blood samples were drawn from the UA, umbilical vein and maternal radial artery to measure blood gas values, lactate, ephedrine and phenylephrine concentrations, and determine maternal and neonatal genotype at non-synonymous single nucleotide polymorphisms at codons 16 (rs1042713) and 27 (rs1042714) of ADRB2 and codon 298 (rs1799983) of NOS. Clinical variables (UA pH, UA lactate and dose of vasopressors) among genotypes were compared, and regression models were created to assess the effect of genotype on vasopressor dose and fetal acid-base status.
Results
Maternal ADRB2 genotype did not affect the ephedrine dose. Neonatal genotype at codon 16 influenced fetal acid-base status. UA pH was higher in Arg16 homozygous neonates (7.31 ± 0.03 in p.16Arg/Arg vs 7.25 ± 0.11 in p.16 Arg/Gly and p.16 Gly/Gly; p < 0.001, 95% C.I of difference 0.03 ~ 0.09) and UA lactate was lower (2.67 mmol/L ± 0.99 in p.16Arg/Arg vs 4.28 mmol/L ± 2.79 in p.16 Arg/Gly and p.16 Gly/Gly; p < 0.001, 95% C.I of difference −2.40 ~ −0.82). In neonates born to mothers receiving ephedrine, the magnitude of the difference among genotypes was even greater (pH 7.30 ± 0.02 in p.16Arg/Arg vs 7.19 ± 0.10 in p.16 Arg/Gly and p.16 Gly/Gly; p < 0.001, 95% C.I of difference 0.07 ~ 0.14) and UA lactate was lower (3.66 mmol/L ± 1.30 in p.16Arg/Arg vs 5.79 mmol/L ± 2.88 in p.16 Arg/Gly and p.16 Gly/Gly; p = 0.003, 95% C.I of difference −3.48 ~ −0.80). In a multiple linear regression model (R2 = 63.6%; P = 0.03), neonatal ADRB2 genotypes (p.16Arg/Arg and p.27Gln/Glu) and lower neonatal birth weight predicted lower UA lactate concentrations.
Phenylephrine dose was not affected by maternal ADRB2 or NOS3 genotypes, and neonatal NOS3 genotype did not affect UA pH or UA lactate.
Conclusion
In contrast to previous findings in a North American cohort, maternal ADRB2 genotype did not affect ephedrine requirements during elective cesarean delivery in a Chinese cohort. However, our findings suggest that neonatal ADRB2 p.Arg16 homozygosity confers a protective effect against developing ephedrine-induced fetal acidemia.
doi:10.1213/ANE.0b013e3182179424
PMCID: PMC3102860  PMID: 21613201
11.  Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension 
Background: Pharmacological treatment of orthostatic hypotension is often limited because of troublesome supine hypertension.
Objective: To investigate a novel approach to treatment using acetylcholinesterase inhibition, based on the theory that enhanced sympathetic ganglion transmission increases systemic resistance in proportion to orthostatic needs.
Design: Prospective open label single dose trial.
Material: 15 patients with neurogenic orthostatic hypotension caused by: multiple system atrophy (n = 7), Parkinson's disease (n = 3), diabetic neuropathy (n = 1), amyloid neuropathy (n = 1), and idiopathic autonomic neuropathy (n = 3).
Methods: Heart rate, blood pressure, peripheral resistance index (PRI), cardiac index, stroke index, and end diastolic index were monitored continuously during supine rest and head up tilt before and one hour after an oral dose of 60 mg pyridostigmine.
Results: There was only a modest non-significant increase in supine blood pressure and PRI. In contrast, acetylcholinesterase inhibition significantly increased orthostatic blood pressure and PRI and reduced the fall in blood pressure during head up tilt. Orthostatic heart rate was reduced after the treatment. The improvement in orthostatic blood pressure was associated with a significant improvement in orthostatic symptoms.
Conclusions: Acetylcholinesterase inhibition appears effective in the treatment of neurogenic orthostatic hypotension. Orthostatic symptoms and orthostatic blood pressure are improved, with only modest effects in the supine position. This novel approach may form an alternative or supplemental tool in the treatment of orthostatic hypotension, specially for patients with a high supine blood pressure.
doi:10.1136/jnnp.74.9.1294
PMCID: PMC1738643  PMID: 12933939
12.  Excessive Nitric Oxide Function and Blood Pressure Regulation in Patients with Autonomic Failure 
Hypertension  2008;51(6):1531-1536.
About 50% of patients with autonomic failure suffer from supine hypertension, even those with very low plasma norepinephrine and renin. Because nitric oxide is arguably the most potent metabolic modulator of blood pressure, we hypothesized that impaired nitric oxide function contributes to supine hypertension in autonomic failure. However, we found that autonomic failure patients (n=14) were more sensitive to the pressor effects of the nitric oxide synthase inhibitor L-NMMA, suggesting increased nitric oxide function rather than deficiency; a lower dose of L-NMMA was needed to produce a similar increase in blood pressure in AF patients, as in healthy controls in whom autonomic failure was induced with the ganglionic blocker trimethaphan (171±37 vs. 512±81 mg, respectively, p=0.001). Furthermore, potentiation of the actions of endogenous nitric oxide with the phosphodiesterase inhibitor sildenafil 25 mg PO decreased nighttime supine systolic blood pressure from 182±11 to 138±4 mmHg in eight autonomic failure patients with supine hypertension (p=0.012 compared to placebo). Finally, autonomic failure patients tolerated a greater degree of upright tilt during infusion of L-NMMA (56±6° vs. 41±4° with placebo, n=7, p=0.014), an improvement in orthostatic tolerance similar to that obtained with equipressor doses of phenylephrine. In conclusion, autonomic failure patients do not have nitric oxide deficiency contributing to supine hypertension. Instead, they have increased nitric oxide function contributing to their orthostatic hypotension. Potentiation of nitric oxide could be used in the treatment of supine hypertension, and its inhibition offers a novel approach to improve orthostatic hypotension.
doi:10.1161/HYPERTENSIONAHA.107.105171
PMCID: PMC2497433  PMID: 18426998
Nitric Oxide; Orthostatic hypotension; Supine Hypertension; Pure Autonomic Failure; Shy Drager Syndrome; Blood Pressure; L-NMMA
13.  Riluzole and d-amphetamine interactions in humans 
In preclinical studies, medications which decrease glutamate release have been shown to block some of the effects of psychostimulants. One such medication is riluzole, marketed for the treatment of Amyotrophic Lateral Sclerosis (ALS). The goal of this study was to determine riluzole’s effects on acute physiological and subjective responses to d-amphetamine in healthy volunteers. Seven male and 5 female subjects participated in an outpatient double-blind, placebo-controlled, crossover study. Across 4 sessions, subjects were randomly assigned to a sequence of 4 oral treatments: placebo, 20 mg d-amphetamine alone, 100 mg riluzole alone, or d-amphetamine plus riluzole. Outcome measures included heart rate, blood pressure, plasma cortisol, performance on the Sustained Attention to Response Test (SART), and subjective measures. D-amphetamine increased heart rate, blood pressure and plasma cortisol levels while inducing psychostimulant-type subjective effects. On the SART, d-amphetamine enhanced the speed of correct responses but also significantly increased the number of errors of commission. Riluzole at 100 mg did not block, the typical subjective and physiological responses to 20 mg d-amphetamine. Riluzole alone induced amphetamine-like subjective responses. On the SART test, riluzole increased the number errors of commission, but unlike d-amphetamine, did not speed reaction time. The mechanism accounting for these findings is unclear, but may involve processes other than decreased glutamate release by riluzole. The effects of glutamate medications on psychostimulant responses need to be further examined.
doi:10.1016/j.pnpbp.2007.05.003
PMCID: PMC2259272  PMID: 17714844
AMPA; d-amphetamine; dopamine; glutamate psychostimulant; riluzole
14.  Chronic Social Stress Induces Cardiomyocyte Contractile Dysfunction and Intracellular Ca2+ Derangement in Rats 
Physiology & behavior  2011;105(2):498-509.
Chronic psychosocial stress triggers cardiovascular diseases although underlying mechanisms are still elusive. This study examined the effect of social stress on cardiomyocyte contractile function and pathological changes in myocardium using the visible burrow system (VBS) model. Chronic social stress was induced using a mixed-sex VBS housing in adult Sprague-Dawley (SD) rats. Contractile and intracellular Ca2+ properties were evaluated in isolated cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), maximal velocity of shortening/relengthening (± dL/dt), Fura-2 fluorescence intensity, and intracellular Ca2+ decay. Myocardial histology was evaluated using Masson trichrome staining. Social stress led to depressed PS, ± dL/dt, shortened TPS and prolonged TR90 compared with the unstressed controls. Baseline and electrically-stimulated rise in Ca2+ were reduced whereas intracellular Ca2+ decay was delayed in stressed rats. Histological analyses exhibited overt interstitial fibrosis and cardiomyocyte hypertrophy in stressed rats. The GSH/GSSG ratio (indicative of oxidative stress status) was reduced whereas oxidative protein carbonyl formation was elevated in stressed rats. Western blot analysis showed unchanged expression of superoxide dismutase 1 (SOD1), β1-adrenoceptor (β1-AR) levels, reduced sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) levels, and elevated phosphorylation of the stress signaling protein kinase JNK but not ERK in myocardium from stressed rats. Short-term in vitro treatment of cardiomyocytes with the stress inducer phenylephrine mimicked cell damage and intracellular Ca2+ mishandling, the effects of which were mitigated by antioxidant, JNK inhibition, carvedilol and SERCA2a adenovirus. These findings indicate that chronic social stress is detrimental to cardiac structure and function possibly via mechanisms associated with oxidative injury and intracellular Ca2+ mishandling.
doi:10.1016/j.physbeh.2011.09.012
PMCID: PMC3225694  PMID: 21952229
social stress; cardiomyocytes; contraction; oxidative stress; intracellular Ca2+
15.  The effect of the intravenous phenylephrine on the level of spinal anesthesia 
Korean Journal of Anesthesiology  2011;61(5):372-376.
Background
Spinal anesthesia causes hypotension and bradycardia due to sympathetic nerve block and it is difficult to predict the level of sensory block and the duration of blockade. Recent studies have reported that intravenous phenylephrine can reduce the rostral spread of spinal anesthesia in pregnant women. We think a phenylephrine infusion will be useful for maintaining the baseline blood pressure by reducing the rostral spread of spinal anesthesia during the elective surgery of non-obstetric patients.
Methods
Sixty patients who were undergoing urologic surgery were randomized into two groups: Group C (the control group without phenylephrine) and Group P (with the addition of phenylephrine). After a bolus infusion of 50 µg phenylephrine following the spinal injection, phenylephrine was continuously infused at the rate of 200 µg/hr. We compared the dermatomal spreads of spinal anesthesia, the hemodynamic parameters (blood pressure, heart rate) and the incidences of hypotension between the two groups.
Results
At 20 minutes, the level of the upper dermatome blocked against cold sensation was a median of T8 (interquartile range: T8-T10) for the phenylephrine group, as compared with T4 (interquartile range: T4-T6) for the control group (P < 0.001).
Conclusions
Intravenous phenylephrine can decrease the rostral spread of spinal anesthesia during urologic surgery.
doi:10.4097/kjae.2011.61.5.372
PMCID: PMC3229014  PMID: 22148084
Cerebrospinal fluid; Dermatomal spread; Phenylephrine; Sensory block; Spinal anesthesia
16.  Baroreflex impairment precedes hypertension during chronic cerebroventricular infusion of hypertonic sodium chloride in rats. 
Journal of Clinical Investigation  1984;74(6):2065-2073.
Osmotic minipumps were implanted chronically for continuous 11-d infusion of hypertonic sodium chloride (NaCl) into the third cerebral ventricle (ICV) of awake rats to determine whether baroreflex sensitivity would be altered. Systolic and mean pressures, recorded from aortic catheters on day 11 while the rats were anesthetized with alpha-chloralose, were significantly higher in rats infused with artificial cerebrospinal fluid (CSF) containing hypertonic NaCl than in controls similarly infused with artificial CSF alone. Reflex changes in heart rate produced by subsequent intravenous infusions of either phenylephrine or sodium nitroprusside were inhibited, but reflex changes in renal nerve activity were unaltered. Magnitude of reflex bradycardia during pressor responses to phenylephrine, as well as of reflex tachycardia during depressor responses to sodium nitroprusside, was consistently smaller in NaCl-infused than in control rats. By contrast, group differences in attendant renal nerve firing were not significant. After sinoaortic denervation, drug-induced blood pressure effects persisted, but reflex responses in heart rate and renal nerve firing were abolished or markedly diminished. Peripheral effects produced by hypertonic NaCl leakage from the infusion site were considered unlikely because after 11 d of ICV infusion, sodium concentration, though appreciably elevated in CSF samples collected from the cisterna magna, was unaffected in corresponding serum samples. When cardiovascular responses to phenylephrine were recorded while chronic ICV infusions were in progress, awake rats receiving hypertonic NaCl were still normotensive on day 2 yet reflex bradycardia was already attenuated. In showing that baroreflex impairment preceded the development of hypertension, our results suggest that by depressing the anterior hypothalamus, chronic ICV infusion of hypertonic NaCl reduces sympatho-inhibition, and the ensuing baroreflex impairment then elevates blood pressure. However, other mechanisms could also be involved.
Images
PMCID: PMC425396  PMID: 6511915
17.  Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome 
Dynamic Medicine  2007;6:2.
Context
Patients with chronic fatigue syndrome and those with orthostatic intolerance share many symptoms, yet questions exist as to whether CFS patients have physiological evidence of orthostatic intolerance.
Objective
To determine if some CFS patients have increased rates of orthostatic hypotension, hypertension, tachycardia, or hypocapnia relative to age-matched controls.
Design
Assess blood pressure, heart rate, respiratory rate, end tidal CO2 and visual analog scales for orthostatic symptoms when supine and when standing for 8 minutes without moving legs.
Setting
Referral practice and research center.
Participants
60 women and 15 men with CFS and 36 women and 4 men serving as age matched controls with analyses confined to 62 patients and 35 controls showing either normal orthostatic testing or a physiological abnormal test.
Main outcome measures
Orthostatic tachycardia; orthostatic hypotension; orthostatic hypertension; orthostatic hypocapnia or combinations thereof.
Results
CFS patients had higher rates of abnormal tests than controls (53% vs 20%, p < .002), but rates of orthostatic tachycardia, orthostatic hypotension, and orthostatic hypertension did not differ significantly between patients and controls (11.3% vs 5.7%, 6.5% vs 2.9%, 19.4% vs 11.4%, respectively). In contrast, rates of orthostatic hypocapnia were significantly higher in CFS than in controls (20.6% vs 2.9%, p < .02). This CFS group reported significantly more feelings of illness and shortness of breath than either controls or CFS patients with normal physiological tests.
Conclusion
A substantial number of CFS patients have orthostatic intolerance in the form of orthostatic hypocapnia. This allows subgrouping of patients with CFS and thus reduces patient pool heterogeneity engendered by use of a clinical case definition.
doi:10.1186/1476-5918-6-2
PMCID: PMC1796865  PMID: 17263876
18.  The diabetes-induced functional and distributional changes of the alpha 1-adrenoceptor of the abdominal aorta and distal mesenteric artery from streptozotocin-induced diabetic rats 
Korean Journal of Anesthesiology  2011;60(4):272-281.
Background
The aim of this study was to evaluate the effect of diabetes on the function and distribution of vascular α1-adrenoceptors in the abdominal aorta and distal mesenteric artery from streptozotocin (STZ)-induced diabetic rats at the level of the α1-adrenoceptor subtypes.
Methods
Diabetes was induced by a single intravenous injection of STZ (60 mg/kg) in 8 week-old male Sprague-Dawley rats (n = 11). Age-matched normal rats (n = 14) were used as a control group. Four weeks after STZ injection, the tilting-induced change of the mean arterial pressure was recorded. The α1-adrenoceptor subtypes mediating the contractions of the distal mesenteric artery and abdominal aorta were investigated using the agonist phenylephrine and subtype-selective antagonists that included prazocin, 5-methylurapidil and BMY 7378. The expressions of the α1-adrenoceptor subtypes of each artery were examined by immunofluorescence staining using the subtype selective antibodies.
Results
The recovery of the mean arterial pressure was delayed after positional change in the diabetic rats. Compared with that of the normal rats, the contractile response to phenylephrine was increased in the abdominal aortas and it was decreased in the distal mesenteric arteries in the diabetic rats. In addition, compared with the normal rats, the fluorescent intensity of all the α1-adrenoceptor subtypes was increased in the abdominal aortas and it was decreased in the mesenteric arteries of the diabetic rats.
Conclusions
Diabetes increased the contractility of the abdominal aorta in response to phenylephrine, yet diabetes decreased that of the mesenteric arteries in the STZ-induced diabetic rats. Those results are mainly based on the overall change of the α1-adrenoceptor, and not on the change of the specific α1-adrenoceptor subtypes.
doi:10.4097/kjae.2011.60.4.272
PMCID: PMC3092963  PMID: 21602978
Abdominal aorta; Alpha-1 adrenergic receptor; Diabetic complications; Experimental diabetes mellitus; Mesenteric artery; Streptozotocin
19.  Orthostatic haemodynamic responses in acute stroke 
Postgraduate Medical Journal  1999;75(882):213-218.
Little is known about orthostatic blood pressure regulation in acute stroke. We determined postural haemodynamic responses in 40 patients with acute stroke (mild or moderate severity) and 40 non-stroke control in-patients, at two days (`Day 1') and one week (`Week 1') post-admission. Following a 10-minute supine rest and baseline readings, subjects sat up and blood pressure and heart rate were taken for 5 minutes. The procedure was repeated with subjects moving from supine to the standing posture. Haemodynamic changes from supine data were analysed. On standing up, the control group had a transient significant fall in mean arterial blood pressure on Day 1 but not Week 1. No significant changes were seen on either day when sitting up. In contrast to controls, the stroke group showed increases in mean arterial blood pressure on moving from supine to the sitting and standing positions on both days. Persistent postural hypotension defined as ⩾20 mmHg systolic fall occurred in <10% of either of the study groups on both days. Sitting and standing heart rates in both groups were significantly faster than supine heart rate on both days. The orthostatic blood pressure elevation is consistent with sympathetic nervous system overactivity which has been reported in acute stroke. Upright positioning as part of early rehabilitation and mobilisation following mild-to-moderate stroke would, therefore, not predispose to detrimental postural reductions in blood pressure.


Keywords: stroke; orthostatic hypotension; hypotension
PMCID: PMC1741196  PMID: 10715760
20.  Sustained Hypoxic Pulmonary Vasoconstriction in the Isolated Perfused Rat Lung: Effect of α1-adrenergic Receptor Agonist  
Background: Alveolar hypoxia induces monophasic pulmonary vasoconstriction in vivo, biphasic vasoconstriction in the isolated pulmonary artery, and controversial responses in the isolated perfused lung. Pulmonary vascular responses to sustained alveolar hypoxia have not been addressed in the isolated perfused rat lung. In this study, we investigated the effect of sustained hypoxic ventilation on pulmonary artery pressure in the present of phenylephrine, an α1-receptor agonist, under the above condition.
Methods: We performed this study in the isolated perfused rat lung. After preparation, the lungs were divided randomly into five groups of normoxic-normocapnia, hypoxic-normocapnia, phenylephrine pre- or post-treated hypoxic-normocapnia and phenylephrine pre-treated normoxic-normocapnia. Pulmonary hemodynamic, airway pressure and lung weight were measured during 60 min of the experiment for each group.
Results: In the phenylephrine-pre-treated hypoxic-normocapnia group we observed a gradual increase in pulmonary artery pressure which approximated the results seen in the phenylephrine-pre-treated normoxic-normocapnia group. In contrast, in the phenylephrine-post-treated hypoxic-normcapnic group, pulmonary artery pressure did not change during the first 3 min of hypoxic-normocapnia. However at 1.5 min after administration of phenylephrine, this pressure began to increase sharply and continued until the end of the experiment. This response was biphasic (0-10 min: acute phase, 10-60 min: sustained phase) with significantly higher pulmonary artery pressure compared to the other groups.
Conclusion: This study, for the first time, showed biphasic hypoxic pulmonary vasoconstriction in the isolated perfused rat lung with the sole administration of phenylephrine after but not before hypoxic gas ventilation. This finding suggested a facilitative role of alveolar hypoxia on pulmonary vasoconstriction induced by an α1-receptor agonist.
PMCID: PMC4027007  PMID: 24850985
Hypoxia; Rat lung; Phenylephrine
21.  Population-Based Study on the Prevalence and Risk Factors of Orthostatic Hypotension in Subjects With Pre-Diabetes and Diabetes  
Diabetes Care  2009;32(1):69-74.
OBJECTIVE—The aim of this study was to investigate the relationship between pre-diabetes and orthostatic hypotension and to examine the prevalence and correlates of orthostatic hypotension in community dwellers with normal glucose tolerance (NGT), pre-diabetes, and diabetes.
RESEARCH DESIGN AND METHODS—All participants were classified as having NGT (n = 1,069), pre-diabetes (n = 412), or diabetes (n = 157). Orthostatic hypotension was defined as a decline in systolic/diastolic blood pressure of ≥20/10 mmHg when an individual changed from a supine to a standing position. The cardiovagal response to standing was the ratio between the longest RR interval around beat 30 and the shortest RR interval around beat 15 after standing (30 max–to–15 min ratio).
RESULTS—The prevalences of orthostatic hypotension were 13.8, 17.7, and 25.5% in subjects with NGT, pre-diabetes, and diabetes, respectively. For all subjects, age, diabetes, hypertension, and a decreased 30 max–to–15 min ratio, but not pre-diabetes, were independently associated with orthostatic hypotension. Age, hypertension, and 30 max–to–15 min ratio were the correlates of orthostatic hypotension in NGT subjects. Age and hypertension were related to orthostatic hypotension in pre-diabetic subjects. A1C and hypertension were the determinants of orthostatic hypotension in diabetic subjects. Supine blood pressure was related to orthostatic hypotension in all subjects and subgroups.
CONCLUSIONS—Pre-diabetic subjects do not have a higher risk of orthostatic hypotension than subjects with NGT, although the risk of orthostatic hypotension is higher in diabetic subjects. Hypertension and supine blood pressure were risk factors for orthostatic hypotension in both pre-diabetic and diabetic subjects. Age and A1C were the correlates of orthostatic hypotension in pre-diabetic and diabetic subjects, respectively. The cardiovagal response to standing is an important determinant of orthostatic hypotension in subjects with NGT but not in pre-diabetic and diabetic subjects.
doi:10.2337/dc08-1389
PMCID: PMC2606833  PMID: 18852335
22.  Gender difference and change of α1-adrenoceptors in the distal mesenteric arteries of streptozotocin-induced diabetic rats 
Korean Journal of Anesthesiology  2011;61(5):419-427.
Background
The purpose of this study was to evaluate the gender-related changes in the function and distribution of α1-adrenoceptors in the distal mesenteric artery of streptozotocin (STZ)-induced diabetic rats at the level of α1-adrenoceptor subtypes.
Methods
Diabetes was induced by intravenous injection of STZ in a dose of 60 mg/kg through the tail vein in 8 week-old male or female Sprague-Dawley rats (n = 13/group). Age-matched normal rats (n = 15) were used as a control group. Four weeks after STZ injection, the change in mean arterial pressure caused by a 45° tilting was recorded. The α1-adrenoceptor subtypes mediating contractions of the distal mesenteric artery were investigated using the agonist, phenylephrine as well as subtype-selective antagonists including prazocin, 5-methylurapidil, and BMY 7378. The expression of α1-adrenoceptor subtypes of each artery was examined by immunofluorescence staining and western blotting using subtype selective antibodies.
Results
Compared with normal male rats, the contractile response to phenylephrine was decreased in the distal mesenteric artery in normal female rats. Moreover, a decrease in contractile force was observed in STZ-induced diabetic rats compared with age-matched controls. Western blotting revealed that there was the difference between normal male and female rats in manifestation of the α1D-adrenoceptor. In STZ-induced male and female diabetic rats, all α1-adrenoceptor subtypes were decreased in distal mesenteric arteries, compared with normal rats.
Conclusions
There was the gender-related functional difference of α1-adrenoceptors in normal rats. In both male and female rats, diabetes decreased the contractile response in mesenteric arteries, which might be caused by the overall change in α1-adrenoceptor.
doi:10.4097/kjae.2011.61.5.419
PMCID: PMC3229022  PMID: 22148092
Alpha-1 adrenergic receptor; Gender; Mesenteric arteries; Streptozotocin diabetes
23.  Sympathetic dysfunction in vasovagal syncope and the postural orthostatic tachycardia syndrome 
Orthostatic intolerance is the inability to tolerate the upright posture and is relieved by recumbence. It most commonly affects young women and has a major impact on quality of life and psychosocial well-being. Several forms of orthostatic intolerance have been described. The most common one is the recurrent vasovagal syncope (VVS) phenotype which presents as a transient and abrupt loss of consciousness and postural tone that is followed by rapid recovery. Another common type of orthostatic intolerance is the postural orthostatic tachycardia syndrome (POTS) which is characterized by an excessive rise in heart rate upon standing and is associated with symptoms of presyncope such as light-headedness, fatigue, palpitations, and nausea. Maintenance of arterial pressure under condition of reduced central blood volume during the orthostasis is accomplished in large part through sympathetic efferent nerve traffic to the peripheral vasculature. Therefore sympathetic nervous system (SNS) dysfunction is high on the list of possible contributors to the pathophysiology of orthostatic intolerance. Investigations into the role of the SNS in orthostatic intolerance have yielded mixed results. This review outlines the current knowledge of the function of the SNS in both VVS and POTS.
doi:10.3389/fphys.2014.00280
PMCID: PMC4112787  PMID: 25120493
syncope; postural tachycardia; orthostatic response; sympathetic nervous activity; tilt table
24.  Expression of SART3 antigen and induction of CTLs by SART3-derived peptides in breast cancer patients 
British Journal of Cancer  2001;84(7):915-919.
We recently reported the SART3 tumour-rejection antigen as possessing tumour epitopes capable of inducing HLA-class I-restricted cytotoxic T lymphocytes (CTLs). This study investigated expression of the SART3 antigen in breast cancer to explore an appropriate molecule for use in specific immunotherapy of breast cancer patients. The SART3 antigen was detected in all of the breast cancer cell lines tested, 30 of 40 (75%) breast cancer tissue samples, and 0 of 3 non-tumourous breast tissue samples. SART3 derived peptides at positions 109–118 and 315–323 induced HLA-A24 restricted CTLs that reacted to breast cancer cells from the peripheral blood mononuclear cells (PBMCs) of breast cancer patients. Therefore, the SART3 antigen and its peptides could be an appropriate molecule for use in specific immunotherapy of the majority of HLA-A24-positive breast cancer patients. © 2001 Cancer Research Campaignhttp://www.bjcancer.com
doi:10.1054/bjoc.2000.1690
PMCID: PMC2363830  PMID: 11286471
SART3 antigen; breast cancer; HLA-A24; immunotherapy; cancer vaccine
25.  Comparison of hemodynamic changes between phenylephrine and combined phenylephrine and glycopyrrolate groups after spinal anesthesia for cesarean delivery 
Background
Hypotension remains a common clinical problem of spinal anesthesia for cesarean delivery and phenylephrine is used as a vasopressor to address this. However, phenylephrine reduces maternal cardiac output (CO) due to reflex bradycardia. Glycopyrrolate is safe for the fetus, and increases heart rate (HR). Using a noninvasive measure of CO, we compared maternal hemodynamic changes between the phenylephrine only group (group P) and the phenylephrine plus glycopyrrolate group (group PG).
Methods
In this randomized study, 60 women scheduled for elective cesarean delivery were allocated to group P (n = 30) or group PG (n = 30). In both groups, phenylephrine was infused at 50 µg/min. This infusions stopped if systolic blood pressure (SBP) was higher than the baseline value, and phenylephrine 100 µg was injected if SBP was lower than 80% of the baseline value from spinal anesthesia to delivery. In group PG, glycopyrrolate 0.2 mg was injected intravenously after spinal anesthesia. Hemodynamic parameters, such as SBP, heart rate (HR), stroke volume index (SVI), cardiac index (CI) were measured before and until 15 min after spinal anesthesia.
Results
There were no significant differences in SBP and SVI compared to the baseline value in each group and between the two groups. HR and CI reduced significantly from 8 min to 15 min in group P compared to the baseline value as well as group PG for each time-point. However, HR and CI were maintained in group PG.
Conclusions
The use of glycopyrrolate added to phenylephrine infusion to prevent hypotension by spinal anesthesia for cesarean delivery was effective in maintaining HR and CI.
doi:10.4097/kjae.2012.62.1.35
PMCID: PMC3272527  PMID: 22323952
Cesarean section; Glycopyrrolate; Hypotension; Phenylephrine; Spinal anesthesia

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