Adrenergic Response Research Articles

Effects of levamisole, a cocaine adulterant, on adrenergic response in the rabbit renal artery

Effects of levamisole, a cocaine adulterant, on adrenergic response in the rabbit renal artery

Insulin-dependent metabolic and inotropic responses in the heart are modulated by hydrogen peroxide from NADPH-oxidase isoforms NOX2 and NOX4

RationaleHydrogen peroxide (H2O2) is a stable reactive oxygen species (ROS) that has long been implicated in insulin signal transduction in adipocytes. However, H2O2's role in mediating insulin's effects on the heart are unknown. ObjectiveWe investigated the role of H2O2 in activating insulin-dependent changes in cardiac myocyte metabolic and inotropic pathways. The sources of insulin-dependent H2O2 generation were also studied. Methods and resultsIn addition to the canonical role of insulin in modulating cardiac metabolic pathways, we found that insulin also inhibited beta adrenergic-induced increases in cardiac contractility. Catalase and NADPH oxidase (NOX) inhibitors blunted activation of insulin-responsive kinases Akt and mTOR and attenuated beta adrenergic receptor-mediated responses. These insulin responses were lost in a mouse model of type 2 diabetes, suggesting a role for these H2O2-dependent pathways in the diabetic heart. The H2O2-sensitive fluorescent biosensor HyPer revealed rapid increases in cytosolic and caveolar H2O2 concentrations in response to insulin treatment, which were blocked by NOX inhibitors and attenuated in NOX2 KO and NOX4 KO mice. In NOX2 KO cardiac myocytes, insulin-mediated phosphorylation of Akt and mTOR was blocked, while these responses were unaffected in cardiac myocytes from NOX4 KO mice. In contrast, insulin's effects on contractility were lost in cardiac myocytes from NOX4 KO animals but were retained in NOX2 KO mice. ConclusionsThese studies identify a proximal point of bifurcation in cardiac insulin signaling through the simultaneous activation of both NOX2 and NOX4. Each NOX isoform generates H2O2 in cardiac myocytes with distinct time courses, with H2O2 derived from NOX2 augmenting Akt-dependent metabolic effects of insulin, while H2O2 from NOX4 blocks beta adrenergic increases in inotropy. These findings suggest that insulin resistance in the diabetic heart may lead to potentially deleterious potentiation of beta adrenergic responses.

An integrative appraisal of the hormonal and metabolic changes induced by acute stress using king penguins as a model

A large number of studies have focused on the reactivity of the hypothalamic–pituitaryadrenal (HPA) axis and the consequences of glucocorticoids (GC) in mediating life-history trade-offs. Although short-term increases in GCs are viewed as adaptive, mobilizing energy substrates allowing animals to deal with impending threats (e.g. stimulating hepatic gluconeogenesis, stimulating lipolysis, mobilizing amino acids), few studies have actually measured the exact time-course of substrate mobilisation in response to acute stress in natural conditions. We evaluated the hormonal and metabolic components of the stress response to acute stress in 32 free-living king penguins (Aptenodytes patagonicus). We monitored changes in blood GCs (corticosterone, CORT), glucose, lactate, ketone bodies (β-hydroxybutyrate), non-esterified fatty acids, and uric acid in response to a standardized capture-restraint protocol lasting for up to 90min. Furthermore, we tested whether the vigilance status of the animal (alert or asleep) affected its perception of the capture, thereby modulating the hormonal and metabolic stress responses. The time course of energy mobilisation followed the characteristic pattern expected from laboratory and theoretical models, with a rapid depletion of those energy stores linked to rapid adrenergic responses (i.e. glucose and ketone bodies), followed by a mobilisation of energy stores associated with the sustained longer-term GC response (i.e. fats and protein stores). HPA reactivity was generally slower than reported in other birds, and there was high inter-individual variability. Sleeping birds had higher GC and glucose responses to acute stress, suggesting a more rapid mobilization of energy stores. Our results highlight the importance of considering HPA and metabolic responses to acute stress against species-specific life history and ecological relevant backgrounds.

P320 Differences in adrenergic components of baroreflex response to Valsalva maneuver in patients with multiple sclerosis and healthy subjects

Objectives To evaluate differences in recently developed, non-standard adrenergic baroreflex sensitivity (BRS) indices between patients with multiple sclerosis (MS) and healthy controls (HC). Methods This retrospective analysis included 153 patients with MS and 20 healthy controls. Systolic blood pressure (sBP) responses during Valsalva maneuver (VM) were divided into three subtypes: balanced – type 1 (a sBP dip below baseline in late phase II (IIL) and recovery in phase IV), suppressed – type 2 (a non-dipping BP) and augmented – type 3 (a BP recovery in phase IIL) autonomic response. Alternative adrenergic component of BRS (BRSa1), and alpha- ( α -BRSa) and beta-adrenergic ( β -BRSa) components of adrenergic BRS were calculated and compared between the groups. For a subset of 103 MS patients, data on epinephrine, norepinephrine and dopamine immediately prior to performing Valsalva maneuver were available for analysis. Results There was no difference in the subtypes of sBP responses during VM between groups. Patients with MS had significantly higher α -BRSa compared to HC (6.36 ± 2.44 vs. 5.02 ± 2.14, p = 0.02). No differences were found for BRSa1 and β -BRSa. When we looked at differences in all three parameters depending on subtypes of sBP responses during VM, significant difference in α -BRSa was maintained only for the subtype 3 (7.27 ± 2.05 vs. 5.88 ± 2.09, p = 0.045). We found positive correlation between epinephrine and BRSa1 (rs 0.226, p = 0.04), negative correlation epinephrine and β -BRSa (rs −0.195, p = 0.050) and positive correlation between norepinephrine and α -BRSa (rs 0.228, p = 0.021). Discussion It has been suggested that new BRSa measurements may help differentiate normal physiologic variants from mild dysautonomia. Conclusion Healthy subjects and MS patients exhibit different alpha-adrenergic response to Valsalva maneuver. Significance A significant correlation between blood catecholamines and alfa and beta adrenergic response to Valsalva maneuver was observed.

3881Restoration of normal sinus node physiology in a model of sick sinus syndrome; Tbx18 overexpression improves heart rate, rate stability and adrenergic response

3881Restoration of normal sinus node physiology in a model of sick sinus syndrome; Tbx18 overexpression improves heart rate, rate stability and adrenergic response

Benzo(a)pyrene triggers desensitization of \u03b22-adrenergic pathway

Exposure to environmental polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene (B(a)P), has been linked to several health-threatening risks. PAHs were also shown to hinder adrenergic receptor (ADR) responses. As we previously demonstrated that B(a)P can directly interact with the β2ADR, we investigated here whether B(a)P could decrease β2ADR responsiveness by triggering receptor desensitization phenomena. We firstly showed that exposure to B(a)P reduced β2ADR-mediated epinephrine-induced induction of NR4A gene mRNAs and of intracellular cAMP. Analysis of β2ADR protein expression demonstrated that B(a)P rapidly decreased membrane expression of β2ADR with a subsequent degradation of receptor protein. B(a)P exposure concomitantly rapidly increased the β2ADR mRNA levels. The use of the β-blockers, propranolol and ICI 118.551, demonstrated the involvement of β2ADR itself in this increase. However, sustained exposure to B(a)P induced a diminution of β2ADR mRNA steady-state as a result of the acceleration of its degradation. Together, these results show that, beside the well-known activation of the aryl hydrocarbon receptor, PAH deleterious effects may involve the dysfunction of adrenergic responses through, in part, the desensitization of β2ADR. This may be taken in consideration when β2-agonists/antagonists are administered in patients exposed to important concentrations of PAHs, e.g. in cigarette smokers.

Association between cytochrome P450 family 2 subfamily E member 1 levels and minimum alveolar concentrations of sevoflurane that block adrenergic responses to pneumoperitoneum stimulation in smokers receiving laparoscopic cholecystectomy

Objective To determine whether smoking affects minimum alveolar concentrations of sevoflurane that block adrenergic responses(MACBAR) in patients receiving laparoscopic cholecystectomy. Methods A total of 90 ASA grade Ⅰ or Ⅱ patients(30-50 years old) receiving laparoscopic cholecystectomy were enrolled in this study, and the patients had 49 smokers and 41 non-smokers. The levels of cytochrome P450 family 2 subfamily E member 1(CYP2E1, a principal enzyme metabolizes sevoflurane) and cotinine (a metabolite of nicotine, a bioactive component in cigarettes) in serum were measured one day before the operation. The patients received similar procedures for the induction of general anesthesia, thereafter, the anesthesia was maintained with sevoflurane. Pneumoperitoneum stimulation was applied to trigger adrenergic responses that were assessed by changes in MAP and HR. Meanwhile, MACBAR was recorded. Results HR and MAP were at the same levels between smokers and non-smokers(P>0.05). As expected, the levels of CYP2E1 and cotinine in serum were significantly higher in smokers than non-smokers(P<0.05). After general anesthesia was induced, HR and MAP were significantly decreased in both smokers and non-smokers(P<0.05). Pneumoperitoneum stimulation elevated these parameters more robustly in smokers than non-smokers(P<0.05). Moreover, MACBAR of sevoflurane and levels of CYP2E1 showed a significant correlation (r=0.51, P<0.05) , and both were higher in smokers than non-smokers(P<0.05). Conclusions Smoking patients had higher levels of CYP2E1, which may accelerate the metabolism of sevoflurance and increase MACBAR. Key words: Smoking; Sevoflurane; Minimum alveolar concentration to block the adrenergic response; Cotinine; Cytochrome P450 family 2 subfamily E member 1

Nitric oxide synthase inhibition restores orthostatic tolerance in young vasovagal syncope patients

ObjectiveSyncope is sudden transient loss of consciousness and postural tone with spontaneous recovery; the most common form is vasovagal syncope (VVS). We previously demonstrated impaired post-synaptic adrenergic responsiveness in young...

Race and sex differences in cardiovascular α-adrenergic and β-adrenergic receptor responsiveness in men and women with high blood pressure.

Hypertension is associated with unfavorable changes in adrenergic receptor responsiveness, but the relationship of race and sex to adrenergic receptor responsiveness in the development of cardiovascular disease is unclear. This study examined α-adrenergic and ß-adrenergic receptor responsiveness in African-American and white men and women with untreated high blood pressure (BP) (HBP) and with normal BP. The study sample comprised 161 African-American and white men and women in the age range 25-45 years. Isoproterenol, a nonselective ß-adrenergic receptor agonist, was administered intravenously to determine the bolus dose required to increase heart rate by 25 bpm, an index of β-adrenergic receptor responsiveness. Similarly, phenylephrine, an α1-adrenergic receptor agonist, was administered to determine the bolus dose required to increase BP by 25 mmHg, an index of vascular α1-adrenergic receptor responsiveness. HBP (P < 0.01), male sex (P = 0.04), and higher BMI (P < 0.01) were all associated with reduced β-adrenergic receptor responsiveness, with a similar trend observed for African-American race (P = 0.07). Conversely, α1-adrenergic receptor responsiveness was increased in association with HBP (P < 0.01), female sex (P < 0.01), and African-American race (P < 0.01). In the early stages of hypertension, cardiovascular β-adrenergic receptors demonstrate blunted responsiveness, whereas conversely α1-adrenergic receptors exhibit increased responsiveness. This pattern of receptor changes is especially evident in men and African-Americans, is exacerbated by obesity, and may contribute to the development of cardiovascular disease.

Electrical Stimulation of Artificial Heart Muscle: A Look Into the Electrophysiologic and Genetic Implications.

Development of tissue-engineered hearts for treatment of myocardial infarction or biologic pacemakers has been hindered by the production of mostly arrhythmic or in-synergistic constructs. Electrical stimulation (ES) of these constructs has been shown to produce tissues with greater twitch force and better adrenergic response. To further our understanding of the mechanisms underlying the effect of ES, we fabricated a bioreactor capable of delivering continuous or intermittent waveforms of various types to multiple constructs simultaneously. In this study, we examined the effect of an intermittent biphasic square wave on our artificial heart muscle (AHM) composed of neonatal rat cardiac cells and fibrin gel. Twitch forces, spontaneous contraction rates, biopotentials, gene expression profiles, and histologic observations were examined for the ES protocol over a 12 day culture period. We demonstrate improved consistency between samples for twitch force and contraction rate, and higher normalized twitch force amplitudes for electrically stimulated AHMs. Improvements in electrophysiology within the AHM were noted by higher conduction velocities and lower latency in electrical response for electrically stimulated AHMs. Genes expressing key electrophysiologic and structural markers peaked at days 6 and 8 of culture, only a few days after the initiation of ES. These results may be used for optimization strategies to establish protocols for producing AHMs capable of replacing damaged heart tissue in either a contractile or electrophysiologic capacity. Optimized AHMs can lead to alternative treatments to heart failure and alleviate the limited donor supply crisis.

Sex-difference in expression and function of beta-adrenoceptors in macrovessels: role of the endothelium.

Estrogen modulates adrenergic reactivity of macrovessels, resulting in weaker α-adrenergic vasoconstriction in females than males. However, the mechanisms governing this important sex-specific difference are not well understood. We hypothesized that vessels of females express more dilatory β-adrenoceptors, which counteract constrictive effects of α-adrenoceptors. This hypothesis was tested using aortas of normotensive (WKY) and hypertensive rats (SHR), along with human mammary artery. Selective blockade of β1 (CGP20712) or β3 (SR59230A), but not β2 (ICI118,551) adrenoceptors, greatly increased α-adrenergic constriction (norepinephrine) of aorta in female SHRs, but not in male SHRs at 12weeks of age. Consistently, the selective β1/β2 (isoproterenol) and β3-adrenergic (BRL37344) relaxation was stronger in female SHRs than in males. Removal of endothelium and use of L-NMMA abolished sex-difference in α-adrenergic constriction and β-adrenergic relaxation. Immunostainings revealed endothelial localization of β1- and β3-adrenoceptors. mRNA levels of aortic β1- and β3-, but not β2-adrenoceptors were markedly higher in female than in male SHRs. The sex-specific differences in α-adrenergic constriction and β-adrenoceptor mRNA levels were age-dependent, predominantly present up to 29weeks and disappeared at 36weeks of age. The sex-specific difference was not strain-dependent and was similarly present in normotensive WKY rats. Human mammary artery of women showed a weaker α-adrenergic constriction than arteries of men. This sex-specific difference was prominent at 45-65years and disappeared with aging. Our results convincingly demonstrate that female macrovessels express more dilatory β1- and β3-adrenoreceptors than male vessels with a predominant endothelial localization. This sex-specific difference is functionally relevant in young adults and is attenuated with aging.

Role of Alpha‐Adrenergic Vasoconstriction in Regulating Skeletal Muscle Blood Flow during Single Leg Knee Extension Exercise with Advancing Age

BackgroundAging is associated with augmented sympathetic nervous system activity, which promotes vasoconstriction in the peripheral circulation through the alpha‐adrenergic pathway. However, whether this age‐related sympathoexcitation restrains exercising skeletal muscle blood flow and vascular conductance remains poorly understood.MethodsIn nine young (4F/5M, 25 ± 5 yr, 178 ± 8 cm, 73 ± 12 kg) and seven old (2F/5M, 63 ± 11 yr, 175 ± 9 cm, 78 ± 15 kg) healthy volunteers, we evaluated changes in leg blood flow (LBF, Doppler ultrasound), mean arterial pressure (MAP) and leg vascular conductance (LVC) before and after femoral intra‐arterial infusion of phentolamine (a nonselective alpha‐adrenergic antagonist) at rest and during knee‐extensor exercise (0, 5, and 10W). Results are presented as the change from control to adrenergic blockade conditions.ResultsAt rest, similar increases in LBF (269 ± 45 vs. 250 ± 60 ml/min, young vs. older) and LVC (3.4 ± 0.6 vs. 2.9 ± 0.6 ml/min/mmHg, young vs. old) were observed between groups following the adrenergic blockade. During exercise, the adrenergic blockade increased LBF to a similar degree in both young (0W: 330 ± 116, 5W: 178 ± 130, and 10W: 239 ± 127ml/min) and old (0W: 209 ± 57, 5W: 251 ± 22, and 10W: 165 ± 75 ml/min), with no difference between work rates in either group. Similarly, LVC increased as a consequence of the adrenergic blockade in both young (0W: 4.6 ± 1.2, 5W: 3.0 ± 1.2, and 10W: 3.1 ± 1.2 ml/min/mmHg) and old (0W: 3.6 ± 1.1, 5W: 4.2 ± 0.9, and 10W: 3.8 ± 0.9 ml/min/mmHg), with no difference between work rates. Both at rest and during exercise, MAP did not differ between groups or as a consequence of drug administration.ConclusionsUsing a pharmacologic approach to locally block alpha adrenergic vasoconstriction, we observed a similar drug‐induced change in leg hemodynamics in both the young and old groups. These data suggest that sympathetic restraint of limb blood flow persists during small muscle mass exercise, and that this adrenergic response is not impacted by advancing age.Support or Funding InformationFunded in part by the National Institutes of Health (HL118313) and the U.S. Department of Veterans Affairs (RX001697, RX001418, E6910R).

Altered Distribution of Adrenergic Constrictor Responses Contributes to Skeletal Muscle Perfusion Abnormalities in Metabolic Syndrome

Although studies have suggested elevations in adrenergic traffic, signaling and vascular responses with development of metabolic syndrome in obese Zucker rats (OZR), the moderate hypertension and modest impact on organ blood flow in OZR questions the multi‐scale validity of these data. To better understand the role of adrenergic function in contributing to vascular reactivity in OZR, we utilized a multi‐scale approach to investigate pressure responses, skeletal muscle blood flow and vascular reactivity in OZR following adrenergic challenge. For OZR under in vivo conditions, adrenergic challenge resulted increased pressor responses vs. LZR that were mediated via α1 receptors, with minimal contribution by either ROS or NO bioavailability. In situ gastrocnemius muscle of OZR exhibited blunted hyperemic responses to elevated metabolic demand, partially restored with α1 inhibition, although improved muscle performance and VO2 required combined treatment with TEMPOL as well. Within in situ cremaster muscle, proximal resistance arterioles of OZR exhibited a more heterogeneous constrictor response to adrenergic challenge, biased toward hyperresponsiveness, as compared to that in LZR. This increasingly heterogeneous pattern was mirrored in ex vivo resistance arterioles as well, mediated via α1 receptors, with roles for ROS and NO bioavailability evident in hyperresponsive vessels only. These results support observations of the central role of the α1 adrenoreceptor for augmented pressor responses and elevations in vascular resistance, but identify an increased heterogeneity of constrictor reactivity with development of metabolic syndrome that is presently of unclear purpose.Support or Funding InformationNational Institutes of Health and American Heart Association

Chronic treatment with fluoxetine modulates vascular adrenergic responses by inhibition of pre- and post-synaptic mechanisms

Fluoxetine, a serotonin reuptake inhibitor (SSRI), has other effects in addition to blocking serotonin reuptake, including changes in the vasomotor tone. Whereas many studies focused on the acute effects of fluoxetine in the vasculature, its chronic effects are still limited. In the present study, we tested the hypothesis that chronic fluoxetine treatment modulates adrenergic vascular responses by interfering with post- and pre-synaptic mechanisms. Wistar rats were treated with vehicle (water) or chronic fluoxetine (10mg/kg/day) for 21 days. Blood pressure (BP) and heart rate were measured. Vascular reactivity was evaluated in perfused mesenteric arterial beds (MAB) and in mesenteric resistance arteries. Protein expression by western blot analysis or immunohistochemistry, β-arrestin recruitment by BRET and calcium influx by FLIPR assay. Fluoxetine treatment decreased phenylephrine (PE)-induced, but not electrical-field stimulation (EFS)-induced vasoconstriction. Fluoxetine-treated rats exhibited increased KCl-induced vasoconstriction, which was abolished by prazosin. Desipramine, an inhibitor of norepinephrine (NA) reuptake, increased EFS-induced vasoconstrictor response in vehicle-treated, but not in fluoxetine-treated rats. Chronic treatment did not alter vascular expression of α1 adrenoceptor, phosphorylation of PKCα or ERK 1/2 and RhoA. On the other hand, vascular contractions to calcium (Ca2+) as well as Ca2+ influx in mesenteric arteries were increased, while intracellular Ca2+ storage was decreased by the chronic treatment with fluoxetine. In vitro, fluoxetine decreased vascular contractions to PE, EFS and Ca2+, but did not change β-arrestin activity. In conclusion, chronic treatment with fluoxetine decreases sympathetic-mediated vascular responses by mechanisms that involve inhibition of NA release/reuptake and decreased Ca2+ stores.

High-fat diet induces protein kinase A and G-protein receptor kinase phosphorylation of β2 -adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts.

Key points Patients with diabetes show a blunted cardiac inotropic response to β‐adrenergic stimulation despite normal cardiac contractile reserve.Acute insulin stimulation impairs β‐adrenergically induced contractile function in isolated cardiomyocytes and Langendorff‐perfused hearts.In this study, we aimed to examine the potential effects of hyperinsulinaemia associated with high‐fat diet (HFD) feeding on the cardiac β2‐adrenergic receptor signalling and the impacts on cardiac contractile function.We showed that 8 weeks of HFD feeding leads to reductions in cardiac functional reserve in response to β‐adrenergic stimulation without significant alteration of cardiac structure and function, which is associated with significant changes in β2‐adrenergic receptor phosphorylation at protein kinase A and G‐protein receptor kinase sites in the myocardium.The results suggest that clinical intervention might be applied to subjects in early diabetes without cardiac symptoms to prevent further cardiac complications. Patients with diabetes display reduced exercise capability and impaired cardiac contractile reserve in response to adrenergic stimulation. We have recently uncovered an insulin receptor and adrenergic receptor signal network in the heart. The aim of this study was to understand the impacts of high‐fat diet (HFD) on the insulin–adrenergic receptor signal network in hearts. After 8 weeks of HFD feeding, mice exhibited diabetes, with elevated insulin and glucose concentrations associated with body weight gain. Mice fed an HFD had normal cardiac structure and function. However, the HFD‐fed mice displayed a significant elevation of phosphorylation of the β2‐adrenergic receptor (β2AR) at both the protein kinase A site serine 261/262 and the G‐protein‐coupled receptor kinase site serine 355/356 and impaired adrenergic reserve when compared with mice fed on normal chow. Isolated myocytes from HFD‐fed mice also displayed a reduced contractile response to adrenergic stimulation when compared with those of control mice fed normal chow. Genetic deletion of the β2AR led to a normalized adrenergic response and preserved cardiac contractile reserve in HFD‐fed mice. Together, these data indicate that HFD promotes phosphorylation of the β2AR, contributing to impairment of cardiac contractile reserve before cardiac structural and functional remodelling, suggesting that early intervention in the insulin–adrenergic signalling network might be effective in prevention of cardiac complications in diabetes.

Altered distribution of adrenergic constrictor responses contributes to skeletal muscle perfusion abnormalities in metabolic syndrome.

Although studies suggest elevated adrenergic activity paralleling metabolic syndrome in OZRs, the moderate hypertension and modest impact on organ perfusion question the multi-scale validity of these data. To understand how adrenergic function contributes to vascular reactivity in OZR, we utilized a multi-scale approach to investigate pressure responses, skeletal muscle blood flow, and vascular reactivity following adrenergic challenge. For OZR, adrenergic challenge resulted in increased pressor responses vs LZRs, mediated via α1 receptors, with minimal contribution by either ROS or NO bioavailability. In situ gastrocnemius muscle of OZR exhibited blunted functional hyperemia, partially restored with α1 inhibition, although improved muscle performance and VO2 required combined treatment with TEMPOL. Within OZR in situ cremaster muscle, proximal arterioles exhibited a more heterogeneous constriction to adrenergic challenge, biased toward hyperresponsiveness, vs LZR. This increasingly heterogeneous pattern was mirrored in ex vivo arterioles, mediated via α1 receptors, with roles for ROS and NO bioavailability evident in hyperresponsive vessels only. These results support the central role of the α1 adrenoreceptor for augmented pressor responses and elevations in vascular resistance, but identify an increased heterogeneity of constrictor reactivity in OZR that is presently of unclear purpose.

Ablation of the cardiac ryanodine receptor phospho-site Ser2808 does not alter the adrenergic response or the progression to heart failure in mice. Elimination of the genetic background as critical variable

BackgroundPhosphorylation of the cardiac ryanodine receptor (RyR2) phospho-site S2808 has been touted by the Marks group as a hallmark of heart failure (HF) and a critical mediator of the physiological fight-or-flight response of the heart. In support of this hypothesis, mice unable to undergo phosphorylation at RyR2-S2808 (S2808A) were significantly protected against HF and displayed a blunted response to adrenergic stimulation. However, the issue remains highly controversial because several groups have been unable to reproduce these findings. An important variable not considered before is the genetic background of the mice used to obtain these divergent results. Methods and resultsWe backcrossed a RyR2-S2808A mouse into a congenic C57Bl/6 strain, the same strain used by the Marks group to conduct their experiments. We then performed several key experiments to confirm or discard the genetic background of the mouse as a relevant variable, including induction of HF by myocardial infarction and tests of integrity of adrenergic response. Congenic C57Bl/6 harboring the S2808A mutation showed similar echocardiographic parameters that indicated identical progression towards HF compared to wild type controls, and had a normal response to adrenergic stimulation in whole animal and cellular experiments. ConclusionsThe genetic background of the different mouse models is unlikely to be the source of the divergent results obtained by the Marks group in comparison to several other groups. Cardiac adrenergic response and progression towards HF proceed unaltered in mice harboring the RyR2-S2808A mutation. Preventing RyR2-S2808 phosphorylation does not preclude a normal sympathetic response nor mitigates the pathophysiological consequences of MI.

Carbon monoxide pollution aggravates ischemic heart failure through oxidative stress pathway

Risk of hospital readmission and cardiac mortality increases with atmospheric pollution for patients with heart failure. The underlying mechanisms are unclear. Carbon monoxide (CO) a ubiquitous environmental pollutant could be involved. We explored the effect of daily exposure of CO relevant to urban pollution on post-myocardial infarcted animals. Rats with ischemic heart failure were exposed 4 weeks to daily peaks of CO mimicking urban exposure or to standard filtered air. CO exposure worsened cardiac contractile dysfunction evaluated by echocardiography and at the cardiomyocyte level. In line with clinical reports, the animals exposed to CO also exhibited a severe arrhythmogenic phenotype with numerous sustained ventricular tachycardias as monitored by surface telemetric electrocardiograms. CO did not affect cardiac β–adrenergic responsiveness. Instead, mitochondrial dysfunction was exacerbated leading to additional oxidative stress and Ca2+ cycling alterations. This was reversed following acute antioxidant treatment of cardiomyocytes with N-acetylcysteine confirming involvement of CO-induced oxidative stress. Exposure to daily peaks of CO pollution aggravated cardiac dysfunction in rats with ischemic heart failure by specifically targeting mitochondria and generating ROS-dependent alterations. This pathway may contribute to the high sensibility and vulnerability of individuals with cardiac disease to environmental outdoor air quality.

Antidiuretic and antinatriuretic response to high salt load in normotensive Wistar-Kyoto rats: Role of alpha-1A-adrenoreceptors

Altered renal adrenergic responses have been recognized as pathophysiological responses to high salt intake. This study aims to investigate the influence of 6weeks of high salt diet on α1A -adrenoceptor regulation of renal tubular antinatriuretic and antidiuretic response in normal Wistar Kyoto rats. To achieve the above objective, antinatriuretic and antidiuretic response to phenylephrine was measured in the absence and presence of 5-methylurapidil (5-MeU) using the inulin clearance method. Systemic mean arterial blood pressure and renal haemodynamics were also measured simultaneously. Six weeks of high salt intake in Wistar-Kyoto (WKY) rats did not bring any significant increase in mean arterial blood pressure. WKY rat on high salt diet (WKYHNa) showed an exaggerated increase in absolute and fractional sodium excretion. There was a significant involvement of α1A -adrenoceptor in carrying out renal tubular antinatriuretic and antidiuretic response in Wistar Kyoto rats on normal sodium diet (WKYNNa). However, α1A -adrenoceptor played a minimal role in handling the tubular reabsorptive response in WKY rats on high salt diet.

Comparison between magnesium sulfate (50 mg/kg) and lignocaine (2 mg/kg) for attenuation of intubation response in hypertensive patients

Aims and Objective: The aim and objective of this study was to compare between magnesium sulfate and lignocaine for attenuation of intubation response in hypertensive patients. Materials and Methods: This prospective, randomized, double-blinded study was conducted in an operating room of Jawaharlal Nehru Medical College Institute, in which 60 adult American Society of Anesthesiologists 1 and 2 controlled hypertensive patients undergoing elective surgery under general anesthesia and requiring endotracheal intubation were selected. Patients were randomized into two groups: Group I with thirty patients who received MgSO4 50 mg/kg half an hour before induction of anesthesia and Group II with thirty patients who received lignocaine 2 mg/kg intravenous bolus. Laryngoscopy and intubation were performed to see response in both the groups. Heart rate (HR) and blood pressure (BP) were recorded before, during, and after endotracheal intubation for 10 min. Results: The changes in the HR and mean arterial pressure (MAP) were compared, and the results showed that Group I patients had minimal response to any changes after intubation while Group II patients showed changes in HR and MAP toward baseline after laryngoscopy and endotracheal intubation. Discussion: Magnesium sulfate developed hypotension at various points, though it is associated with good control of adrenergic response during intubation, while lignocaine developed rate pressure changes which were not so good, also showing cardiac instability. Conclusion: Magnesium sulfate 50 mg/kg has a better control of BP during intubation in hypertensive patients with some incidence of hypotension when compared with lignocaine 2 mg/kg.