Adrenergic Response Research Articles

Sympathetic regulation of blood pressure in normotension and hypertension: when sex matters.

What is the topic of this review? Hypertension is a major problem in Western society. Risk of hypertension increases with age, especially in women, who have lower risk compared with men until menopause. This review outlines the sex differences in the sympathetic control of blood pressure and how these mechanisms change with age. What advances does it highlight? It has recently been recognized that men and women regulate blood pressure by different physiological mechanisms. This is important for both the understanding and the clinical management of individual patients with hypertension. This review summarizes recent advances in understanding how the regulation of blood pressure in hypertension by the sympathetic nervous system differs between men and women. The sympathetic nervous system has a central role in the regulation of arterial blood pressure (BP) and in the development of hypertension in humans. Recent evidence points to differences between the sexes in the integrative mechanisms by which BP is controlled, suggesting that the development of hypertension may follow distinct pathways in women compared with men. An important aspect of sympathetic control of BP is its substantial interindividual variability. In healthy young men, the variability in sympathetic nerve activity (SNA) is balanced by variability in cardiac output and vascular adrenergic responses, such that BP remains similar, and normal, across a severalfold range of resting SNA values. In young women, variability in resting SNA is similar to that seen in men, but the 'balancing' mechanisms are strikingly different; women exhibit greater β-adrenergic vasodilatation compared with men, which minimizes the pressor effects of a given level of SNA. Ageing is associated with increased SNA and a loss of the balancing factors seen in younger people, leading to an increased risk of hypertension in older people. Loss of oestrogen with menopause in women appears to be linked mechanistically with the decrease in β-adrenergic vasodilatation and the increased risk of hypertension in older women. Other important factors contributing to hypertension via sympathetic mechanisms are obesity and arterial stiffening, both of which increase with ageing. We conclude with a discussion of important areas in which more work is needed to understand and manage appropriately the sex-specific mechanisms in the development and maintenance of hypertension.

Determination of the minimum alveolar concentration of isoflurane that blunts adrenergic responses in sheep and evaluation of the effects of fentanyl.

To determine the minimum alveolar concentration that blunts adrenergic responses (MACBAR) for isoflurane and evaluate effects of fentanyl on isoflurane MACBAR in sheep. ANIMALS 13 healthy adult Dorset-cross adult ewes. In a crossover design, each ewe was anesthetized 2 times for determination of isoflurane MACBAR. Anesthesia was induced with propofol administered IV. Sheep initially received fentanyl (5 μg/kg, IV, followed by a constant rate infusion of 5 μg/kg/h) or an equivalent volume of saline (0.9% NaCl) solution (control treatment). After a washout period of at least 8 days, the other treatment was administered. For MACBAR determination, a mechanical nociceptive stimulus (ie, sponge forceps) was applied at the coronary band for 1 minute. The MACBAR values of the 2 treatments were compared by means of a paired t test. During MACBAR determination, blood samples were collected for measurement of plasma fentanyl concentration. Mean ± SD isoflurane MACBAR of the fentanyl and control treatments was 1.70 ± 0.28% and 1.79 ± 0.35%, respectively; no significant difference was found between the 2 treatments. Plasma concentration of fentanyl reached a median steady-state concentration of 1.69 ng/mL (interquartile range [25th to 75th percentile], 1.47 to 1.79 ng/mL), which was maintained throughout the study. Administration of fentanyl at 5 μg/kg, IV, followed by a constant rate infusion of the drug at 5 μg/kg/h did not decrease isoflurane MACBAR. Further studies to determine the effect of higher doses of fentanyl on inhalation anesthetic agents and their potential adverse effects are warranted.

Randomized double-blind comparison of remifentanil and alfentanil in patients undergoing laparoscopic cholecystectomy using total intravenous anesthesia.

Background and Aims:To compare the use of remifentanil and alfentanil to suppress intraoperative adrenergic response of pain and the influence of these drugs on the recovery profile in patients undergoing laparoscopic cholecystectomy using a total intravenous anesthesia (TIVA) technique.Material and Methods:One hundred patients undergoing elective laparoscopic cholecystectomy were randomized to be managed with either remifentanil (group R) or alfentanil (group A). During general anesthesia, we evaluated adrenergic responses to intubation to first surgical incision and over the surgical procedure. We also recorded time to first spontaneous breathing, time to successful ventilation, time to respond to verbal orders, and time to extubation.Results:The R group reported a significantly lower number of responses to intubation and responses to first surgical incision (14% vs. 30%; P = 0.013 and 8% vs. 18%; P = 0,037, respectively). The event of one or more responses during the surgical procedure was also lower in the R group (56% vs. 70%; P = 0.017). Hypertensive response to surgical stimuli during the procedure was lower in the R group as well as a lower frequency of tachycardia episodes in this group (34% vs. 56%; P = 0.033 and 28% vs. 44%; P = 0.041, respectively). No differences were found between groups relating to the percentage of hypotensive episodes and no episodes of bradycardia were appreciated. Both groups were similar relating to recovery times: time to the first spontaneous breathing, time to successful ventilation, time to respond to verbal orders, and time to extubation.Conclusion:Remifentanil showed a more stable hemodynamic response during the surgery compared with the use of alfentanil in anesthetized patients undergoing laparoscopic cholecystectomy using TIVA. Both opioids, alfentanil and remifentanil, have a similar recovery profile, and they do not delay time to awakening.

Investigation in the Role of Lamin A (LMNA) Deficiency in Heart Block and Dilated Cardiomyopathy (DCM) Using Human Induced Pluripotent Stem Cell Derived Cardiomyocytes

Investigation in the Role of Lamin A (LMNA) Deficiency in Heart Block and Dilated Cardiomyopathy (DCM) Using Human Induced Pluripotent Stem Cell Derived Cardiomyocytes

Downregulation of cystathionine γ lyase and endothelial nitric oxide synthase and reduced responsiveness of α1A adrenergic receptors in the kidneys of left ventricular hypertrophied Wistar Kyoto rats

This article explores the relationship between the renal expression of cystathionine gamma lyase (CSE) and endothelial nitric oxide synthase (eNOS) and the responsiveness of α1A adrenergic receptors in the renal vasculature following left ventricular hypertrophy (LVH) in rats. LVH was established by administering isoprenaline (5 mg/kg, 5 injections subcutaneously, 72 h apart) with 62 mg/L caffeine in drinking water for 2 weeks. Renal vasoconstrictor responses were measured using local administration of adrenergic agonists noradrenaline (NA), phenylephrine (PE), and methoxamine (ME) and the selective α1A adrenergic antagonist 5-methylurapidil (5-MeU). Mean arterial blood pressure was higher (144 ± 9 vs. 116 ± 4 mmHg) and renal cortical blood perfusion was lower in the LVH group (102 ± 5 vs. 157 ± 19 bpu) compared to the control group (P < 0.05). There was a 68% downregulation of mRNA for renal CSE and 79% for eNOS in the LVH group compared to the control group (taken as 100%) (P < 0.05). The high dose of 5-MeU attenuated the vasoconstrictor responses to NA by 33%, PE by 44%, and ME by 43% in the LVH group compared to the same dose in the control group. The reductions in basal renal cortical perfusion and α1A adrenergic receptor vasoconstrictor responses in LVH were associated with the downregulation of the CSE/H2S and eNOS/NO pathways.

Physiological Adrenergic Responses in Albino Rats in Experimental Hyperthyroidism

Physiological Adrenergic Responses in Albino Rats in Experimental Hyperthyroidism

Esmolol reduces anesthetic requirements thereby facilitating early extubation; a prospective controlled study in patients undergoing intracranial surgery.

BackgroundAdequate cerebral perfusion pressure with quick and smooth emergence from anesthesia is a major concern of the neuroanesthesiologist. Anesthesia techniques that minimize anesthetic requirements and their effects may be beneficial. Esmolol, a short acting hyperselective β-adrenergic blocker is effective in blunting adrenergic response to several perioperative stimuli and so it might interfere in the effect of the anesthetic drugs on the brain. This study was designed to investigate the effect of esmolol on the consumption of propofol and sevoflurane in patients undergoing craniotomy.MethodForty-two patients that underwent craniotomy for aneurysm clipping or tumour dissection were randomly divided in two groups (four subgroups). Anesthesia was induced with propofol, fentanyl and a single dose of cis-atracurium, followed by continuous infusion of remifentanil and either propofol or sevoflurane. Patients in the esmolol group received 500 mcg/kg of esmolol bolus 10 min before induction of anesthesia, followed by additional 200 mcg/kg/min of esmolol. Monitoring of the depth of anesthesia was also performed using the Bispectral Index-BIS and cardiac output. The inspired concentration of sevoflurane and the infusion rate of propofol were adjusted in order to maintain a BIS value between 40–50. Intraoperative emergence was detected by the elevation of BIS value, HR or MAP.ResultsThe initial and the intraoperative doses of propofol and sevoflurane were 18–50 mcg/kg/min and 0.2–0.5 MAC respectively in the esmolol group, whereas in the control group they where 100–150 mcg/kg/ and 0.9–2.0 MAC respectively (p = 0.000 for both groups). All procedures were anesthesiologically uneventful with no episodes of intraoperative emerge.ConclusionsEsmolol is effective not only in attenuating intraoperative hemodynamic changes related to sympathetic overdrive but also in minimizing significant propofol and sevoflurane requirements without compromising the hemodynamic status.ClinicalTrials.gov Identifier: NCT02455440. Registered 26 May 2015.

Deletion of protein tyrosine phosphatase 1b in proopiomelanocortin neurons reduces neurogenic control of blood pressure and protects mice from leptin- and sympatho-mediated hypertension

Protein tyrosine phosphatase 1b (Ptp1b), which represses leptin signaling, is a promising therapeutic target for obesity. Genome wide deletion of Ptp1b, increases leptin sensitivity, protects mice from obesity and diabetes, but alters cardiovascular function by increasing blood pressure (BP). Leptin-control of metabolism is centrally mediated and involves proopiomelanocortin (POMC) neurons. Whether these neurons contribute to leptin-mediated increases in BP remain unclear. We hypothesized that increasing leptin signaling in POMC neurons with Ptp1b deletion will sensitize the cardiovascular system to leptin and enhance neurogenic control of BP. We analyzed the cardiovascular phenotype of Ptp1b+/+ and POMC-Ptp1b−/− mice, at baseline and after 7 days of leptin infusion or sympatho-activation with phenylephrine. POMCPtp1b deletion did not alter baseline cardiovascular hemodynamics (BP, heart rate) but reduced BP response to ganglionic blockade and plasma catecholamine levels that suggests a decreased neurogenic control of BP. In contrast, POMC-Ptp1b deletion increased vascular adrenergic reactivity and aortic α-adrenergic receptors expression. Chronic leptin treatment reduced vascular adrenergic reactivity and blunted diastolic and mean BP increases in POMC-Ptp1b−/− mice only. Similarly POMC-Ptp1b−/− mice exhibited a blunted increased in diastolic and mean BP accompanied by a gradual reduction in adrenergic reactivity in response to chronic vascular sympatho-activation with phenylephrine. Together these data rule out our hypothesis but suggest that deletion of Ptp1b in POMC neurons protects from leptin- and sympatho-mediated increases in BP. Vascular adrenergic desensitization appears as a protective mechanism against hypertension, and POMC-Ptp1b as a key therapeutic target for the treatment of metabolic and cardiovascular dysfunctions associated with obesity.

Detrimental Effects of Hyperglycemia in Acute Coronary Syndromes: from Pathophysiological Mechanisms to Therapeutic Strategies.

Hyperglycemia recognized during hospitalization for acute coronary syndromes (ACS) is common. It is a powerful predictor of worse prognosis in patients both with and without previously known diabetes mellitus. Hyperglycemia during ACS is caused by an inflammatory and adrenergic response to ischemic stress, when catecholamines are released and glycogenolysis induced. The link between hyperglycemia and prognosis in ACS patients is multi-factorial. Hyperglycemia exerts detrimental effects on left ventricular and platelet function and it also activates other systemic pathological processes that contribute to cellular and tissue injury such as increasing oxidative stress and worsening endothelial function. Glucose management strategies in ACS may improve outcome in patients with hyperglycemia, by reducing inflammatory and clotting mediators, by improving endothelial function and fibrinolysis and by reducing infarct size. Most of available oral anti-diabetic drugs are contraindicated for the increased risk of hypoglycemia. Thus, insulin is the preferred agent for glycemic control in ACS and conversion from intravenous to subcutaneous therapy commonly occurs when the critical acute phase of ACS resolves. Pharmacodynamics of insulin allows it to be adaptable to the changing physiology of the ACS patient, is easily titrated and has no dosage threshold. Nevertheless, findings concerning the effect on ACS-related mortality of the control of glucose levels by intravenous infusion of insulin have been conflicting and intervention trials are needed to optimize the definition of hyperglycemia and to establish appropriate modalities and goals of glucose lowering treatment. In particular, the clinical benefit of an aggressive treatment with insulin is yet unproved.

A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress.

We investigated cardiac contractility in the ACTC E361G transgenic mouse model of dilated cardiomyopathy (DCM). No differences in cardiac dimensions or systolic function were observed in young mice, whereas young adult mice exhibited only mild diastolic abnormalities. Dobutamine had an inotropic and lusitropic effect on the mouse heart. In papillary muscle at 37°C, dobutamine increased relaxation rates [∼50% increase of peak rate of force decline normalized to force (dF/dtmin/F), 25% reduction of time to 90% relaxation (t90) in nontransgenic (NTG) mice], but in the ACTC E361G mouse, dF/dtmin/F was increased 20-30%, and t90 was only reduced 10% at 10 Hz. Pressure-volume measurements showed increases in maximum rate of pressure decline and decreases in time constant of left ventricular pressure decay in the ACTC E361G mouse that were 25-30% of the changes in the NTG mouse, consistent with blunting of the lusitropic response. The inotropic effect of dobutamine was also blunted in ACTC E361G mice, and the dobutamine-stimulated increase in cardiac output (CO) was reduced from 2,100 to 900 μl/min. Mice were treated with high doses of ANG II for 4 wk. The chronic stress treatment evoked systolic dysfunction in ACTC E361G mice but not in NTG. There was a significant reduction in rates of pressure increase and decrease, as well as reduced end-systolic pressure and increased volume. Ejection fraction and CO were reduced in the ACTC E361G mouse, indicating DCM. In vitro DCM-causing mutations uncouple the relationship between Ca(2+) sensitivity and troponin I phosphorylation. We conclude that this leads to the observed, reduced response to β1 agonists and reduced cardiac reserve that predisposes the heart to DCM under conditions of chronic stress.

Abstract B43: The degree of adrenergic stress signaling regulates the severity of graft versus host disease following allogeneic hematopoietic cell transplantation

Abstract Adrenergic stress is recognized to influence multiple arms of the immune system. Recent work in our lab supports the observation that conditions which cause physiologic stress (i.e., increase adrenergic stress) reduce T cell function. T cells are crucial mediators of graft versus host disease (GVHD), a common and often lethal side effect of allogeneic hematopoietic cell transplantation (allo-HCT). As many patients succumb to GVHD, being able to understand underlying factors that regulate its severity is paramount. Our recent work led us to hypothesize that stress induced β-adrenergic receptor (AR) agonists such as norepinephrine may dampen GVHD following allo-HCT. To investigate the role of β-AR signaling on GVHD we performed MHC-mismatched allo-HCT in which recipient mice were treated with PBS (β-AR signaling intact) or a β-AR antagonist, propranolol, (i.e., a β-blocker) to inhibit β-AR signaling. Following allo-HCT, GVHD was significantly increased in mice treated with propranolol as evidenced by more weight loss (P&amp;lt;0.01) and decreased survival (P&amp;lt;0.01) compared to mice treated with PBS. To confirm that the weight loss and decreased survival were indicative of T cell-mediated GVHD, we performed allo-HCT with T cell depleted bone marrow. No GVHD was observed in PBS- or propranolol-treated groups when the graft did not contain allogeneic T cells. Furthermore, syngeneic transplants also yielded no GVHD in PBS- or propranolol-treated groups. We next evaluated pathology in the liver, small and large intestine. We found that liver pathology was significantly increased (P&amp;lt;0.05) in mice treated with propranolol compared to the PBS treated group. Thus, for the first time we have found that the level of systemic β-AR-mediated stress signaling regulates the severity of GVHD. We next asked whether we could regulate GVHD by manipulating endogenous levels of the β-AR agonist, norepinephrine, by exposing mice to physiological stress. To test this we used mildly cool housing temperature to activate the adrenergic stress response as temperature manipulation is a classic means to study norepinephrine-driven stress signaling. We housed mice at 22°C, a temperature in which mice are cold stressed, and 30°C, a temperature in which the adrenergic stress response is significantly reduced. Therefore in this model, we predicted that GVHD would be reduced in severity in mice housed at 22°C compared to those housed at 30°C. We first confirmed that mice housed at 22°C were more stressed by measuring norepinephrine levels, finding that norepinephrine was significantly elevated both pre- and 13 days post-allo-HCT (P&amp;lt;0.05). As predicted, cold stressed mice housed at 22°C had significantly less GVHD as evidenced by reduced weight loss (P&amp;lt;0.01), improved survival (P&amp;lt;0.01), and less liver pathology (P&amp;lt;0.05) when compared to mice housed at 30°C. This strongly supports our results obtained using pharmacological inhibition of β-AR signaling. At 30°C, there is minimal norepinephrine-driven stress, and therefore is not surprising that propranolol treatment of these mice had no effect on the severity of GVHD. Thus, these findings suggest that allogeneic graft vs. host responses were responsible for weight loss and decreased survival in conditions in which adrenergic stress was alleviated (housing at 30°C) or the stress response was blocked (treatment with propranolol). Therefore β-AR signaling plays a vital and previously unrecognized role in modulating the severity of GVHD. Clinically, using β-blockers to achieve pharmacologic inhibition of β-AR signaling is commonly used to alleviate symptoms of hypertension or other age-related diseases in elderly patients. Of note, β-blockers are also routinely given post allo-HCT to ameliorate symptoms such as hypertension and tachycardia. Thus, following allo-HCT, it may be important to reconsider the use of β-blockers as our findings suggest that the degree of β-AR signaling regulates the severity of GVHD. Citation Format: Nicholas D. Leigh, Kathleen M. Kokolus, Jason W-L Eng, Jingxin Qiu, George L. Chen, Philip L. McCarthy, Xuefang Cao, Elizabeth A. Repasky. The degree of adrenergic stress signaling regulates the severity of graft versus host disease following allogeneic hematopoietic cell transplantation. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B43.

Dexmedetomidine ameliorates gut lactate production and impairment of exogenous lactate clearance in an endotoxic sheep model

The mechanisms of persistent hyperlactemia during endotoxic shock are probably multifactorial. Both hypoperfusion-related anaerobic production and adrenergic-driven aerobic generation have been implicated. More recently an early and severe impairment in exogenous lactate clearance has also been described [1]. Theoretically, an excessive adrenergic response could influence all these mechanisms and thus aggravate the problem.

Novel approaches to examine the regulation of voltage-gated calcium channels in the heart.

The cardiac L-type Ca(2+) channel plays a key role in cardiac excitation-contraction coupling, action potential duration, and gene expression. Abnormalities in CaV1.2 function, including increased long-opening-mode gating and blunted adrenergic responsiveness, are associated with heart failure and hypertrophy. The increased activation of CaV1.2, in turn, triggers Ca(2+) -responsive signaling pathways, which contribute to the pathogenesis of heart failure and hypertrophy. CaV1.2 in heart is associated with large supramolecular complexes that impact on channel trafficking, localization, turnover, and function. Much of the prevailing dogma relating to mechanisms underlying CaV1.2 trafficking and modulation is derived from studies using recombinant channels reconstituted in heterologous expression systems. However, recent results using knock-in mice indicate that several long-standing "facts" about CaV1.2 regulation derived from heterologous expression studies are not replicated in native heart, emphasizing the critical need for mechanistic studies in the context of actual cardiomyocytes. In this review, we discuss the use of the use of knockin and knockout mice as well as new tools, including doxycycline-induced expression of informative α1C mutants within cardiomyocytes to probe adrenergic regulation of CaV1.2.

Hyperglycemia in acute coronary syndromes: from mechanisms to prognostic implications.

Hyperglycemia is a frequent condition in patients with acute coronary syndromes (ACS). Hyperglycemia during ACS is caused by an inflammatory and adrenergic response to ischemic stress, when catecholamines are released and glycogenolysis induced. Although the involved pathophysiological mechanisms have not yet been fully elucidated, it is believed that hyperglycemia is associated with an increase in free fat acids (which induce cardiac arrhythmias), insulin resistance, chemical inactivation of nitric oxide and the production of oxygen reactive species (with consequent microvascular and endothelial dysfunction), a prothrombotic state, and vascular inflammation. It is also related to myocardial metabolic disorders, leading to thrombosis, extension of the damaged area, reduced collateral circulation, and ischemic preconditioning. In the last few years, several observational studies demonstrated that hyperglycemia in ACS is a powerful predictor of survival, increasing the risk of immediate and long-term complications in patients both with and without previously known diabetes mellitus. Glucose management strategies in ACS may improve outcomes in patients with hyperglycemia, perhaps by reducing inflammatory and clotting mediators, by improving endothelial function and fibrinolysis and by reducing infarct size. Recent clinical trials of insulin in ACS have resulted in varying levels of benefit, but the clinical benefit of an aggressive treatment with insulin is yet unproved.

Abstract 236: Cardiac Overexpression of Thioredoxin-1 Delays Mitochondrial Damage and Prolongs Survival in Septic Mice

Introduction: Current evidence suggests a main role of thioredoxin-1 (trx1) in the protection against oxidative stress. However, it is unknown yet a putative role of trx1 in the regulation of contractility and mitochondrial function, dynamics and biogenesis in sepsis-induced myocardial dysfunction in which oxidative stress is an underlying cause. Methods: Transgenic male mice (Tg-trx1) and its wildtype (wt) were subjected to cecal ligation and double puncture or sham operation. After 6, 18 and 24 h, antioxidant enzymes, protein carbonylation and mitocondrial function were evaluated. Hearts were isolated and perfused using the Langendorff technique. Inotropism was evaluated through left ventricular developed pressure (LVDP) and contractile reserve after β-adrenergic stimulus by addition of isoproterenol (ISO) (1 μM). Evaluation of mitochondrial fusion-fission dynamics (Drp1, Mfn2, Opa1) and biogenesis (PGC-1α, NRF-1 and TFAM) were made by real-time qPCR. Results: Over the time course of sepsis, there was an improvement in average life expectancy in Tg-trx1 (Tg-trx1: 36, wt: 28 h; p=0.0204), and 15 percentages points higher β -adrenergic response at 6 h compared to wt (22.8 vs 7.8%, means of relative percentage differences respectively). Inhibition of complex I activity, protein oxidation, and loss of membrane potential was lower in Tg-trx1, with a sustained MnSOD activity at 24 h. mRNA levels of Opa1 were significantly reduced in sepsis, accompanied by ultrastructural alterations in mitochondrial cristae, while significant Drp1 activation (measured by Ser P616 phosphorylation) was observed in wt mice at 24 h. PGC-1 α mRNA decreased at 6 h in both groups, and then, showed a 2.5-fold increase in Tg-trx1 at 24 h. Autophagy was demonstrated by increased LC3-II/LC3-I ratios in both groups during the progression of sepsis, although the levels were early higher in Tg-Trx1. No indicators of apoptosis were observed. Conclusions: The results show that mice with cardiac-specific overexpression of Trx1 have higher survival. Trx1 provides protection against oxidative stress, which seems to preserve contractile reserve and keep mitochondrial biogenesis. Associated with mitochondrial autophagy-processes allow mitochondrial renewal and life extension.

Atrial chronotropic reactivity to catecholamines in neonatal rats: Contribution of β-adrenoceptor subtypes

Although increase in heart rate is a crucial determinant for enhancement of cardiac output in the neonate, information on the chronotropic reactivity to catecholamines during postnatal development is scarce. The present study was aimed at investigating the role of β-adrenoceptor subtypes and catecholamine removal mechanisms in the adrenergic chronotropic response during the early post-natal period. Right atria isolated from immature (0–21 day old) and adult (4–6 month old) rats were used for determination of the responsiveness to agonists and quantitation of the transcripts of proteins involved in β-adrenergic signaling. The main results were: (a) the maximum response (Rmax) to norepinephrine increased with age, whereas sensitivity decreased; (b) age-dependent differences in sensitivity to norepinephrine were abolished by inhibition of the neuronal norepinephrine transporter; (c) Rmax to isoproterenol was similar in immature and adult atria, and depressed only in the former by β2-adrenoceptor blockade with ICI118,551; (d) neonatal atria showed greater β2-adrenoceptor mRNA levels, and more prominent positive chronotropic response to the β2- and β3-adrenoceptor agonists zinterol and YM178, respectively (nanomolar range); (e) in atria of immature rats, transcript levels of the extraneuronal monoamine transporter were lower, and its inhibition did not affect sensitivity to isoproterenol; and (f) reactivity to forskolin and 3-isobutyl-1-methylxanthine was not affected by age. The increased β2- and β3-adrenoceptor participation in the adrenergic chronotropic response, in addition to weaker catecholamine removal, may compensate for the immature cardiac innervation and the apparently reduced efficiency of β1-adrenoceptor signaling in the neonate, increasing the responsiveness to endogenous and exogenous β2-adrenoceptor agonists.

Hot water immersion induces an acute cytokine response in cervical spinal cord injury

The dysfunctional sympathetic nervous system in individuals with cervical spinal cord injury (CSCI) impairs adrenergic responses and may, therefore, contribute to the blunted post-exercise cytokine response. The purpose of this study was to investigate an alternative way to exercise to induce an acute cytokine response by passive core temperature elevation in CSCI. Seven male participants with a motor complete CSCI and 8 male able-bodied controls were immersed for 60min in water set at a temperature 2°C above the individuals' resting oesophageal temperature. Blood was collected pre, post, and every hour up to 4h post-immersion. Hot water immersion resulted in an IL-6 plasma concentration mean increase of 133±144% in both groups (P=0.001). On a group level, IL-6 plasma concentrations were 68±38% higher in CSCI (P=0.06). In both groups, IL-8 increased by 14±11% (P=0.02) and IL-1ra by 18±17% (P=0.05). Catecholamine plasma concentrations were significantly reduced in CSCI (P<0.05) and did not increase following immersion. Passive elevation of core temperature acutely elevates IL-6, IL-8 and IL-1ra in CSCI despite a blunted adrenergic response, which is in contrast to earlier exercise interventions in CSCI. The present study lays the foundation for future studies to explore water immersion as an alternative to exercise to induce an acute cytokine response in CSCI.

β-2 Adrenergic receptor gene polymorphism and response to propranolol in cirrhosis.

To evaluate the association of β-2 adrenergic receptor (β2-AR) gene polymorphism with response of variceal pressure to propranolol in cirrhosis. Sixty-four non-related cirrhotic patients participated in this study and accepted variceal pressure measurement before and after propranolol administration. Polymorphism of the β2-AR gene was determined by directly sequencing of the polymerase chain reaction products from the DNA samples that were prepared from the patients. The prevalence of Gly16-Glu/Gln27 and Arg16-Gln27 homozygotes, and compound heterozygotes was 29.7%, 10.9%, and 59.4%, respectively. Patients with cirrhosis with Gly16-Glu/Gln27 homozygotes had a greater decrease of variceal pressure after propranolol administration than those with Arg16-Gln27 homozygotes or with compound heterozygotes (22.4% ± 2.1%, 13.1% ± 2.7% and 12.5% ± 3.1%, respectively, P < 0.01). The variceal pressure response to propranolol was associated with polymorphism of β2-AR gene. Patients with the Gly(16)-Glu/Gln(27) homozygotes probably benefit from propranolol therapy.

PP.21.22

Objective: To evaluate whether usual antihypertensive drugs modify cardiac morphology in spontaneously hypertensive rats (SHR). We show that these drugs modify cardiac function in SHR in other study presented in this congress. Design and method: Male SHR 8 weeks age were randomly assigned to different antihypertensive oral treatment (n = 18/group) for 16 months: losartan 30 mg/kg (L), hydralazine 11 mg/kg (H), rosuvastatin 10 mg/kg (R), carvedilol 20 mg/kg (C) (n = 16), water (SHRw treatment control). Hypertension control group was comprised of 18 normotensive Wistar Kyoto rats (WKY). Histology: conventional light microscopy. Morphology: Image-Pro Plus 6.0 software. Morphometry: area of 237 ± 50 myocytes (transversal section, μm2), number of myocytes/mm2, number of capillaries/mm2 (N). Average oxygen diffusion distance (myocyte-to-capillary) was calculated (R, μm). Stereology: determination of the number of points by counting (Pp), estimation of volumetric density (Vv) for myocardium, interstitium and coronary capillaries as Vv (%) = [Pp /Ptotal] x 100. Statistics: Kruskal Wallis non parametric test, Dunn test for multiple comparisons (Graph Pad Prism, 5.0). Significance: p < 0.05. Results: Table 1 (on the following page) shows full morphometry data; (n) = number of cases, a p < 0.01 vs SHRw; b p < 0.05 vs SHRw; c p < 0.01 vs SHRw, C, H, R, WKY; d p < 0.05 vs R, H.Conclusions: Losartan treatment increased the number of capillaries and cardiomyocytes of normal size, reduced interstitial volume and myocyte-to-capillary distance in LV. Rosuvastatin treatment increased the number of capillaries in both ventricles. These findings and inhibition of LVH development with normalization of basal inotropism and beta adrenergic response as shown in other presentation in this Congress, point out that Losartan might be the most effective antihypertensive of those presently examined. It follows that activation of angiotensin II receptors might be a key step in LVH development with decline in beta adrenergic response in hypertension. The presence of LVH or cardiac failure was associated with expression of thioredoxins only in some cases suggesting that oxidative stress may not be determinant in LVH development.

Metabolic Heat Stress Adaption in Transition Cows: Differences in Macronutrient Oxidation between Late-Gestating and Early-Lactating German Holstein Dairy Cows.

High ambient temperatures have severe adverse effects on biological functions of high-yielding dairy cows. The metabolic adaption to heat stress was examined in 14 German Holsteins transition cows assigned to two groups, one heat-stressed (HS) and one pair-fed (PF) at the level of HS. After 6 days of thermoneutrality and ad libitum feeding (P1), cows were challenged for 6 days (P2) by heat stress (temperature humidity index (THI) = 76) or thermoneutral pair-feeding in climatic chambers 3 weeks ante partum and again 3 weeks post-partum. On the sixth day of each period P1 or P2, oxidative metabolism was analyzed for 24 hours in open circuit respiration chambers. Water and feed intake, vital parameters and milk yield were recorded. Daily blood samples were analyzed for glucose, β-hydroxybutyric acid, non-esterified fatty acids, urea, creatinine, methyl histidine, adrenaline and noradrenaline. In general, heat stress caused marked effects on water homeorhesis with impairments of renal function and a strong adrenergic response accompanied with a prevalence of carbohydrate oxidation over fat catabolism. Heat-stressed cows extensively degraded tissue protein as reflected by the increase of plasma urea, creatinine and methyl histidine concentrations. However, the acute metabolic heat stress response in dry cows differed from early-lactating cows as the prepartal adipose tissue was not refractory to lipolytic, adrenergic stimuli, and the rate of amino acid oxidation was lower than in the postpartal stage. Together with the lower endogenous metabolic heat load, metabolic adaption in dry cows is indicative for a higher heat tolerance and the prioritization of the nutritional requirements of the fast-growing near-term fetus. These findings indicate that the development of future nutritional strategies for attenuating impairments of health and performance due to ambient heat requires the consideration of the physiological stage of dairy cows.