Lutz Hein

Publications of Lutz Hein

• Involvement of α(2)-Adrenoceptor Subtypes A and C in Glucose Homeostasis and Adrenaline-Induced Hyperglycaemia.

  Authors: Suvi T Ruohonen, Saku Ruohonen, Ralf Gilsbach, Eriika Savontaus, Mika Scheinin, Lutz Hein

  Neuroendocrinology. 02/2012;

  Background and Aims: Insulin secretion is controlled by pancreatic α(2A)-adrenoceptors. Mice lacking α(2A)-adrenoceptors (α(2A)AR(-/-) mice) show hyperinsulinaemia, reduced blood glucose levels andBackground and Aims: Insulin secretion is controlled by pancreatic α(2A)-adrenoceptors. Mice lacking α(2A)-adrenoceptors (α(2A)AR(-/-) mice) show hyperinsulinaemia, reduced blood glucose levels and improved glucose tolerance. Methods: In the present study, we used α(2AC)AR(-/-), α(2C)AR(-/-) and α(2A)AR(-/-) mice and a mouse line with adrenergic cell-specific expression of α(2A)-adrenoceptors (lacking these receptors in non-adrenergic cells), and their wild-type (WT) controls, to assess the glucoregulatory role of the α(2C)-adrenoceptor subtype in vivo. Glucose and insulin tolerance tests were performed and blood glucose and serum insulin levels were determined after fasting and glucose stimulation. Plasma catecholamines were also measured. In addition, the effect of pretreatment with (±)-propranolol was determined in α(2C)AR(-/-) mice. Results: α(2AC)AR(-/-) mice had a similar glucose and insulin phenotype as α(2A)AR(-/-) mice and mice with restored α(2A)-autoreceptors, suggesting that only deletion of postsynaptic α(2A)-adrenoceptors has major effects on glucose disposition. However, α(2AC)AR(-/-) mice were more sensitive to the glucose-lowering effect of insulin than WT mice. This was not observed in α(2A)AR(-/-) mice. The α(2C)AR(-/-) mice showed impaired glucose tolerance that was reversed by pretreatment with (±)-propranolol. No difference in insulin secretion was observed in α(2C)AR(-/-) mice compared with WT animals. Conclusion: The results underline that depletion of postsynaptic pancreatic α(2A)-adrenoceptors has major effects on the regulation of glucose homeostasis in α(2AC)AR(-/-) and α(2A)AR(-/-) mice. Deletion of the α(2C) subtype leads to increased adrenaline secretion and has the potential to increase blood glucose levels via enhanced glycogenolysis.

• [Structure and evolution of adrenergic receptors].

  Authors: Lutz Hein

  Pharmazie in unserer Zeit. 11/2011; 40(6):470-3.

• [α -Adrenoceptors: three subtypes for a broad spectrum of activity].

  Authors: Ralf Gilsbach, Sebastian Preissl, Lutz Hein

  Pharmazie in unserer Zeit. 11/2011; 40(6):462-8.

• [Editorial: Pharmazie in unserer Zeit 6/2011].

  Authors: Lutz Hein, Ulrike Holzgrabe

  Pharmazie in unserer Zeit. 11/2011; 40(6):447.

• α(2)-adrenoceptors do not mediate neuroprotection in acute ischemic stroke in mice.

  Authors: Marc Brede, Stefan Braeuninger, Friederike Langhauser, Lutz Hein, Norbert Roewer, Guido Stoll, Christoph Kleinschnitz

  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 07/2011; 31(10):e1-7.

  We assessed the neuroprotective potential of α(2)-adrenoceptors in ischemic stroke using mice with targeted deletions of individual α(2)-adrenoceptor subtypes (α(2A)(-/-), α(2B)(-/-), α(2C)(-/-),We assessed the neuroprotective potential of α(2)-adrenoceptors in ischemic stroke using mice with targeted deletions of individual α(2)-adrenoceptor subtypes (α(2A)(-/-), α(2B)(-/-), α(2C)(-/-), α(2A/C)(-/-)). The effects of the α(2)-adrenoceptor agonist clonidine were studied in parallel. Focal cerebral ischemia was induced with or without clonidine pretreatment by transient middle cerebral artery occlusion. Neurologic outcome and infarct volumes were evaluated on day 1. Cerebral blood flow (CBF) and mean arterial pressure were determined. α(2)-Adrenoceptor null mice did not display larger infarct volumes compared with wild-type (WT) mice under basal conditions (P>0.05). In line with this finding, pretreatment with clonidine did not protect from ischemic brain damage in WT mice or α(2A)(-/-), α(2B)(-/-), and α(2C)(-/-) mice. Clonidine induced smaller infarct volumes only in α(2A/C)(-/-) mice (P<0.05), but this did not translate into improved neurologic function (P>0.05). Importantly, while clonidine caused a significant decrease in arterial blood pressure in all groups, it had no blood pressure lowering effect in α(2A/C)(-/-) mice, and this correlated with higher CBF and smaller infarct volumes in this group. In summary, we could not demonstrate a neuroprotective function of α(2)-adrenoceptors in focal cerebral ischemia. Careful controlling of physiological parameters relevant for stroke outcome is recommended in experimental stroke studies.

• Are the pharmacology and physiology of α₂ adrenoceptors determined by α₂-heteroreceptors and autoreceptors respectively?

  Authors: Ralf Gilsbach, Lutz Hein

  British journal of pharmacology. 06/2011; 165(1):90-102.

  α(2)-Adrenoceptors are important mediators of physiological responses to the endogenous catecholamines noradrenaline and adrenaline. In addition, α(2)-adrenoceptors are pharmacological targets forα(2)-Adrenoceptors are important mediators of physiological responses to the endogenous catecholamines noradrenaline and adrenaline. In addition, α(2)-adrenoceptors are pharmacological targets for the treatment of hypertension, sympathetic overactivity and glaucoma. α(2)-Adrenoceptors are also targeted to induce sedation and analgesia in anaesthesia and intensive care. α(2)-Adrenoceptors were first described as presynaptic receptors inhibiting the release of various transmitters from neurons in the central and peripheral nervous systems. In addition to these presynaptic neuronal receptors, α(2)-adrenoceptors were also identified in many non-neuronal cell types of the body. Gene-targeting in mice provided a comprehensive assignment of the physiological and pharmacological functions of these receptors to specific α(2A)-, α(2B) - and α(2C)-adrenoceptor subtypes. However, the specific cell types and signalling pathways involved in these subtype-specific α(2)-adrenoceptor functions were largely unexplored until recently. This review summarizes recent findings from transgenic mouse models, which were generated to define the role of α(2)-adrenoceptors in adrenergic neurons, that is, α(2)-autoreceptors, versus α(2)-adrenoceptors in non-adrenergic neurons, termed α(2)-heteroreceptors. α(2)-Autoreceptors are primarily required to limit release of noradrenaline from sympathetic nerves and adrenaline from adrenal chromaffin cells at rest. These receptors are desensitized upon chronic activation as it may for instance occur due to enhanced sympathetic activity during chronic heart failure. In contrast, pharmacological effects of acutely administered α(2)-adrenoceptor agonist drugs essentially require α(2)-heteroreceptors in non-adrenergic neurons, including analgesia, sedation, hypothermia and anaesthetic-sparing as well as bradycardia and hypotension. Thus a clear picture has emerged of the significance of auto- versus heteroreceptors in mediating the physiological functions of α(2)-adrenoceptors and the pharmacological functions of α(2)-adrenoceptor agonist drugs respectively.

• Chronic cardiac pressure overload induces adrenal medulla hypertrophy and increased catecholamine synthesis.

  Authors: Johanna Schneider, Achim Lother, Lutz Hein, Ralf Gilsbach

  Basic research in cardiology. 06/2011; 106(4):591-602.

  Increased activity of the sympathetic system is an important feature contributing to the pathogenesis and progression of chronic heart failure. While the mechanisms and consequences of enhancedIncreased activity of the sympathetic system is an important feature contributing to the pathogenesis and progression of chronic heart failure. While the mechanisms and consequences of enhanced norepinephrine release from sympathetic nerves have been intensely studied, the role of the adrenal gland in the development of cardiac hypertrophy and progression of heart failure is less well known. Thus, the aim of the present study was to determine the effect of chronic cardiac pressure overload in mice on adrenal medulla structure and function. Cardiac hypertrophy was induced in wild-type mice by transverse aortic constriction (TAC) for 8 weeks. After TAC, the degree of cardiac hypertrophy correlated significantly with adrenal weight and adrenal catecholamine storage. In the medulla, TAC caused an increase in chromaffin cell size but did not result in chromaffin cell proliferation. Ablation of chromaffin α(2C)-adrenoceptors did not affect adrenal weight or epinephrine synthesis. However, unilateral denervation of the adrenal gland completely prevented adrenal hypertrophy and increased catecholamine synthesis. Transcriptome analysis of microdissected adrenal medulla identified 483 up- and 231 downregulated, well-annotated genes after TAC. Among these genes, G protein-coupled receptor kinases 2 (Grk2) and 6 and phenylethanolamine N-methyltransferase (Pnmt) were significantly upregulated by TAC. In vitro, acetylcholine-induced Pnmt and Grk2 expression as well as enhanced epinephrine content was prevented by inhibition of nicotinic acetylcholine receptors and Ca(2+)/calmodulin-dependent signaling. Thus, activation of preganglionic sympathetic nerves innervating the adrenal medulla plays an essential role in inducing adrenal hypertrophy, enhanced catecholamine synthesis and induction of Grk2 expression after cardiac pressure overload.

• The identification of phosducin as a novel candidate gene for hypertension and its role in sympathetic activation.

  Authors: Ulrich Broeckel, Monika Stoll, Lutz Hein

  Current opinion in nephrology and hypertension. 03/2011; 20(2):118-24.

  The primary objective of this review is to familiarize readers with the recent identification of phosducin (Pdc) as a novel candidate gene for stress-induced hypertension using comparative geneticsThe primary objective of this review is to familiarize readers with the recent identification of phosducin (Pdc) as a novel candidate gene for stress-induced hypertension using comparative genetics and the elucidation of its role in sympathetic activation. Phosducin was previously identified as a G-protein regulator expressed in the retina and pineal gland. Knowledge of its physiological role as a G-protein regulator was limited. A recent study by Beetz et al. based on comparative genetics of mice and humans establishes Pdc as a novel candidate gene for stress-induced hypertension. This study further delineates the role of phosducin as a regulator of sympathetic activity in postsynaptic ganglia and highlights the importance of sympathetic function in blood pressure regulation. In addition, it demonstrates the utility of the complementary approaches of population-based association testing and animal model genetics in the discovery of genes for complex phenotypes. The identification of Pdc as a gene for stress-induced hypertension offers new insights into the relationship between sympathetic nervous system activation, blood pressure regulation and genetic factors. It has implications for both the treatment of hypertension and kidney disease and may represent a new target for novel therapeutics.

• Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction.

  Authors: Daniela Fraccarollo, Stefan Berger, Paolo Galuppo, Susanne Kneitz, Lutz Hein, Günther Schütz, Stefan Frantz, Georg Ertl, Johann Bauersachs

  Circulation. 02/2011; 123(4):400-8.

  Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied leftMineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MR(MLCCre)) that were generated with a conditional MR allele (MR(flox)) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter. Control (MR(flox/flox), MR(flox/wt)) and MR(MLCCre) mice underwent coronary artery ligation. MR ablation had no detectable baseline effect on cardiac morphology and function. The progressive left ventricular chamber enlargement and functional deterioration in infarcted control mice, detected by echocardiography and conductance catheter analysis during the 8-week observation period, were substantially attenuated in MR(MLCCre) mice. Chronically infarcted MR(MLCCre) mice displayed attenuated pulmonary edema, reduced cardiac hypertrophy, increased capillary density, and reduced accumulation of extracellular matrix proteins in the surviving left ventricular myocardium. Moreover, cardiomyocyte-specific MR ablation prevented the increases in myocardial and mitochondrial O(2)(·-) production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MR(MLCCre) mice exhibited enhanced infarct neovessel formation and collagen structural organization associated with reduced infarct expansion. Mechanistically, cardiomyocytes lacking MR displayed accelerated stress-induced activation and subsequent suppression of nuclear factor-κB and reduced apoptosis early after myocardial infarction. Cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure, highlighting the importance of cardiomyocyte MR for heart failure development and progression.

• Ablation of mineralocorticoid receptors in myocytes but not in fibroblasts preserves cardiac function.

  Authors: Achim Lother, Stefan Berger, Ralf Gilsbach, Stephan Rösner, Andreas Ecke, Frederico Barreto, Johann Bauersachs, Günther Schütz, Lutz Hein

  Hypertension. 02/2011; 57(4):746-54.

  Antagonists of the mineralocorticoid receptor improve morbidity and mortality in patients with severe heart failure. However, the cell types involved in these beneficial effects are only partiallyAntagonists of the mineralocorticoid receptor improve morbidity and mortality in patients with severe heart failure. However, the cell types involved in these beneficial effects are only partially known. The aim of this work was to evaluate whether genetic deletion of mineralocorticoid receptors in mouse cardiomyocytes or fibroblasts in vivo is cardioprotective after chronic left ventricular pressure overload. After transverse aortic constriction, mice deficient in myocyte mineralocorticoid receptors but not those deficient in fibroblast mineralocorticoid receptors were protected from left ventricular dilatation and dysfunction. After pressure overload, left ventricular ejection fraction was significantly higher in mice lacking myocyte mineralocorticoid receptors (70.2±4.4%) as compared with control mice (54.3±2.5%; P<0.01). Myocyte mineralocorticoid receptor-deficient mice showed mild cardiac hypertrophy at baseline, contributing to reduced left ventricular wall tension at baseline and after pressure overload. Cardiac levels of phospho-extracellular signal-regulated kinase 1/2 were higher in myocyte mineralocorticoid receptor-deficient mice than in control mice after pressure overload. Neither fibroblast nor myocyte mineralocorticoid receptor ablation altered the development of cardiac hypertrophy or fibrosis after pressure overload. Both mineralocorticoid receptor mutant mouse strains developed similar degrees of myocyte apoptosis, proinflammatory gene expression, and macrophage infiltration after pressure overload. Thus, mineralocorticoid receptors in cardiac myocytes but not in fibroblasts protect from cardiac dilatation and failure after chronic pressure overload.

• Cardiovascular effects of chronic treatment with a β2-adrenoceptor agonist relieving neuropathic pain in mice.

  Authors: Nada Choucair-Jaafar, Nadine Beetz, Ralf Gilsbach, Ipek Yalcin, Elisabeth Waltisperger, Marie-José Freund-Mercier, Laurent Monassier, Lutz Hein, Michel Barrot

  Neuropharmacology. 02/2011; 61(1-2):51-60.

  Neuropathic pain is often a chronic condition, disabling and difficult to treat. Using a murine model of neuropathic pain induced by placing a polyethylene cuff around the main branch of the sciaticNeuropathic pain is often a chronic condition, disabling and difficult to treat. Using a murine model of neuropathic pain induced by placing a polyethylene cuff around the main branch of the sciatic nerve, we have shown that chronic treatment with β-AR agonists is effective against neuropathic allodynia. β-mimetics are widely used against asthma and chronic obstructive pulmonary disease and may offer an interesting option for neuropathic pain management. The most prominent adverse effects of chronic treatment with β-mimetics are cardiovascular. In this study, we compared the action of low doses of the selective β(2)-AR agonist terbutaline and of a high dose of the mixed β(1)/β(2)-AR agonist isoproterenol on cardiovascular parameters in a neuropathic pain context. Isoproterenol was used as a positive control for some heart-related changes. Cardiac functions were studied by echocardiography, hemodynamic measurements, histological analysis of fibrosis and cardiac hypertrophy, and by quantitative real time PCR analysis of atrial natriuretic peptide (Nppa), periostin (Postn), connective tissue growth factor (Ctgf) and β-myosin heavy chain (Myh7). Our data show that a chronic treatment with the β(2)-AR agonist terbutaline at low antiallodynic dose does not affect cardiovascular parameters, whereas the mixed β(1)/β(2)-AR agonist isoproterenol induces cardiac hypertrophy. These data suggest that low doses of β(2)-AR agonists may provide a suitable treatment with rare side effects in neuropathic pain management. This study conducted in an animal model requires clinical confirmation in humans.

• Pre- versus postsynaptic signaling by α(2)-adrenoceptors.

  Authors: Ralf Gilsbach, Julián Albarrán-Juárez, Lutz Hein

  Current topics in membranes. 01/2011; 67:139-60.

• Regulation of renal sympathetic neurotransmission by renal α(2A)-adrenoceptors is impaired in chronic renal failure.

  Authors: Henning Hoch, Johannes Stegbauer, Sebastian A Potthoff, Lutz Hein, Ivo Quack, Lars Christian Rump, Oliver Vonend

  British journal of pharmacology. 01/2011; 163(2):438-46.

  The mechanisms underlying increased renal noradrenaline in renal failure are still unclear. In this study, the role of α(2A)-adrenoceptors in controlling sympathetic neurotransmission in chronicThe mechanisms underlying increased renal noradrenaline in renal failure are still unclear. In this study, the role of α(2A)-adrenoceptors in controlling sympathetic neurotransmission in chronic renal failure was evaluated in a subtotal nephrectomy model. Also, the influence of this receptor subtype on angiotensin II (Ang II)-mediated noradrenaline release was evaluated. α(2A)-adrenoceptor-knockout (KO) and wild-type (WT) mice underwent subtotal (5/6) nephrectomy (SNx) or SHAM-operation (SHAM). Kidneys of WT and KO mice were isolated and perfused. Renal nerves were stimulated with platinum electrodes and noradrenaline release was measured by HPLC. Noradrenaline release induced by renal nerve stimulation (RNS) was significantly increased in WT mice after SNx. RNS-induced noradrenaline release was significantly higher in SHAM-KO compared with SHAM-WT, but no further increase in noradrenaline release could be observed in SNx-KO. α-adrenoceptor antagonists increased RNS-induced noradrenaline release in SHAM-WT but not in SHAM-KO. After SNx, the effect of α₂-adrenoceptor blockade on renal noradrenaline release was attenuated in WT mice. The mRNA expression of α(2A)-adrenoceptors was not altered, but the inhibitory effect of α₂-adrenoceptor agonists on cAMP formation was abolished after SNx. Ang II facilitated RNS-induced noradrenaline release in SHAM-WT but not in SHAM-KO and SNx-WT. In our model of renal failure autoregulation of renal sympathetic neurotransmission was impaired. Presynaptic inhibition of noradrenaline release was diminished and the facilitatory effect of presynaptic angiotensin AT₁ receptors on noradrenaline release was markedly decreased in renal failure and depended on functioning α(2A)-adrenoceptors.

• Reelin signals through apolipoprotein E receptor 2 and Cdc42 to increase growth cone motility and filopodia formation.

  Authors: Jost Leemhuis, Elisabeth Bouché, Michael Frotscher, Frank Henle, Lutz Hein, Joachim Herz, Dieter K Meyer, Marina Pichler, Günter Roth, Carsten Schwan, Hans H Bock

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 11/2010; 30(44):14759-72.

  Lipoprotein receptor signaling regulates the positioning and differentiation of postmitotic neurons during development and modulates neuronal plasticity in the mature brain. Depending on theLipoprotein receptor signaling regulates the positioning and differentiation of postmitotic neurons during development and modulates neuronal plasticity in the mature brain. Depending on the contextual situation, the lipoprotein receptor ligand Reelin can have opposing effects on cortical neurons. We show that Reelin increases growth cone motility and filopodia formation, and identify the underlying signaling cascade. Reelin activates the Rho GTPase Cdc42, known for its role in neuronal morphogenesis and directed migration, in an apolipoprotein E receptor 2-, Disabled-1-, and phosphatidylinositol 3-kinase-dependent manner. We demonstrate that neuronal vesicle trafficking, a Cdc42-controlled process, is increased after Reelin treatment and further provide evidence that the peptidergic VIP/PACAP38 system and Reelin can functionally interact to promote axonal branching. In conclusion, Reelin-induced activation of Cdc42 contributes to the regulation of the cytoskeleton of individual responsive neurons and converges with other signaling cascades to orchestrate Rho GTPase activity and promote neuronal development. Our data link the observation that defects in Rho GTPases and Reelin signaling are responsible for developmental defects leading to neurological and psychiatric disorders.

• {Alpha}2B-adrenoceptor deficiency leads to postnatal respiratory failure in mice.

  Authors: Miriam Haubold, Ralf Gilsbach, Lutz Hein

  The Journal of biological chemistry. 10/2010; 285(44):34213-9.

  α(2)-Adrenoceptors belong to the family of adrenergic receptors, which regulate the neuronal release of norepinephrine as part of a negative feedback loop. Among the α(2)-adrenoceptors, theα(2)-Adrenoceptors belong to the family of adrenergic receptors, which regulate the neuronal release of norepinephrine as part of a negative feedback loop. Among the α(2)-adrenoceptors, the α(2B)-subtype may also influence developmental signaling pathways involved in angiogenesis of the placenta. Thus, the aim of the present study was to determine whether α(2B)-adrenoceptors are also involved in other developmental processes beyond placental angiogenesis. Ablation of α(2B)-adrenoceptors led to lethality of mutant mice during the first hours after birth. Despite normal breathing and drinking behavior, mutant mice developed cyanosis, which could be traced back to a defect in lung morphology with significantly reduced alveolar volume and thickened interalveolar septi. In α(2B)-deficient lungs and in isolated alveolar type II cells, expression of sonic hedgehog (SHH) was significantly increased, resulting in mesenchymal proliferation. In vitro α(2B)-adrenoreceptor stimulation suppressed expression of sonic hedgehog and the cell cycle genes cyclin D1 and Ki67. In vivo inhibition of enhanced SHH signaling by the smoothened antagonist cyclopamine partially rescued perinatal lethality, lung morphology, and altered gene expression in mutant mice. Thus, α(2B)-adrenoceptors in lung epithelia play an important role in suppressing sonic hedgehog-mediated proliferation of mesenchymal cells and thus prevent respiratory failure.

• The physiological roles of phosducin: from retinal function to stress-dependent hypertension.

  Authors: Nadine Beetz, Lutz Hein

  Cellular and molecular life sciences : CMLS. 10/2010; 68(4):599-612.

  In the time since its discovery, phosducin's functions have been intensively studied both in vivo and in vitro. Phosducin's most important biochemical feature in in vitro studies is its binding toIn the time since its discovery, phosducin's functions have been intensively studied both in vivo and in vitro. Phosducin's most important biochemical feature in in vitro studies is its binding to heterotrimeric G protein βγ-subunits. Data on phosducin's in vivo relevance, however, have only recently been published but expand the range of biological actions, as shown both in animal models as well as in human studies. This review gives an overview of different aspects of phosducin biology ranging from structure, phylogeny of phosducin family members, posttranscriptional modification, biochemical features, localization and levels of expression to its physiological functions. Special emphasis will be placed on phosducin's function in the regulation of blood pressure. In the second part of this article, findings concerning cardiovascular regulation and their clinical relevance will be discussed on the basis of recently published data from gene-targeted mouse models and human genetic studies.

• Sympathetic alpha(2)-adrenoceptors prevent cardiac hypertrophy and fibrosis in mice at baseline but not after chronic pressure overload.

  Authors: Ralf Gilsbach, Johanna Schneider, Achim Lother, Stefanie Schickinger, Jost Leemhuis, Lutz Hein

  Cardiovascular research. 06/2010; 86(3):432-42.

  alpha(2)-Adrenoceptors modulate cardiovascular function by vasoconstriction or dilatation, by central inhibition of sympathetic activity, or by feedback inhibition of norepinephrine release fromalpha(2)-Adrenoceptors modulate cardiovascular function by vasoconstriction or dilatation, by central inhibition of sympathetic activity, or by feedback inhibition of norepinephrine release from sympathetic neurons. Despite detailed knowledge about subtype-specific functions of alpha(2)-receptors, the relative contributions of sympathetic vs. non-sympathetic receptors involved in these cardiovascular effects have not been identified. The aim of this study was to define the physiological and pharmacological role of alpha(2A)-adrenoceptors in adrenergic vs. non-adrenergic cells at baseline and during sympathetic stress. Transgenic mice expressing alpha(2A)-adrenoceptors under control of the dopamine beta-hydroxylase (Dbh) promoter were generated and crossed with mice carrying a constitutive deletion in the alpha(2A)- and alpha(2C)-adrenoceptor genes. alpha(2AC)-deficient mice showed increased norepinephrine plasma levels, cardiac hypertrophy, and fibrosis at baseline. Expression of the Dbh-alpha(2A) transgene in sympathetic neurons prevented these effects. In contrast, Dbh-alpha(2A) receptors mediated only a minor part of the bradycardic and hypotensive effects of the alpha(2)-agonist medetomidine. After chronic pressure overload as induced by transverse aortic constriction in mice, the Dbh-alpha(2A) transgene did not reduce norepinephrine spillover, cardiac dysfunction, hypertrophy, or fibrosis. In isolated wild-type atria, alpha(2)-agonist-induced inhibition of [3H]norepinephrine release was significantly desensitized after pressure overload. In primary sympathetic neurons from Dbh-alpha(2A) transgenic mice, norepinephrine and medetomidine induced endocytosis of alpha(2A)-adrenoceptors into neurite processes. alpha(2A)-Adrenoceptors expressed in adrenergic cells are essential feedback inhibitors of sympathetic norepinephrine release to prevent cardiac hypertrophy and fibrosis at baseline. However, these receptors are desensitized by chronic pressure overload which in turn may contribute to the pathogenesis of this condition.

• Induction of heart failure by minimally invasive aortic constriction in mice: reduced peroxisome proliferator-activated receptor γ coactivator levels and mitochondrial dysfunction.

  Authors: Gloria Faerber, Frederico Barreto-Perreia, Maria Schoepe, Ralf Gilsbach, Andrea Schrepper, Michael Schwarzer, Friedrich W Mohr, Lutz Hein, Torsten Doenst

  The Journal of thoracic and cardiovascular surgery. 05/2010; 141(2):492-500, 500.e1.

  Mitochondrial dysfunction has been suggested as a potential cause for heart failure. Pressure overload is a common cause for heart failure. However, implementing pressure overload in mice isMitochondrial dysfunction has been suggested as a potential cause for heart failure. Pressure overload is a common cause for heart failure. However, implementing pressure overload in mice is considered a model for compensated hypertrophy but not for heart failure. We assessed the suitability of minimally invasive transverse aortic constriction to induce heart failure in C57BL/6 mice and assessed mitochondrial biogenesis and function. Minimally invasive transverse aortic constriction was performed through a ministernotomy without intubation (minimally invasive transverse aortic constriction, n = 68; sham operation, n = 43). Hypertrophy was assessed based on heart weight/body weight ratios and histologic analyses, and contractile function was assessed based on intracardiac Millar pressure measurements. Expression of selected metabolic genes was assessed with reverse transcription-polymerase chain reaction and Western blotting. Maximal respiratory capacity (state 3) of isolated mitochondria was measured with a Clark-type electrode. Survival was 62%. Within 7 weeks, minimally invasive transverse aortic constriction induced significant hypertrophy (heart weight/body weight ratio: 10.08±0.28 mg/g for minimally invasive transverse aortic constriction vs 4.66±0.07 mg/g for sham operation; n=68; P<.01). Fifty-seven percent of mice undergoing minimally invasive transverse aortic constriction displayed signs of heart failure (pleural effusions, dyspnea, weight loss, and dp/dtmax of 3114±422 mm Hg/s, P<.05). All of them had heart weight/body weight ratios of greater than 10. Mice undergoing minimally invasive transverse aortic constriction with heart weight/body weight ratios of less than 10 had normal contractile function (dp/dtmax of 6471±292 mm Hg/s vs dp/dtmax of 6933±205 mmHg/s in sham mice) and no clinical signs of heart failure. The mitochondrial coactivator peroxisome proliferator-activated receptor γ coactivator alpha (PGC-1α) was downregulated in failing hearts only. PGC-1α and fatty acid oxidation gene expression were also decreased in failing hearts. State 3 respiration of isolated mitochondria was significantly reduced in all hearts subjected to pressure overload. Contractile dysfunction and heart failure can be induced in wild-type mice by means of minimally invasive aortic constriction. Pressure overload-induced heart failure in mice is associated with mitochondrial dysfunction, as characterized by downregulation of PGC-1α and reduced oxidative capacity.

• Alpha2-adrenoceptor blockade accelerates the neurogenic, neurotrophic, and behavioral effects of chronic antidepressant treatment.

  Authors: Sudhirkumar U Yanpallewar, Kimberly Fernandes, Swananda V Marathe, Krishna C Vadodaria, Dhanisha Jhaveri, Karen Rommelfanger, Uma Ladiwala, Shanker Jha, Verena Muthig, Lutz Hein, Perry Bartlett, David Weinshenker, Vidita A Vaidya

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 01/2010; 30(3):1096-109.

  Slow-onset adaptive changes that arise from sustained antidepressant treatment, such as enhanced adult hippocampal neurogenesis and increased trophic factor expression, play a key role in theSlow-onset adaptive changes that arise from sustained antidepressant treatment, such as enhanced adult hippocampal neurogenesis and increased trophic factor expression, play a key role in the behavioral effects of antidepressants. alpha(2)-Adrenoceptors contribute to the modulation of mood and are potential targets for the development of faster acting antidepressants. We investigated the influence of alpha(2)-adrenoceptors on adult hippocampal neurogenesis. Our results indicate that alpha(2)-adrenoceptor agonists, clonidine and guanabenz, decrease adult hippocampal neurogenesis through a selective effect on the proliferation, but not the survival or differentiation, of progenitors. These effects persist in dopamine beta-hydroxylase knock-out (Dbh(-/-)) mice lacking norepinephrine, supporting a role for alpha(2)-heteroceptors on progenitor cells, rather than alpha(2)-autoreceptors on noradrenergic neurons that inhibit norepinephrine release. Adult hippocampal progenitors in vitro express all the alpha(2)-adrenoceptor subtypes, and decreased neurosphere frequency and BrdU incorporation indicate direct effects of alpha(2)-adrenoceptor stimulation on progenitors. Furthermore, coadministration of the alpha(2)-adrenoceptor antagonist yohimbine with the antidepressant imipramine significantly accelerates effects on hippocampal progenitor proliferation, the morphological maturation of newborn neurons, and the increase in expression of brain derived neurotrophic factor and vascular endothelial growth factor implicated in the neurogenic and behavioral effects of antidepressants. Finally, short-duration (7 d) yohimbine and imipramine treatment results in robust behavioral responses in the novelty suppressed feeding test, which normally requires 3 weeks of treatment with classical antidepressants. Our results demonstrate that alpha(2)-adrenoceptors, expressed by progenitor cells, decrease adult hippocampal neurogenesis, while their blockade speeds up antidepressant action, highlighting their importance as targets for faster acting antidepressants.

• Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice.

  Authors: Nadine Beetz, Michael D Harrison, Marc Brede, Xiangang Zong, Michal J Urbanski, Anika Sietmann, Jennifer Kaufling, Michel Barrot, Mathias W Seeliger, Maria Augusta Vieira-Coelho [......] Mary Kaldunski, Rolf Nüsing, Bela Szabo, Howard J Jacob, Allen W Cowley, Martin Biel, Monika Stoll, Martin J Lohse, Ulrich Broeckel, Lutz Hein

  The Journal of clinical investigation. 12/2009; 119(12):3597-3612.

  Hypertension and its complications represent leading causes of morbidity and mortality. Although the cause of hypertension is unknown in most patients, genetic factors are recognized as contributingHypertension and its complications represent leading causes of morbidity and mortality. Although the cause of hypertension is unknown in most patients, genetic factors are recognized as contributing significantly to an individual's lifetime risk of developing the condition. Here, we investigated the role of the G protein regulator phosducin (Pdc) in hypertension. Mice with a targeted deletion of the gene encoding Pdc (Pdc-/- mice) had increased blood pressure despite normal cardiac function and vascular reactivity, and displayed elevated catecholamine turnover in the peripheral sympathetic system. Isolated postganglionic sympathetic neurons from Pdc-/- mice showed prolonged action potential firing after stimulation with acetylcholine and increased firing frequencies during membrane depolarization. Furthermore, Pdc-/- mice displayed exaggerated increases in blood pressure in response to post-operative stress. Candidate gene-based association studies in 2 different human populations revealed several SNPs in the PDC gene to be associated with stress-dependent blood pressure phenotypes. Individuals homozygous for the G allele of an intronic PDC SNP (rs12402521) had 12-15 mmHg higher blood pressure than those carrying the A allele. These findings demonstrate that PDC is an important modulator of sympathetic activity and blood pressure and may thus represent a promising target for treatment of stress-dependent hypertension.