Search PubMed⌕ Search

Biomedical subjects

Kirsten Leineweber

Publications and source records attributed to Kirsten Leineweber.

At least 19 recordsLinked to original sources
PubMed2007

Release of TNF-alpha during stent implantation into saphenous vein aortocoronary bypass grafts and its relation to plaque extrusion and restenosis.

The reduction in plaque volume during stent implantation is associated with the release of particulate debris and plaque-derived soluble substances. We studied the potential release of the proinflammatory cytokine TNF-alpha into the coronary circulation and whether such release is related to the reduction in plaque volume and, possibly, a predictor for restenosis. In 18 male patients (n = 24 stents) with severe stenosis in a saphenous vein aortocoronary bypass graft (SVG), we used a distal balloon occlusion-aspiration device during stent implantation. The aspirate TNF-alpha levels were determined before and after stent implantation and related to the angiographic and intravascular ultrasound-assessed severity of stenosis and restenosis. We found that TNF-alpha is, indeed, released into the aspirate of stented SVG (9 +/- 1 and 28 +/- 3 pg/ml before and after stent implantation, respectively, P < 0.0001) and that such release is related to the reduction in plaque volume (r = 0.88, P < 0.0001) and associated with restenosis after 5 mo (r = 0.71, P = 0.001). The periprocedural release of plaque-derived TNF-alpha possibly represents the amount and activity of the atherosclerotic process and might be a predictor for restenosis.

Atherosclerosis↗
PubMed2006

CaMKII-mediated increased lusitropic responses to beta-adrenoreceptor stimulation in ANP-receptor deficient mice.

OBJECTIVE: Mice with genetic disruption of the guanylyl cyclase-A (GC-A) receptor for atrial natriuretic peptide (ANP), have chronic arterial hypertension and marked cardiac hypertrophy. Intriguingly, despite pronounced remodeling, cardiac contractile functions and cardiomyocyte Ca(2+)-handling are preserved and even enhanced. The present study aimed to characterize the specific molecular mechanisms preventing cardiac failure. METHODS AND RESULTS: Contractile function and expression as well as phosphorylation of regulatory proteins were evaluated in isolated perfused working hearts from wild-type and GC-A KO mice under baseline conditions and during beta(1)-adrenergic stimulation. Ca(i)(2+)-transients were monitored in Indo-1 loaded isolated adult cardiomyocytes. Cardiac contractile, especially lusitropic responsiveness to beta-adrenergic stimulation was significantly increased in GC-A KO mice. This was concomitant to enhanced expression and activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), increased dual-site phosphorylation of phospholamban (PLB) at Ser(16) and Thr(17), enhanced amplitude of Ca(i)(2+) transients, and accelerated Ca(i)(2+) decay. In contrast, the expression of cardiac ryanodine receptors and phosphorylation at Ser(2809) and Ser(2815) was not altered. Pharmacological inhibition of CaMKII-but not of protein kinase A-mediated PLB phosphorylation totally abolished the increased effects of beta-adrenergic stimulation on cardiac contractility and Ca(i)(2+)-handling. Thus, acceleration of sarcoplasmic reticulum Ca(2+)-uptake and increased availability of Ca(2+) for contraction, both secondary to increased CaMKII-mediated PLB phosphorylation, seem to mediate the augmented responsiveness of GC-A KO hearts to catecholamines. CONCLUSION: Our observations show that increased CaMKII activity enhances the contractile relaxation response of hypertrophic GC-A KO hearts to beta-adrenergic stimulation and emphasize the critical role of CaMKII-dependent pathways in beta(1)-adrenoreceptor modulation of myocardial Ca(2+)-homeostasis and contractility.

Adrenergic beta-Agonists↗
PubMed2006

Is there a role of the Thr164Ile-beta(2)-adrenoceptor polymorphism for the outcome of chronic heart failure?

OBJECTIVE: The Thr164Ile-beta(2)-adrenoceptor (AR) polymorphism exhibits lower affinities for catecholamines and reduced basal and agonist-stimulated adenylyl cyclase activity in vitro. It has been suggested that patients with chronic heart failure (CHF) due to ischemic or dilated cardiomyopathy carrying the Thr164Ile-beta(2)AR polymorphism exhibit much more rapid progression to death or heart transplantation (HTX) than CHF-patients carrying the homozygous Thr164-beta(2)AR. This study aimed to further evaluate the role of the Thr164Ile-beta(2)AR in CHF. For this we hypothesized that the Thr164Ile-beta(2)AR variant should be more abundant in HTX-patients than in patients with stable CHF or healthy controls. METHODS AND RESULTS: We genotyped 309 HTX-patients, 520 stable CHF-patients and 328 healthy controls for the three beta(2)AR variants Arg16Gly, Gln27Glu and Thr164Ile. The prevalence of the Thr164Ile-beta(2)AR variant was not considerably different in HTX-patients (2.3%) from that in CHF-patients (1.9%) or healthy controls (2.1%). Similarly, the frequency of the minor Ile164-allele was f(-)=0.0106 in HTX-patients, f(-)=0.0096 in CHF-patients and f(-)=0.0113 in healthy controls. CONCLUSIONS: The prevalence of the hypofunctional Thr164Ile-beta(2)AR variant and the frequency of the Ile164-allele were almost identical in CHF-patients, who had undergone HTX, with those in patients with stable CHF or in healthy controls. Thus, the role of the Thr164Ile-beta(2)AR in CHF remains questionable.

Adolescent↗
PubMed2006

Cardiac adrenoceptors: physiological and pathophysiological relevance.

At present, nine adrenoceptor (AR) subtypes have been identified: alpha(1A)-, alpha(1B)-, alpha(1D)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, beta(2)-, and beta(3)AR. In the human heart, beta(1)- and beta(2)AR are the most powerful physiologic mechanism to acutely increase cardiac performance. Changes in betaAR play an important role in chronic heart failure (CHF). Thus, due to increased sympathetic activity in CHF, betaAR are chronically (over)stimulated, and that results in beta(1)AR desensitization and alterations of down-stream mechanisms. However, several questions remain open: What is the role of beta(2)AR in CHF? What is the role of increases in cardiac G(i)-protein in CHF? Do increases in G-protein-coupled receptor kinase (GRK)s play a role in CHF? Does betaAR-blocker treatment cause its beneficial effects in CHF, at least partly, by reducing GRK-activity? In this review these aspects of cardiac AR pharmacology in CHF are discussed. In addition, new insights into the functional importance of beta(1)- and beta(2)AR gene polymorphisms are discussed. At present it seems that for cardiovascular diseases, betaAR polymorphisms do not play a role as disease-causing genes; however, they might be risk factors, might modify disease, and/or might influence progression of disease. Furthermore, betaAR polymorphisms might influence drug responses. Thus, evidence has accumulated that a beta(1)AR polymorphism (the Arg389Gly beta(1)AR) may affect the response to betaAR-blocker treatment.

Adrenergic beta-1 Receptor Agonists↗
PubMed2006

Intense vasoconstriction in response to aspirate from stented saphenous vein aortocoronary bypass grafts.

OBJECTIVES: We sought to identify soluble vasoconstrictor substances that are released during stent implantation into saphenous vein aortocoronary bypass grafts. BACKGROUND: Atherosclerotic saphenous vein aortocoronary bypass grafts are particularly vulnerable to plaque rupture. Protection devices prevent particulate debris from being embolized. Additional soluble vasoconstrictor substances possibly also contribute to impaired microvascular perfusion. METHODS: Peripheral venous blood (VB) and aspirate (AS) were obtained from 14 patients with a significant stenosis in a saphenous vein graft during stent implantation under protection with a distal balloon occlusion device. In five additional patients, arterial blood (AB) was also taken distal to the stented lesion before intervention. Vasomotor substances in VB, AB, and AS plasma were identified in a bioassay of rat mesenteric arteries with intact (+E) and denuded endothelium (-E). Vasoconstriction was normalized to that induced by potassium chloride depolarization (100%). RESULTS: Venous blood, AB, and AS plasma induced maximum vasoconstriction within six minutes. The AS plasma induced a vasoconstriction of 138 +/- 13% (-E) and 87 +/- 14% (+E); VB, of 70 +/- 14% (-E) and 23 +/- 4% (+E); and AB plasma obtained before intervention, of 49 +/- 9% (-E) and 36 +/- 8% (+E). The vasoconstrictor potency of AS plasma in endothelium-denuded vessels was related to the severity of anginal symptoms, angiographic stenosis severity, plaque volume, and plaque burden as determined by intravascular ultrasound. The AS plasma-induced vasoconstriction was largely attenuated by combined serotonin/5-hydroxytryptamine (5-HT)(2A/2C)- and 5-HT(1A/1B)-receptor blockade and eliminated by additional thromboxane A2 thromboxane-prostanoid (TP)-receptor blockade. CONCLUSIONS: Stent implantation releases, apart from and in addition to particulate debris, soluble vasoconstrictor substances that possibly contribute to impaired microvascular perfusion.

Animals↗
PubMed2006

Coronary atherosclerosis and cardiovascular risk in masters male marathon runners. Rationale and design of the "marathon study".

BACKGROUND: Regular physical exercise is recommended to reduce cardiovascular mortality. And yet, atherosclerosis is the main cause of exercise-associated death in persons beyond age 35. The need for risk stratification in marathon runners is under discussion. The predictive value of modern imaging- and non-imaging-based markers of risk that can be used for risk stratification in masters endurance athletes still deserves exploration. METHODS: Male runners > 50 years who have completed at least five marathon races during the preceding 3 years and do not suffer from coronary artery disease, angina nor diabetes mellitus are studied to assess the predictive value of established and modern imaging- based and biochemical cardiovascular risk factors. Laboratory parameters including clinical chemistry, hematology and hormone measurements are determined. Lifestyle-related risk factors, psychosocial and socioeconomic variables are explored using standardized questionnaires. Coronary, carotid, femoral and aortic atherosclerosis is measured using electronbeam computed tomography and ultrasound. In addition, a resting ECG, a bicycle stress test and heart rate variability are performed. Myocardial morphology and function are assessed using echocardiography and magnetic resonance imaging. Participants are invited to compete in a marathon race to quantify the association of coronary atherosclerosis with marathon-related changes of cardiac troponin levels and the extent of marathon-induced inflammation. At the cellular level, the effect on the amount of circulating progenitor cells (EPCs) is determined by FACS analysis. Changes in laboratory parameters and hormone levels are also studied. Annual long-term follow-up including hospital records and death certificates is performed. Data are compared with those from a general unselected cohort from the Heinz Nixdorf Recall Study. CONCLUSION: This study should contribute to cardiovascular risk assessment in the growing number of masters marathon runners with a focus on assessing the predictive value of modern imaging techniques and biochemical markers for comprehensive risk stratification.

Adult↗
PubMed2006

Inhibition of Na+/H+-exchanger with sabiporide attenuates the downregulation and uncoupling of the myocardial beta-adrenoceptor system in failing rabbit hearts.

Chronic heart failure (HF) is characterized by left ventricular (LV) structural remodeling, impaired function, increased circulating noradrenaline (NA) levels and impaired responsiveness of the myocardial beta-adrenoceptor (betaAR)-adenylyl cyclase (AC) system. In failing hearts, inhibition of the sodium/proton-exchanger (NHE)-1 attenuates LV remodeling and improves LV function. The mechanism(s) involved in these cardioprotective effects remain(s) unclear, but might involve effects on the impaired betaAR-AC system. Therefore, we investigated whether NHE-1 inhibition with sabiporide (SABI; 30 mg kg(-1) day(-1) p.o.) might affect myocardial betaAR density and AC activity in relation to changes in LV end-diastolic diameter (LVEDD) and LV systolic fractional shortening (LVS-FS) after 3 weeks of rapid LV pacing in rabbits. After 3 weeks of rapid LV pacing LVEDD was significantly increased (Shams 17+/-0.2 mm, n=9 vs 3 wksHF 20+/-0.5 mm, n=8; P<0.05) and LVS-FS decreased (Shams 31+/-1%, n=9 vs 3 wksHF 10+/-1%, n=8; P<0.05). SABI treatment significantly improved LV function independent of whether rabbits were treated after 1 week of pacing (3 wksHF+2 wksSABI (n=7): LVEDD 18+/-1 mm; LVS-FS 16+/-4%) or before pacing (3 wksHF+3wksSABI (n=9): LVEDD 18+/-1 mm; LVS-FS 18+/-6%). After 3 weeks of rapid LV pacing, SABI treatment significantly attenuated increases in serum NA content (Shams 0.83+/-0.19, 3 wksHF 2.68+/-0.38, 3 wksHF+2 wksSABI 1.22+/-0.32, 3 wksHF+3wksSABI 1.38+/-0.33 ng ml(-1)). Moreover, betaAR density (Shams 64+/-5, 3 wksHF 38+/-3, 3 wksHF+2 wksSABI 48+/-4, 3 wksHF+3 wksSABI 55+/-3 fmol mg(-1) protein) and responsiveness (isoprenaline-stimulated AC activity. (Shams 57.6+/-4.9, 3 wksHF 36.3+/-6.0, 3 wksHF+2 wksSABI 56.9+/-6.0, 3 wksHF+3 wksSABI 54.5+/-4.8 pmol cyclic AMP mg(-1) protein(-1) min(-1)) were significantly improved in SABI-treated rabbits. From the present data we cannot address whether the improved betaAR-AC system permitted improved LV function and/or whether the improved LV function resulted in less activation of the sympathetic nervous system and by this in a reduced stimulation of the betaAR-AC system. Accordingly, additional studies are needed to fully establish the cause-and-effect relationship between NHE-1 inhibition and the restoration of the myocardial betaAR system.

Adenylyl Cyclases↗
PubMed2006

The Arg389Gly beta1-adrenoceptor polymorphism does not affect cardiac effects of exercise after parasympathetic inhibition by atropine.

UNLABELLED: In vitro, Arg389Gly beta1-adrenoceptor (AR) polymorphism exhibits decreased beta-AR signalling. In vivo, beta1-AR-mediated cardiac effects of exercise showed no genotype-dependent differences in Arg389 vs. Gly389 beta1-AR subjects. We studied in 16 male subjects homozygous Arg389 or Gly389 beta1-AR, whether blockade of parasympathetic activity might unmask genotype-dependence of exercise effects. Subjects were infused with atropine (10 microg/kg i.v. loading dose followed by continuous i.v. infusion of 0.15 microg/kg/min throughout exercise-time); 20 min after start of atropine bicycle-exercise in supine position (25, 50, 75 and 100 W for 5 min each) was performed and heart rate, contractility, blood pressure, plasma noradrenaline and plasma-renin activity were assessed. Exercise-evoked increases in all but one parameters were not different between Arg389 and Gly389 beta1-AR subjects; only plasma noradrenaline increased slightly more in Gly389 vs. Arg389 beta1-AR subjects. IN CONCLUSION: It appears to be unlikely that lack of Arg389Gly beta1-AR genotype-dependence of exercise-effects can be explained by influences of parasympathetic activity.

Amino Acid Substitution↗
PubMed2005

The Arg389Gly beta1-adrenoceptor polymorphism and catecholamine effects on plasma-renin activity.

OBJECTIVES: The purpose of this research was to find out whether, in humans, dobutamine-induced hemodynamic effects and increase in plasma-renin activity (PRA) might be beta1-adrenoceptor (beta1AR) genotype-dependent. BACKGROUND: In vitro Arg389Gly-beta1AR polymorphism exhibits decreased receptor signaling. METHODS: We studied 10 male homozygous Arg389-beta1AR subjects and 8 male homozygous Gly389beta1AR subjects; to avoid influences of codon 49 polymorphism, all were homozygous Ser49-beta1AR. Subjects were infused with dobutamine (1 to 6 microg/kg/min) with or without bisoprolol (10 mg orally) pretreatment, and PRA, heart rate, contractility, and blood pressure were assessed. RESULTS: With regard to PRA, dobutamine increased PRA more potently in Arg389-beta1AR versus Gly389-beta1AR subjects. Bisoprolol markedly suppressed the dobutamine-induced PRA increase in Arg389- but only marginally in Gly389-beta1AR subjects. With regard to hemodynamics, dobutamine caused larger heart rate and contractility increases and diastolic blood pressure decreases in Arg389- versus Gly389-beta1AR subjects. Bisoprolol reduced dobutamine-induced heart rate and contractility increases and diastolic blood pressure decreases more potently in Arg389- versus Gly389-beta1AR subjects. CONCLUSIONS: Codon 389 beta1AR polymorphism is a determinant not only of hemodynamic effects but also of PRA. Thus, beta1AR polymorphisms may be useful for predicting therapeutic responses to betaAR-blocker treatment.

Adrenergic beta-Antagonists↗
PubMed2005

Interaction between simvastatin and metoprolol with respect to cardiac beta-adrenoceptor density, catecholamine levels and perioperative catecholamine requirements in cardiac surgery patients.

UNLABELLED: Beta-blockade is a standard cardiovascular therapy known to induce the up-regulation of beta-adrenoceptor density. Upon ligand-binding, beta-adrenoceptors are normally internalised via the arrestin pathway, and after dissociation they are re-inserted into the membrane. This means that at high catecholamine levels the adrenoceptor density is low and under beta-blockade it is high. The insertion of receptors into the membrane is often dependent on farnesylation processes that can be inhibited by statins. We carried out a prospective, controlled, observational study to determine whether beta-blockade-induced up-regulation of beta-adrenoceptor density is attenuated by statin therapy and whether this would subsequently affect catecholamine consumption during surgery. We obtained pre-operative blood samples and intra-operative biopsies of the right atrial appendage from 39 patients (age: 65+/-5 years; BMI: 28+/-1) undergoing coronary bypass surgery with or without simvastatin (20 mg/day) therapy and with or without concomitant metoprolol therapy (50 mg/day). The atrial tissue was used for radioligand-binding studies with (-)-[125I]-iodocyanopindolol (ICYP) and for assessment of the beta-adrenoceptor subtype distribution following standard protocols. In the blood samples, plasma adrenaline and noradrenaline concentrations were determined using HPLC. In all tissue samples, we found a total beta-adrenoceptor density of 38+/-4 fmol/mg protein in untreated controls; this which was up-regulated to 55+/-5 fmol/mg protein in patients receiving metoprolol. This increase in receptor number was nearly prevented completely by simvastatin therapy (42+/-5 fmol/mg protein). The up-regulation could be attributed to increases in the beta1-adrenoceptor subtype. In contrast, simvastatin alone had no effect on beta-adrenoceptor density. Pre-operative adrenaline levels were slightly reduced in all drug therapy groups (nonsignificant differences), while the levels noradrenaline were not significantly different among the groups. With respect to the perioperative catecholamine requirements, patients on metoprolol needed significantly less dopamine than control patients, while patients undergoing simvastatin/metoprolol therapy needed as much as the controls. The post-operative total catecholamine requirements were not different among the four groups of patients. There were no differences in plasma metoprolol concentration between patients receiving metoprolol alone and those receiving a combination of metoprolol and simvastatin. IN CONCLUSION: Simvastatin therapy seems to counter-regulate the up-regulation of beta-adrenoceptor density. In the up-regulated state induced by metoprolol therapy, the patients seemed to need less catecholamines during cardiac surgery, which may be due to the higher number of beta-adrenoceptors. Additional simvastatin therapy did not reduce post-operative catecholamine consumption.

Adrenergic beta-Antagonists↗
PubMed2005

G-protein-coupled receptor kinase activity in human heart failure: effects of beta-adrenoceptor blockade.

OBJECTIVES: In human end-stage heart failure as well as in experimental animal models of heart failure, G-protein-coupled receptor kinase activity (GRK) is increased while beta-adrenoceptor responsiveness is diminished. In animal studies, beta-adrenoceptor blockers reverse the GRK-mediated desensitization and down-regulation of myocardial beta-adrenoceptors. The aim of this study was to investigate whether alterations in GRK activity are an early or late accompaniment of human heart failure and whether also in humans beta-adrenoceptor blocker treatment is able to influence myocardial GRK activity. METHODS: We assessed in right atria, obtained from patients at different stages of heart failure, treated with or not treated with beta-adrenoceptor blockers, and in the four chambers of explanted hearts, obtained from patients with end-stage heart failure, beta-adrenoceptor density (by (-)-[(125)I]-iodocyanopindolol binding) and GRK activity (by an in vitro rhodopsin phosphorylation assay). RESULTS: With increasing severity of heart failure, plasma noradrenaline levels increased while myocardial beta-adrenoceptor density decreased with a maximum in GRK activity in end-stage heart failure. However, in relation to the progression of heart failure, we found that GRK activity transiently increased at an early stage of heart failure (NYHA I and II) but decreased back to control values in patients at NYHA III and IV. beta-Adrenoceptor blockers were able to reduce the early increase in GRK activity at NYHA I and II to control levels, whereas in those patients who did not have increased GRK activity (NYHA III and IV), they had only a marginal effect. CONCLUSION: According to our results, an increase in GRK activity is an early and transient event in the course of heart failure that can be prevented by beta-adrenoceptor blocker treatment.

Adrenergic beta-Antagonists↗
PubMed2005

Pressure overload and neurohumoral activation differentially affect the myocardial proteome.

Treatment with monocrotaline causes pulmonary hypertension in rats. This results in severe pressure overload-induced hypertrophy of the right ventricles, whilst the normally loaded left ventricles do not hypertrophy. Both ventricles are affected by enhanced neuroendocrine stimulation in this model. We analyzed in this model load-induced and catecholamine-induced changes of right and left ventricular proteome by two-dimensional gel electrophoresis, tryptic in-gel digest, and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. All analyzed animals showed right ventricular hypertrophy without signs of heart failure. Changes of 27 proteins in the right and 21 proteins in the left ventricular myocardium were found. Given the hemodynamic features of this animal model, proteome changes restricted to the right ventricle are caused by pressure overload. We describe for the first time a potentially novel pathway (BRAP2/BRCA1) that is involved in myocardial hypertrophy. Furthermore, we demonstrate that increased afterload-induced hypertrophy leads to striking changes in the energy metabolism with down-regulation of pyruvate dehydrogenase (subunit beta E1), isocitrate dehydrogenase, succinyl coenzyme A ligase, NADH dehydrogenase, ubiquinol-cytochrome C reductase, and propionyl coenzyme A carboxylase. These changes go in parallel with alterations of the thin filament proteome (troponin T, tropomyosin), probably associated with Ca(2+) sensitization of the myofilaments. In contrast, neurohumoral stimulation of the left ventricle increases the abundance of proteins relevant for energy metabolism. This study represents the first in-depth analysis of global proteome alterations in a controlled animal model of pressure overload-induced myocardial hypertrophy.

Amino Acid Sequence↗
PubMed2005

Human beta2-adrenergic receptor gene haplotypes and venodilation in vivo.

BACKGROUND AND OBJECTIVE: beta2-Adrenergic receptors (beta2-ARs) are polymorphic. In vitro studies have shown that agonist-promoted down-regulation is enhanced for Arg16Gly and blunted for Gln27Glu beta2-AR variants; Thr164Ile beta2-ARs exhibit reduced responsiveness to agonist stimulation. Our objective was to determine whether beta2-AR polymorphisms affect beta2-AR-mediated venodilation in healthy subjects in vivo. METHODS: We studied dilation of phenylephrine-preconstricted dorsal hand veins induced by terbutaline (50-1000 ng/min) using the Aellig hand vein technique in subjects homozygous for the 3 most common beta2-AR haplotypes (group A, Arg16Gln27Thr164 [wild type (WT)] [n = 10]; group B, Gly16Gln27Thr164 [n = 8]; and group C, Gly16Glu27Thr164 [n = 9]) and in 8 subjects heterozygous for Thr164Ile beta2-AR (group D) at baseline and after 2 weeks of treatment with oral terbutaline, 5 mg 3 times daily. RESULTS: Terbutaline dose-dependently dilated hand veins; sensitivity to terbutaline was 2-fold higher in haplotype group A versus group B or C; maximal dilation, however, was not haplotype-dependent. In Thr164Ile subjects terbutaline sensitivity but not maximal dilation was 4-fold lower than in WT subjects. Long-term terbutaline treatment desensitized venous beta2-AR in a haplotype-dependent manner: The extent of desensitization (reduction in maximal venodilation) was largest for haplotype A, modest for haplotype B, and almost absent for haplotype C. Long-term terbutaline treatment also desensitized venous Thr164Ile beta2-AR; after terbutaline treatment, dose-response curves for terbutaline-induced venodilation were superimposable in WT and Thr164Ile beta2-AR subjects. CONCLUSION: beta2-AR-mediated dilation of human hand veins is influenced by the 3 most common beta2-AR haplotypes and blunted in subjects heterozygous for Thr164Ile beta2-AR. Long-term terbutaline treatment desensitizes venous beta2-AR in a haplotype-dependent manner, with haplotype A (Arg16Gln27Thr164) showing greater desensitization than haplotype B (Gly16Gln27Thr164), which shows greater desensitization than haplotype C (Gly16Glu27Thr164).

Adrenergic beta-2 Receptor Agonists↗
PubMed2005

Beta2-adrenoceptor gene polymorphisms.

Beta2-adrenoceptors (AR) play an important role in regulation of vascular and bronchial smooth muscle tone; functional beta2-AR, however, also exist in human heart where they can mediate positive inotropic and chronotropic effects. Recent studies have discovered that beta2-AR are polymorphic. The most common single nucleotide polymorphisms (SNPs) are: Arg16Gly, Gln27Glu, Thr164Ile in the coding region, and Arg-19Cys in the 5' upstream peptide. These SNPs affect receptor function in vitro; however, conflicting data exist on their functional relevance in vivo. This might be due to the fact that the four SNPs in the 5' upstream peptide and in the coding region, respectively, are linked and form certain haplotypes. This review gives an overview on the contribution of beta2-AR polymorphisms to cardiovascular diseases or altered drug responses. In addition, the relevance of SNPs vs. haplotypes for beta2-AR functional responsiveness is discussed.

Adrenergic beta-Agonists↗
PubMed2004

Autonomic receptor systems in the failing and aging human heart: similarities and differences.

Changes in autonomic receptor systems (alpha- and beta-adrenoceptors and muscarinic receptors) were compared in the aging and failing human heart. In both settings responsiveness of beta-adrenoceptors and all other receptor systems that evoke their effects via cyclic AMP accumulation was diminished. Muscarinic receptor function, on the other hand, was decreased in the aging, but unchanged in the failing heart; in contrast, G protein-coupled receptor kinase activity was increased in the failing, but unchanged in the aging heart. alpha-Adrenoceptor function was unchanged or slightly decreased in the failing heart. However, nothing is known on alpha-adrenoceptor changes in the aging heart. These results indicate that in the failing human heart all autonomic receptor systems appear to be altered in the direction to attenuate beta-adrenoceptor responses to sympathetic (over)stimulation while in the aging human heart autonomic receptor systems appear to be altered in a direction that protects the heart against too pronounced reduction in beta-adrenoceptor responsiveness.

Aging↗
PubMed2004

Beta2-adrenoceptor polymorphisms: relation between in vitro and in vivo phenotypes.

Beta2-adrenoceptors are expressed in many cell types throughout the body and play a pivotal role in the regulation of the cardiac, pulmonary, vascular, endocrine and central nervous system. Recent studies have discovered that Beta2-adrenoceptor are polymorphic. Three common polymorphisms appear to influence receptor function: Arg16Gly, Gln27Glu, and Thr164Ile. In vitro studies of agonist-stimulation have shown that the Gly16 Beta2-adrenoceptors demonstrate enhanced agonist-promoted down-regulation, while Glu27 variants seem to be resistant. The Ile164 variant, on the other hand, demonstrates decreased responsiveness to agonist stimulation in vitro. However, the functional relevance and phenotypic consequence of such Beta2-adrenoceptor variants in vivo is still unclear. The aim of this review is therefore to provide an overview about the somewhat controversy in vitro, ex vivo and in vivo studies.

Cells, Cultured↗
PubMed2004

Beta-adrenergic receptor polymorphism in human cardiovascular disease.

Beta-adrenoceptors are polymorphic. Two common polymorphisms in the beta1-adrenoceptor (Ser49Gly and Arg389Gly) and three in the beta2-adrenoceptor (Arg16Gly, Gln27Glu, and Thr164Ile) appear to influence receptor function. In vitro studies of agonist-stimulation have shown that the Gly49 beta1-adrenoceptor and the Gly16 beta2-adrenoceptors are more susceptible to down-regulation, while the Glu27 beta2-adrenoceptor variant seems to be resistant. Whereas the Arg389 beta1-adrenoceptor demonstrates increased responsiveness to agonist stimulation in vitro, the Ile164 beta2-adrenoceptor variant, on the other hand, exhibits a decreased responsiveness. Although several studies in humans (ex vivo and in vivo) do support those functional effects, the literature on the phenotypic consequences of these beta-adrenoceptor polymorphisms in vivo is still far from being conclusive. At present, it appears that these beta-adrenoceptor polymorphisms are very likely not disease-causing genes, but might be risk factors, might modify disease and/or might influence progression of disease.

Animals↗