Biomedical subjects

Otto-Erich Brodde

Publications and source records attributed to Otto-Erich Brodde.

At least 19 recordsLinked to original sources

PubMed2007

Beta-adrenoceptor blocker treatment and the cardiac beta-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure.

Recent studies showed that chronic beta-adrenoceptor (AR) blocker treatment exerts beneficial effects in patients with chronic heart failure (CHF). In CHF, sympathetic drive to the heart is increased, and this causes pathological changes in cardiac beta-AR-G-protein(s)-adenylyl cyclase system: Cardiac beta-1 AR are decreased, and amount and activity of cardiac G(i)-protein and G-protein-coupled receptor kinase (GRK) are increased resulting in diminished cardiac beta-AR functional responsiveness. One possible mechanism of beneficial effects of beta-AR blockers could be that they prevent adverse effects of increased sympathetic activity and up-regulate cardiac (and vascular) beta-AR density, and by this, enhance beta-AR-mediated effects. Another possibility could be that chronic beta-AR blocker treatment normalizes activity of G(i)-protein and may thereby restore beta-AR functional responsiveness. Moreover, failing human heart exhibits an inverse force-frequency relationship. beta-AR blockers reduce heart rate; this may, therefore, improve force of contraction. One of the strongest stimuli to activate GRK is increased sympathetic activity (as in CHF) via beta-AR stimulation. beta-AR blockers, by blocking beta-AR, can prevent GRK activation and/or can reduce the (previously enhanced) GRK activity, and this might-at least partly-contribute to beneficial effects of beta-AR blockers in CHF treatment. Finally, the "loss-of-function" Arg389Gly beta-1 AR polymorphism seems to determine heart rate and blood pressure responses to beta-1 AR blocker administration: Arg389Arg beta-1 AR subjects exhibit stronger effects than subjects with one or two Gly389 alleles. Thus, it might be predicted that patients homozygous Arg389 beta-1 AR should be good responders, whereas patients homozygous Gly389 beta-1 AR polymorphism should be poor or non-responders.

Adenylyl Cyclases↗

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

Selective upregulation of beta1-adrenergic receptors and dephosphorylation of troponin I in end-stage heart failure patients supported by ventricular assist devices.

In terminal failing hearts, adrenergic receptors are downregulated and intracellular adrenergic signal transduction is inhibited. Mechanical circulatory support by ventricular assist devices (VAD) is used to bridge patients to heart transplantation. Mechanical unloading by VAD may induce reverse remodeling in heart transplantation (HTx) candidates. However, little is known on beta-adrenergic receptor subtype regulation and adrenergic signal transduction under VAD-support. We investigated paired myocardial samples from 16 VAD-supported patients and 9 non-failing donor hearts. We analyzed beta-adrenergic receptor subtype regulation by real-time PCR and radioligand binding and cardiac troponin I phosphorylation (by phospho-cTnI-specific antibodies). We found that the beta1-adrenergic receptor (beta1AR) is downregulated at VAD-implantation on mRNA and protein levels whereas the beta2-adrenergic receptor (beta2AR) was not. After VAD-support, beta1AR protein but not its mRNA was upregulated, whereas the degree of cTnI-phosphorylation was reduced. Upregulation of beta1AR was enhanced by beta blocking medication during VAD-support. However, in 9 out of 15 patients, beta1AR-density remained below the 0.25 percentile of donor hearts. VAD-support is associated with partial normalization of the betaAR-signal transduction pathways. This beneficial effect is related to a posttranscriptional increase in beta1AR-density.

Adult↗

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

Agonist-specific activation of the beta2-adrenoceptor/Gs-protein and beta2-adrenoceptor/Gi-protein pathway in adult rat ventricular cardiomyocytes.

In rat ventricular cardiomyocytes beta2-adrenoceptors (AR) couple to Gs- and Gi-protein, and evidence has accumulated that beta2-AR agonists can differentially activate either Gs- or Gs- and Gi-protein. In this study, in isolated adult rat ventricular cardiomyocytes, we assessed the effects of pertussis toxin (PTX) on beta2-AR agonist (terbutaline (TER), salbutamol (SAL) and fenoterol (FEN)) evoked inhibition of phenylephrine (PE)-induced increase in the rate of protein synthesis (assessed as [3H]phenylalanine incorporation) to find out which beta2-AR agonist activates selectively Gs- or Gs- and Gi-protein. PE (1 microM) increased the rate of protein synthesis from 100% to 130+/-2% (n = 34). FEN, TER and SAL (1 nM-10 microM) inhibited PE-induced increase in the rate of protein synthesis concentration-dependently. FEN inhibited PE effects almost completely (from 132+/-3 to 101+/-1%), whereas TER and SAL caused only partial inhibition (from 131+/-2 to 114+/-2 and 129+/-1 to 111+/-2%, respectively). Pretreatment of cardiomyocytes with PTX (250 ng ml(-1) for 16 h at 37 degrees C) did not affect FEN effects, but converted TER- and SAL-evoked partial inhibition into complete inhibition. Inhibitory effects of the three beta2-AR agonists were markedly attenuated by beta1-AR selective antagonist CGP 20712A (CGP) (300 nM); in contrast, beta2-AR selective antagonist ICI 118,551 (55 nM) inhibited the inhibitory effects of the three beta2-AR agonists only in PTX-pretreated cardiomyocytes,with beta1-AR blocked by CGP. We conclude that, in adult rat ventricular cardiomyocytes, FEN activates selectively the Gs protein-pathway, while TER and SAL activate the Gs- and Gi-protein pathways. Part of the effects of these three beta2-AR agonists appears to be mediated by beta1-AR.

Adrenergic alpha-Agonists↗

PubMed2006

Decellularized xenogenic heart valves reveal remodeling and growth potential in vivo.

We have developed an advanced tissue processing technique on porcine pulmonary heart valves for pulmonary valve replacement and its initial clinical application during the autograft operation according to Ross. The novel concept consists of a cell-free matrix achieved by deoxycholic acid treatment that is repopulated by host cells in vivo. Molecular biology, radioligand binding, and electron microscopy consistently showed that these valves are almost free of cellular components. Animal experiments and clinical investigations revealed excellent hemodynamic properties of the valves, no need for antithrombotic therapy, and repopulation by host cells without any signs of calcification. In juvenile sheep the internal diameter of the implanted valves significantly increased in growing animals by approximately 10 mm. The repopulation of the decellularized heart valves was found not only in sheep but also in humans, which indicates that the underlying mechanisms, presumably repair mechanisms, might be common in mammals. If these findings can be confirmed by others, they will lead to new concepts in the field of cardiovascular tissue engineering that will eliminate the need for in vitro construction of autologous heart valves.

Animals↗

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

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

Beta 2-adrenoceptor-mediated intrinsic sympathomimetic activity of carteolol: an in vivo study.

The intrinsic sympathomimetic activity (ISA) of a beta-adrenoceptor blocker can be mediated by beta(1)- or beta(2)-adrenoceptors. The aim of this study was to characterize the ISA of the beta-adrenoceptor blocker carteolol in healthy volunteers. Two approaches were employed. First, we assessed the effects of carteolol (20, 40 or 80 mg p.o.) on blood pressure, heart rate and heart-rate corrected duration of electromechanical systole (QS(2)c, a measure of cardiac contractility) in the volunteers. Carteolol dose-dependently increased systolic blood pressure, heart rate and contractility and decreased diastolic blood pressure. The beta(1)-adrenoceptor blocker bisoprolol did not attenuate these carteolol effects, but rather enhanced the effects on heart rate and systolic blood pressure. Second, we treated volunteers for 7 days with 1 x 20 mg/day carteolol and assessed lymphocyte beta(2)-adrenoceptor density (by (-)-[(125)I]-iodocyanopindolol binding) and functional responsiveness (by 10 muM isoprenaline-induced increase in lymphocyte cyclic AMP content). Carteolol significantly reduced lymphocyte beta(2)-adrenoceptor density and function. After withdrawal of carteolol lymphocyte beta(2)-adrenoceptor density and function recovered only very slowly and had not returned to control levels 11 days after carteolol withdrawal. In conclusion, the fact that, on the one hand, the cardiovascular effects of carteolol were not attenuated by the beta(1)-adrenoceptor blocker bisoprolol and, on the other, carteolol significantly decreased lymphocyte beta(2)-adrenoceptor density and function is in favour of the idea that the ISA of carteolol is mediated by beta(2)-adrenoceptors. Involvement of an additional receptor site (e.g. the propranolol-resistant state of the beta(1)-adrenoceptor), however, cannot be excluded.

Adrenergic beta-2 Receptor Antagonists↗

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↗

PubMed2003

Existence of functional M3-muscarinic receptors in the human heart.

It has been recently shown that, in adult rat ventricular cardiomyocytes, functional muscarinic receptors (M-receptors) of the M(3)-subtype exist that mediate inositol phosphate (IP) formation. The aim of this study was to characterize the M-receptor subtype mediating IP formation in the human heart. For this purpose in [3H]-myo-inositol labeled slices of human right atria, carbachol-induced [3H]-IP formation and its inhibition by several M-receptor antagonists was assessed. Carbachol (0.1 microM-100 microM) increased [3H]-IP formation; maximal increase at 100 microM was 93+/-16% above basal ( n=20); the pEC(50)-value for carbachol was 5.56. Atropine (1 microM) completely suppressed 100 microM carbachol-induced [3H]-IP formation. Among the M-receptor subtype "selective" antagonists himbacine (1 microM) and pirenzepine (1 microM) only marginally affected carbachol-induced [3H]-IP formation whereas the M(3)-receptor antagonist darifenacin (1 nM-1 microM) concentration-dependently inhibited carbachol-induced [3H]-IP formation with a pK(i)-value of 8.49. We conclude that in human right atrium there exist functional M(3)-receptors that couple to IP formation.

Aged↗

PubMed2003

Thr164Ile polymorphism of the human beta2-adrenoceptor exhibits blunted desensitization of cardiac functional responses in vivo.

In subjects heterozygous for Thr164Ile beta2-adrenoceptor (beta2AR) polymorphism, cardiac responses to beta2AR agonist stimulation are blunted. In this study, we investigated agonist-induced desensitization of Thr164Ile beta2ARs. For this purpose, we assessed in six subjects with heterozygous Thr164Ile beta2ARs and in 10 subjects with homozygous wild-type (WT) beta2ARs the effects of 2-wk oral treatment with 3 x 5 mg/day terbutaline on terbutaline infusion-induced increases in heart rate (HR) and contractility [measured as shortening of HR-corrected duration of electromechanical systole (QS2c)]. Compared with WT beta2AR subjects, Thr164Ile subjects exhibited a blunted terbutaline-induced maximum increase in HR (WT 32 +/- 4 beats/min, Thr164Ile 19 +/- 3 beats/min, P < 0.05) and contractility (WT -54 +/- 2 ms, Thr164Ile -37 +/- 6 ms, P < 0.05). Two-week oral terbutaline treatment desensitized cardiac beta2AR responses to terbutaline infusion (increase in HR: WT 10 +/- 2 beats/min, Thr164Ile 8 +/- 4 beats/min; increase in contractility: WT -22 +/- 5 ms Thr164Ile: -17 +/- 6 ms); however, the extent of desensitization was larger in WT than Thr164Ile beta2AR subjects. Thus, after 2-wk oral terbutaline treatment cardiac, beta2AR responses did not differ anymore between WT and Thr164Ile beta2AR subjects. We conclude that agonist-induced desensitization of cardiac beta2ARs is more pronounced in WT than Thr164Ile subjects. Thus cardiac Thr164Ile subjects appear to be somewhat protected against agonist-induced desensitization.

Adrenergic beta-Agonists↗