Otto-Erich Brodde

The Thr164Ile-β₂-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-β₂AR polymorphism exhibit much more rapid progression to death or heart transplantation (HTX) than CHF-patients carrying the homozygous Thr164-β₂AR. This study aimed to further evaluate the role of the Thr164Ile-β₂AR in CHF. For this we hypothesized that the Thr164Ile-β₂AR variant should be more abundant in HTX-patients than in patients with stable CHF or healthy controls.

In rat ventricular cardiomyocytesβ₂‐adrenoceptors (AR) couple to G_s‐ and G_i‐protein, and evidence has accumulated thatβ₂‐AR agonists can differentially activate either G_s‐ or G_s‐ and G_i‐protein. In this study, in isolated adult rat ventricular cardiomyocytes, we assessed the effects of pertussis toxin (PTX) onβ₂‐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 whichβ₂‐AR agonist activates selectively G_s‐ or G_s‐ and G_i‐protein. PE (1 μM) increased the rate of protein synthesis from 100% to 130±2% (n=34). FEN, TER and SAL (1 nM–10 μM) 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⁻¹for 16 h at 37°C) did not affect FEN effects, but converted TER‐ and SAL‐evoked partial inhibition into complete inhibition. Inhibitory effects of the threeβ₂‐AR agonists were markedly attenuated byβ₁‐AR selective antagonist CGP 20712A (CGP) (300 nM); in contrast,β₂‐AR selective antagonist ICI 118,551 (55 nM) inhibited the inhibitory effects of the threeβ₂‐AR agonists only in PTX‐pretreated cardiomyocytes, withβ₁‐AR blocked by CGP. We conclude that, in adult rat ventricular cardiomyocytes, FEN activates selectively the G_sprotein‐pathway, while TER and SAL activate the G_s‐ and G_i‐protein pathways. Part of the effects of these threeβ₂‐AR agonists appears to be mediated byβ₁‐AR. British Journal of Pharmacology(2006)147, 714–719. doi:10.1038/sj.bjp.0706674

At present, nine adrenoceptor (AR) subtypes have been identified: α1A-, α1B-, α1D-, α2A-, α2B-, α2C-, β1-, β2-, and β3AR. In the human heart, β1- and β2AR are the most powerful physiologic mechanism to acutely increase cardiac performance. Changes in βAR play an important role in chronic heart failure (CHF). Thus, due to increased sympathetic activity in CHF, βAR are chronically (over)stimulated, and that results in β1AR desensitization and alterations of down-stream mechanisms. However, several questions remain open: What is the role of β2AR in CHF? What is the role of increases in cardiac Gi-protein in CHF? Do increases in G-protein-coupled receptor kinase (GRK)s play a role in CHF? Does βAR-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 β1- and β2AR gene polymorphisms are discussed. At present it seems that for cardiovascular diseases, βAR 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, βAR polymorphisms might influence drug responses. Thus, evidence has accumulated that a β1AR polymorphism (the Arg389Gly β1AR) may affect the response to βAR-blocker treatment.

In vitro, Arg389Gly β₁-adrenoceptor (AR) polymorphism exhibits decreased β-AR signalling. In vivo, β₁-AR-mediated cardiac effects of exercise showed no genotype-dependent differences in Arg389 vs. Gly389 β₁-AR subjects. We studied in 16 male subjects homozygous Arg389 or Gly389 β₁-AR, whether blockade of parasympathetic activity might unmask genotype-dependence of exercise effects. Subjects were infused with atropine (10 μg/kg i.v. loading dose followed by continuous i.v. infusion of 0.15 μg/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 β₁-AR subjects; only plasma noradrenaline increased slightly more in Gly389 vs. Arg389 β₁-AR subjects. In conclusion: It appears to be unlikely that lack of Arg389Gly β₁-AR genotype-dependence of exercise-effects can be explained by influences of parasympathetic activity.

β2-Adrenoceptors (AR) play an important role in regulation of vascular and bronchial smooth muscle tone; functional β2-AR, however, also exist in human heart where they can mediate positive inotropic and chronotropic effects. Recent studies have discovered that β2-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 β2-AR polymorphisms to cardiovascular diseases or altered drug responses. In addition, the relevance of SNPs vs. haplotypes for β2-AR functional responsiveness is discussed.

The intrinsic sympathomimetic activity (ISA) of a β-adrenoceptor blocker can be mediated by β₁- or β₂-adrenoceptors. The aim of this study was to characterize the ISA of the β-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 (QS₂c, 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 β₁-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 1×20 mg/day carteolol and assessed lymphocyte β₂-adrenoceptor density (by (−)-[¹²⁵I]-iodocyanopindolol binding) and functional responsiveness (by 10 μM isoprenaline-induced increase in lymphocyte cyclic AMP content). Carteolol significantly reduced lymphocyte β₂-adrenoceptor density and function. After withdrawal of carteolol lymphocyte β₂-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 β₁-adrenoceptor blocker bisoprolol and, on the other, carteolol significantly decreased lymphocyte β₂-adrenoceptor density and function is in favour of the idea that the ISA of carteolol is mediated by β₂-adrenoceptors. Involvement of an additional receptor site (e.g. the propranolol-resistant state of the β₁-adrenoceptor), however, cannot be excluded.

Patients with cardiovascular diseases are often treated by concurrent multiple drug therapy. It is therefore plausible that with an increasing number of drugs the risk of drug interactions increases. Such interactions can be either pharmacodynamic (and are due to the mechanism of the administered drugs) or they can be pharmacokinetic (resulting in a reduction or enhancement of drug elimination). Pharmacokinetic interactions can be either due to interactions at the level of drug metabolizing enzymes (most important cytochrome P450 (CYP) enzymes) or interactions at the level of drug transporter proteins (for example P-glycoprotein (MDR1)). It is important to distinguish between both mechanisms because interactions at transporter proteins can be attributed to those drugs that are not enzymatically metabolized. The scope of this article is to give an overview on clinically relevant interactions of the four β-blockers widely used in the therapy of cardiovascular diseases namely atenolol (CAS 29122-68-7), bisoprolol (CAS 66722-44-9), metoprolol (CAS 37350-58-6) (each β-1 selective), and carvedilol (CAS 72956-09-3) (β-1 and β-2 nonselective). Among these β-blockers atenolol is mainly eliminated by renal excretion, bisoprolol is in part excreted as parent compound via the renal route (50 %), the other 50% are hepatically metabolised, whereas metoprolol and carvedilol are metabolised by CYP2D6. In addition, evidence is accumulating that carvedilol is a substrate for P-glycoprotein. For these four β-blockers various pharmacodyamic and pharmacokinetic interactions have been demonstrated. Such interactions that result in an altered pharmacokinetics are mainly observed with those β-blockers that are excreted via metabolism (metoprolol and carvedilol). Accordingly these drugs have a higher potential for drug intercations. However, it should be emphasized that, in general, β-blockers are well tolerated safe drugs with a large therapeutic index. Interaktionspotential von β-Adrenozeptorenblockern Patienten mit Herz-Kreislauf-Erkrankungen erhalten häufig mehrere Arzneimittel gleichzeitig. Es ist daher naheliegend, daß mit steigender Zahl der Arzneimittel das Risiko von Arzneimittelinteraktionen steigt. Solche Interaktionen haben in den letzten Jahren dazu geführt, daß −auf Grund schwerer unerwünschter Wirkungen (z. T. tödlich) − Arzneimittel sogar vom Markt genommen werden mußten. Solche Interaktionen können pharmakodynamischer Natur sein (und lassen sich aus dem Wirkungsmechanismus der Substanzen ableiten), oder sie sind pharmakokinetisch bedingt. Für die zweite Möglichkeit gibt es zwei grundlegend unterschiedliche Mechanismen, nämlich Wechselwirkungen um verstoffwechselnde Enzyme (besonders wichtig hier Cytochrom (CYP) Enzyme) und zum zweiten Interaktionen um Transportproteine (z. B. P-Glykoprotein (MDR1)). Dieser Unterschied ist deswegen so relevant, weil über den zweiten Mechanismus auch solche Substanzen Interaktionen zeigen können, die nicht verstoffwechselt werden. Ziel dieses Review ist es, eine Übersicht über klinisch relevante Interaktionen der vier zur Standardtherapie von Herz-Kreislauf-Erkrankungen gehörenden β-Blocker Atenolol (CAS 29122-68-7), Bisoprolol (CAS 66722-44-9), Metoprolol (CAS 37350-58-6) (alle β-1-selektiv) und Carvedilol (CAS 72956-09-3) (β-1- und β-2-unselektiv) mit die Therapie begleitenden Arzneimitteln zu geben. Von diesen wird Atenolol nahezu unverändert renal ausgeschieden, Bisoprolol wird zu 50 % unverändert renal ausgeschieden, zu 50 % hepatisch metabolisiert, während Metoprolol und Carvedilol über das hepatische CYP2D6 metabolisiert werden. Darüber hinaus mehren sich Hinweise, daβ Carvedilol ein hochaffines Substrat für P-Glykoprotein darstellt. Für diese β-Blocker ist eine Reihe von pharmakodynamischen und pharmakokinetischen Interaktionen beschrieben worden. Solche Wechselwirkungen, die zu einer veränderten Pharmakokinetik führen, werden bevorzugt bei solchen Substanzen beobachtet, die zur Elimination verstoffwechselt werden (Metoprolol und Carvedilol). Somit haben diese Substanzen ein höheres Potential für Arzneimittelinteraktionen. Insgesamt bleibt jedoch festzuhalten, daβ es sich bei den β-Blockern um in aller Regel gut verträgliche Substanzen mit groβer therapeutischer Breite handelt.