Selective regulation of β₁‐and β₂‐adrenoceptors in the human heart by chronic β‐adrenoceptor antagonist treatment

Abstract

In 44 patients undergoing coronary artery bypass grafting, the effect of chronic administration of the fi-adrenoceptor antagonists sotalol, propranolol, pindolol, metoprolol and atenolol on fiadrenoceptor density in right atria (containing 70% PB-and 30% P2-adrenoceptors) and in lymphocytes (having only f2-adrenoceptors) was studied.2 fl-Adrenoceptor density in right atrial membranes and in intact lymphocytes was assessed by (-)[1225I]-iodocyanopindolol (ICYP) binding; the relative amount of right atrial P,-and #2-adrenoceptors was determined by inhibition of ICYP binding by the selective #2-adrenoceptor antagonist ICI 118,551 and analysis of the resulting competition curves by the iterative curve fitting programme LIGAND. 3 With the exception of pindolol, all f-adrenoceptor antagonists increased right atrial ,Badrenoceptor density compared to that observed in atria from patients not treated with fadrenoceptor antagonists. 4 All f-adrenoceptor antagonists increased right atrial fi-adrenoceptor density; on the other hand, only sotalol and propranolol also increased right atrial f2-adrenoceptor density, whereas metoprolol and atenolol did not affect it and pindolol decreased it. 5 Similarly, in corresponding lymphocytes, only sotalol or propranolol increased fi2-adrenoceptor density, while metoprolol and atenolol did not affect it and pindolol decreased it.6 It is concluded that P-adrenoceptor antagonists subtype-selectively regulate cardiac and lymphocyte ,B-adrenoceptor subtypes. The selective increase in cardiac fi1-adrenoceptor density evoked by metoprolol and atenolol may be one of the reasons for the beneficial effects observed in patients with end-stage congestive cardiomyopathy following intermittent treatment with low doses of selective fl-adrenoceptor antagonists.

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

“…It has been shown in a variety of recombinant systems that long-term treatment with inverse agonists causes much larger increases in receptor density than do "neutral" antagonists (Milligan and Bond 1997). Thus, because the "second generation" β-1 AR blockers bisoprolol and metoprolol have been shown the exert considerable inverse agonism activity (Maack et al 2001), it might well be that the increase in β-AR density observed in human heart during longterm treatment with these β-1 AR blockers Gilbert et al 1996;Heilbrunn et al 1989;Michel et al 1988;Sigmund et al 1996;Waagstein et al 1989) is due to their inverse agonism activity. In this context, it is interesting to note that also carvedilol has been found to exert (weak) inverse agonism (Maack et al 2000), but as discussed earlier it did not increase cardiac β-AR density in CHF.…”

“…On the other hand, for bucindolol, several authors have found that it exerts partial intrinsic sympathomimetic activity (ISA) in the human myocardium (Maack et al 2000(Maack et al , 2003Andreka et al 2002). Previous studies had shown, however, that β-AR blockers with intrinsic sympathomimetic activity decrease cardiac β-AR density (Michel et al 1988), and this would explain the lack of cardiac β-AR up-regulation during chronic bucindolol treatment.…”

“…NS β-Blocker patients treated with nonselective β-AR blocker propranolol and sotalol; β 1 -Blocker patients treated with the β 1 -AR selective blocker metoprolol, atenolol and bisoprolol. Modified from Michel et al (1988) and Brodde et al (1989) 1998). CHF patients show marked reduction in the positive force-frequency relationship (for references, see Just 1996) and no augmentation by β-AR stimulation (Bhargava et al 1998).…”

Non-Isotopic Competitive Reverse Transcription Polymerase Chain Reaction Coupled with High Performance Liquid Chromatography to Measure β 2 -Receptor Messenger RNA in the Human Heart

“…/ON Λ , , lates the samples to be compared. Moreover, the effichange m 2 -adrenoceptor density (2). On the other .…”

“…, f , j ι· * ι ο steps needed before PCR amplification cannot be accumarkedly increased due to enhanced coupling of the β 2 -, " t A , , rately monitored. Nevertheless, quantification of an adrenoceptor to effector mechanisms after atenolol treat-·; .…”