Different intrinsic activities of bucindolol, carvedilol and metoprolol in human failing myocardium - PubMed (original) (raw)

Different intrinsic activities of bucindolol, carvedilol and metoprolol in human failing myocardium

C Maack et al. Br J Pharmacol. 2000 Jul.

Abstract

1. Clinical studies have shown different effects of beta-blockers on the beta-adrenergic system, tolerability and outcome in patients with heart failure. 2. The study examines beta-adrenoceptor-G-protein coupling and intrinsic activity of bucindolol, carvedilol and metoprolol in human ventricular myocardium. 3. Radioligand binding studies ([(125)I]-Iodocyanopindolol) were performed in membrane preparations of human failing and nonfailing myocardium. Functional experiments were carried out in isolated muscle preparations of human left ventricular myocardium from failing hearts. 4. Bucindolol and carvedilol bound non-selectively to beta(1)- and beta(2)-adrenoceptors and exerted guanine nucleotide modulatable binding. Metoprolol was 35-fold beta(1)-selective and lacked guanine nucleotide modulatable binding. 5. All beta-blockers antagonized isoprenaline-induced enhancement of contractility. 6. In preparations in which the coupling of the stimulatory G-protein to adenylate cyclase was facilitated by forskolin, bucindolol increased force of contraction in three and decreased it in five experiments. Carvedilol increased force in one and decreased it in six experiments. Metoprolol decreased force in all experiments by 89. 4+/-2.2% (P<0.01 metoprolol vs carvedilol and bucindolol). The negative inotropic effect of metoprolol was antagonized by bucindolol. 7. It is concluded that differences in intrinsic activity can be detected in human myocardium and have an impact on cardiac contractility. In human ventricular myocardium, bucindolol displays substantially higher intrinsic activity than metoprolol and carvedilol. Bucindolol can behave as partial agonist or partial inverse agonist depending on the examined tissue. 8. Differences in intrinsic activity may contribute to differences in beta-adrenoceptor regulation and possibly to differences in tolerability and outcomes of patients with heart failure.

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Figures

Figure 1

Figure 1

[125I]-ICYP competition curves in human left ventricular myocardium from nonfailing hearts. (A) ICYP-isoprenaline competition in the absence and presence of 100 μmol l−1 of Gpp(NH)p. (B) ICYP-metoprolol competition in the absence and presence of Gpp(NH)p. (C) ICYP-carvedilol competition, both curves in the presence of ICI 118,551 (50 nmol l−1), in the absence and presence of Gpp(NH)p. (D) ICYP-carvedilol competition, both curves in the presence of CGP 20712A (300 nmol l−1), in the absence and presence of Gpp(NH)p. (E, F) ICYP-bucindolol competition, identical conditions like C, D. A, data are the means±s.e.mean from _n_=4 experiments. B–F, data are from one representative experiment. β-ARs, β-adrenoceptors.

Figure 2

Figure 2

The effects of metoprolol (_n_=6 experiments from n_=5 hearts, A), carvedilol (n_=6/5, B) and bucindolol (n_=6/5, C) at Ki and 100×_Ki on isoprenaline (Iso, 0.1 μmol l−1) enhanced force of contraction (FOC) in human left ventricular myocardium from patients with heart failure. Results are from cumulative dose-response experiments, but only Ki_- and 100×_Ki_-values are indicated as bar graphs. Ki_-values are derived from radioligand binding experiments. The concentrations used in the experiment are 0.01 (Ki) and 1 μmol l−1 (100×_Ki) for bucindolol, 0.001 (Ki) and 0.1 μmol l−1 (100×_Ki) for carvedilol and 1 (Ki) and 100 μmol l−1 (100×_Ki) for metoprolol. These concentrations are used to achieve approximately 50% (Ki) and 100% (100×_Ki) β-adrenoceptor occupation, respectively.

Figure 3

Figure 3

The effects of metoprolol (_n_=6 experiments from six hearts, A, B), carvedilol (Carv, _n_=7/4, C, D) and bucindolol (Buc, n_=8/5, E, F) at Ki and 100×_Ki on forskolin (0.3 μmol l−1) enhanced force of contraction (FOC) in human left ventricular myocardium from patients with heart failure. _Ki_-values are the same as in Figure 2. Bar graphs (A,C,E) give the means of all experiments in per cent of basal FOC at the indicated concentrations. In B,D,F, cumulative concentrations of the respective β-adrenoceptor antagonists are plotted against the change in FOC (mN). In D, F, the total group (dashed line) is divided into one group of muscles with a positive inotropic response to β-blocker (_n_=1 for carvedilol, _n_=3 for bucindolol), and the other group with a negative inotropic response.

Figure 4

Figure 4

Negative inotropic effect of metoprolol in the presence (+) and absence (−) of bucindolol (0.1 μmol l−1), and in the presence of forskolin (0.3 μmol l−1), respectively. Ordinate: per cent of maximum forskolin-enhanced force of contraction (FOC).

Figure 5

Figure 5

Comparison of intrinsic activity of bucindolol, carvedilol and metoprolol. (A) FOC in per cent of basal values after 100×Ki of carvedilol (abscissa) is plotted against FOC in per cent of basal values after 100×Ki of bucindolol (ordinate) in preparations from the same hearts, after forskolin (0.3 μmol l−1) prestimulation of left ventricular myocardium from patients with heart failure. (B) bucindolol (abscissa) against metoprolol (ordinate), the same conditions as in A.

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