(-)-CGP 12177 increases contractile force and hastens relaxation of human myocardial preparations through a propranolol-resistant state of the β₁-adrenoceptor

Abstract.

Two forms of the activated β₁-adrenoceptor exist, one that is stabilized by (-)-noradrenaline and is sensitive to blockade by (-)-propranolol and another which is stabilized by partial agonists such as (-)-pindolol and (-)-CGP 12177 but is relatively insensitive to (-)-propranolol. We investigated the effects of stimulation of the propranolol-resistant β₁-adrenoceptor in the human heart. Myocardium from non-failing and failing human hearts were set up to contract at 1 Hz. In right atrium from non-failing hearts in the presence of 200 nM (-)-propranolol, (-)-CGP 12177 caused concentration-dependent increases in contractile force (–logEC₅₀[M] 7.3±0.1, E _max 23±1% relative to maximal (-)-isoprenaline stimulation of β₁- and β₂-adrenoceptors, n=86 patients), shortening of the time to reach peak force (–logEC₅₀[M] 7.4±0.1, E _max 37±5%, n=61 patients) and shortening of the time to reach 50% relaxation (t _50%, –logEC₅₀[M] 7.3±0.1, E _max 33±2%, n=61 patients). The potency and maxima of the positive inotropic effects were independent of Ser49Gly- and Gly389Arg-β₁-adrenoceptor polymorphisms but were potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (–logEC₅₀[M] 7.7±0.1, E _max 68±6%, n=6 patients, P<0.0001). In the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine, the potency (–logEC₅₀[M] 7.4±0.1, P=0.0013, n=9 patients) but not the maximal effect of (-)-CGP 12177 was reduced in right atrium from failing hearts, which was associated with 64% and 52% reductions in the densities of low-affinity and high-affinity (-)-[³H]CGP 12177 binding sites. In the presence of (-)-propanolol and 3-isobutyl-1-methylxanthine, (-)-CGP 12177 increased atrial cyclic AMP levels and activated cyclic AMP-dependent protein kinase in right atrium from non-failing hearts. In right ventricle from failing hearts (-)-CGP 12177 increased contractile force (–logEC₅₀[M] 7.4±0.1, E _max 34±3%, n=13 patients) and hastened the time to peak force (–logEC₅₀[M] 7.6±0.1) and time to reach 50% relaxation (–logEC₅₀[M] 7.4±0.1) in the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine. Our results show that (-)-CGP 12177 increases contractility and hastens relaxation through a cyclic AMP pathway in human myocardium, consistent with mediation through a (-)-propranolol-resistant state of the β₁-adrenoceptor. The reduction in heart failure of atrial inotropic potency of (-)-CGP 12177, as well as of the high-affinity and low-affinity binding sites for (-)-[³H]CGP 12177, is consistent with the β₁-adrenoceptor nature of these sites.