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(-)-CGP 12177 increases contractile force and hastens relaxation of human myocardial preparations through a propranolol-resistant state of the β-adrenoceptor
Journal article   Peer reviewed

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

D Sarsero, Fraser D Russell, J A Lynham, G Rabnott, I Yang, K M Fong, L Li, A J Kaumann and P Molenaar
Naunyn-Schmiedeberg's Archives of Parmacology, Vol.367(1), pp.10-21
2003
DOI: https://doi.org/10.1007/s00210-002-0652-9
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https://doi.org/10.1007/s00210-002-0652-9View
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Abstract

Pharmacology and Pharmaceutical Sciences (-)-CGP 12177 positive inotropy lusitropy cyclic AMP cyclic AMP-dependent protein kinase (-)-Propranolol-resistant β 1 -adrenoceptors human heart heart failure
Two forms of the activated #1-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 #1-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, Emax 23-1% relative to maximal (-)-isoprenaline stimulation of #1- and #2-adrenoceptors, n=86 patients), shortening of the time to reach peak force (-logEC50[M] 7.4-0.1, Emax 37-5%, n=61 patients) and shortening of the time to reach 50% relaxation (t50%, -logEC50[M] 7.3-0.1, Emax 33-2%, n=61 patients). The potency and maxima of the positive inotropic effects were independent of Ser49Gly- and Gly389Arg-#1-adrenoceptor polymorphisms but were potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (-logEC50[M] 7.7-0.1, Emax 68-6%, n=6 patients, P less than 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, Emax 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 #1-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 #1-adrenoceptor nature of these sites.

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