IngentaConnect HUMAN HEART -ADRENOCEPTORS: 1-ADRENOCEPTOR DIVERSIFICATION THROUG...

Abstract:

SUMMARY

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In atrium and ventricle from failing and non-failing human hearts, activation of β₁- or β₂-adrenoceptors causes increases in contractile force, hastening of relaxation, protein kinase A-catalysed phosphorylation of proteins implicated in the hastening of relaxation, phospholamban, troponin I and C-protein, consistent with coupling of both β₁- and β₂-adrenoceptors to stimulatory G_sa-protein but not inhibitory G_ia-protein.

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Two `affinity states', namely β_1H and β_1L, of the β₁-adrenoceptor exist. In human heart, noradrenaline elicits powerful increases in contractile force and hastening of relaxation. These effects are blocked with high affinity by β-adenoceptor antagonists, including propranolol, (-)-pindolol, (-)-CGP 12177 and carvedilol. Some beta-blockers, typified by (-)-pindolol and (-)-CGP 12177, not only block the receptor, but also activate it, albeit at much higher concentrations (approximately 2 log units) than those required to antagonize the effects of catecholamines. In human heart, both (-)-CGP 12177 and (-)-pindolol increase contractile force and hasten relaxation. However, the involvement of the β₁-adrenoceptor was not immediately obvious because (-)-pindolol- and (-)-CGP 12177-evoked responses were relatively resistant to blockade by (-)-propranolol. Abrogation of cardiostimulant effects of (-)-CGP 12177 in β₁-/β₂-adrenoceptor double-knockout mice, but not β₂-adrenoceptor-knockout mice, revealed an obligatory role of the β₁-adrenoceptor. On the basis of these results, two `affinity states' have been designated, the β_1H- and β_1L-adrenoceptor, where the β_1H-adrenoceptor is activated by noradrenaline and blocked with high affinity by beta-blockers and the β_1L-adrenoceptor is activated by drugs such as (-)-CGP 12177 and (-)-pindolol and blocked with low affinity by beta-blockers such as (-)-propranolol. The β_1H- and β_1L-adrenoceptor states are consistent with high- and low-affinity binding sites for (-)-[³H]-CGP 12177 radioligand binding found in cardiac muscle and recombinant β₁-adrenoceptors.

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There are two common polymorphic locations of the β₁-adrenoceptor, at amino acids 49 (Ser/Gly) and 389 (Arg/Gly). Their existence has raised several questions, including their role in determining the effectiveness of heart failure treatment with beta-blockers. We have investigated the effect of long-term maximally tolerated carvedilol administration (> 1 year) on left ventricular ejection fraction (LVEF) in patients with non-ischaemic cardiomyopathy (mean left ventricular ejection fraction 23 ± 7%; n = 135 patients). The administration of carvedilol improved LVEF to 37 ± 13% (P < 0.005); however, the improvement was variable, with 32% of patients showing £ 5% improvement. Upon segregation of patients into Arg389Gly-β₁-adrenoceptors, it was found that carvedilol caused a greater increase in left ventricular ejection faction in patients carrying the Arg389 allele with Arg389Arg > Arg389Gly > Gly389Gly.

HUMAN HEART β-ADRENOCEPTORS: β1-ADRENOCEPTOR DIVERSIFICATION THROUGH `AFFINITY STATES' AND POLYMORPHISM

HUMAN HEART β-ADRENOCEPTORS: β₁-ADRENOCEPTOR DIVERSIFICATION THROUGH `AFFINITY STATES' AND POLYMORPHISM