HUMAN HEART β‐ADRENOCEPTORS: β1‐ADRENOCEPTOR DIVERSIFICATION THROUGH ‘AFFINITY STATES’ AND POLYMORPHISM

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SUMMARY: 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 Gsa‐protein but not inhibitory Gia‐protein. Two ‘affinity states’, namely β1Hand β1L, 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 β1H‐ and β1L‐adrenoceptor, where the β1H‐adrenoceptor is activated by noradrenaline and blocked with high affinity by beta‐blockers and the β1L‐adrenoceptor is activated by drugs such as (–)‐CGP 12177 and (–)‐pindolol and blocked with low affinity by beta‐blockers such as (–)‐propranolol. The β1H‐ and β1L‐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. 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.

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