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Background and Purpose PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1 μM) or PDE4 inhibitor rolipram (1-10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. Experimental Approach Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β1 adrenoceptors (β2 adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β2 adrenoceptors (β1 adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from - logEC50s. Key Results Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation ( P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. Conclusions and Implications Metoprolol induces a control by PDE3 of ventricular effects mediated through both β1 and β2 adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β2 adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle. Linked Article This article is commented on by Eschenhagen, pp 524-527 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12168 [ABSTRACT FROM AUTHOR]

Abstract: β-Adrenoceptor blocking agents (β-blockers) that at low concentrations antagonize cardiostimulant effects of catecholamines, but at high concentrations also cause cardiostimulation, have been appearing since the late 1960s. These cardiostimulant β-blockers, coined non-conventional partial agonists, antagonize the effects of catecholamines through a high-affinity site (β1HAR), but cause cardiostimulation mainly through a low-affinity site (β1LAR) of the myocardial β1-adrenoceptor. The experimental non-conventional partial agonist (−)-CGP12177 increases cardiac L-type Ca2+ current density and Ca2+ transients, shortens action potential duration but augments action potential plateau, increases heart rate and force, as well as causes arrhythmic Ca2+ transients and arrhythmic cardiocyte contractions. Other β-blockers, which do not cause cardiostimulation, consistently have lower affinity for β1LAR than β1HAR. These sites were verified and the cardiac pharmacology of non-conventional partial agonists confirmed on recombinant β1-adrenoceptors and on β1-adrenoceptors overexpressed into the heart. A targeted mutation of Asp138 to Glu138 virtually abolished the pharmacology of β1HAR but left intact the pharmacology of β1LAR. Non-conventional partial agonists may be beneficial for the treatment of peripheral autonomic neuropathy but probably due to their arrhythmic propensities, may be harmful for the treatment of chronic heart failure. [Copyright &y& Elsevier]

1. 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. 2. Two ‘affinity states’, namely β1H and 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. 3. 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. [ABSTRACT FROM AUTHOR]