The β-blockers
carvedilol and
metoprolol provide important therapeutic strategies for
heart failure treatment.
Therapy with
metoprolol facilitates the control by
phosphodiesterase PDE3, but not PDE4, of inotropic effects of
catecholamines in human failing ventricle. However, it is not known whether
carvedilol has the same effect. We investigated whether the PDE3-selective inhibitor
cilostamide (0.3 μM) or PDE4-selective inhibitor
rolipram (1 μM) modified the positive inotropic and lusitropic effects of
catecholamines in ventricular myocardium of
heart failure patients treated with
carvedilol. Right ventricular trabeculae from explanted hearts of nine
carvedilol-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 the PDE inhibitors. The inotropic potency, estimated from -logEC50s, was unchanged for (-)-
noradrenaline but decreased 16-fold for (-)-
adrenaline in
carvedilol-treated compared to non-β-blocker-treated patients, consistent with the previously reported β2-adrenoceptor-selectivity of
carvedilol.
Cilostamide caused 2- to 3-fold and 10- to 35-fold potentiations of the inotropic and lusitropic effects of (-)-
noradrenaline and (-)-
adrenaline, respectively, in trabeculae from
carvedilol-treated patients.
Rolipram did not affect the inotropic and lusitropic potencies of (-)-
noradrenaline or (-)-
adrenaline. Treatment of
heart failure patients with
carvedilol induces PDE3 to selectively control the positive inotropic and lusitropic effects mediated through ventricular β2-adrenoceptors compared to β1-adrenoceptors. The β2-adrenoceptor-selectivity of
carvedilol may provide protection against β2-adrenoceptor-mediated ventricular overstimulation in
PDE3 inhibitor-treated patients. PDE4 does not control β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in
carvedilol-treated patients.