PDE3, but not PDE4, reduces β₁ - and β₂-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients

Abstract

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.

Figure 1

Effects of chronic administration of metoprolol compared with no-β-blocker on inotropic effects of (-)-noradrenaline through activation of β₁ adrenoceptors (A) and (-)-adrenaline through activation of β₂ adrenoceptors (B) in right ventricular trabeculae from failing hearts. Note the increased potency of (-)-noradrenaline and (-)-adrenaline for inotropic effects in metoprolol-treated patients. See text and Table 1 for further detail. β adrenoceptor blockade did not significantly increase basal force [P = 0.07 for (-)-noradrenaline, P = 0.095 for (-)-adrenaline] and maximum force [P = 0.10 for (-)-noradrenaline, P = 0.054 for (-)-adrenaline]. Data from four [(-)-noradrenaline experiments] or five [(-)-adrenaline experiments] patients with heart failure not treated with a β-blocker and seven patients with heart failure treated with metoprolol.

Figure 2

Lack of effect of cilostamide on the inotropic responses of (-)-noradrenaline and (-)-adrenaline in right ventricular trabeculae from four [(-)-noradrenaline experiments] or five [(-)-adrenaline experiments] patients with heart failure not treated with a β-blocker. Shown are concentration–effect curves to (-)-noradrenaline (A) and (-)-adrenaline (B) in the absence or presence of cilostamide (300 nM). Cilostamide did not significantly increase basal force (P = 0.36 for the noradrenaline group, P = 0.46 for the adrenaline group) or enhance the maximum force caused by (-)-noradrenaline (P = 0.41) or (-)-adrenaline (P = 0.13).

Figure 3

Representative experiment carried out on right ventricular trabeculae obtained from a 48-year-old male patient with ischaemic heart disease, left ventricular ejection fraction 25 %, chronically administered metoprolol 142.5 mg daily. Shown are original traces for (-)-noradrenaline and (-)-adrenaline in the absence or presence of cilostamide (Cil, 300 nM), rolipram (Rol, 1 μM), or Cil + Rol, followed by (-)-isoprenaline (ISO, 200 μM). The bottom panels show the corresponding graphical representation with non-linear fits. Note the clear potentiation of inotropic effects of both (-)-noradrenaline and (-)-adrenaline in the presence of cilostamide but the lack of potentiation by rolipram.

Figure 4

Potentiation of the inotropic effects of (-)-adrenaline by cilostamide (P < 0.05) in right ventricular trabeculae from seven patients from Brisbane/Dresden with heart failure chronically administered with metoprolol (B). In the same hearts, cilostamide caused a leftward shift of the inotropic effects of (-)-noradrenaline (A) which was not quite significant (P = 0.06). Rolipram had no effect on the inotropic effects of (-)-noradrenaline or (-)-adrenaline. See text for further explanation. Shown are concentration–effect curves to (-)-noradrenaline (A) and (-)-adrenaline (B) in the absence or presence of cilostamide (300 nM) or rolipram (1 μM).

Figure 5

Cilostamide potentiates the inotropic effects of (-)-adrenaline in left ventricular trabeculae from seven [(-)-noradrenaline experiments] or eight Oslo patients [(-)-adrenaline experiments] with heart failure and chronically administered with metoprolol. Shown are concentration–effect curves to (-)-noradrenaline (A) and (-)-adrenaline (B) in the absence or presence of cilostamide (1 μM) or rolipram (10 μM). Inotropic data are normalized as a percentage of the maximal response to (-)-noradrenaline or (-)-adrenaline.

Figure 6

Effects of the combination of cilostamide and rolipram on the inotropic responses of (-)-noradrenaline (A) and (-)-adrenaline (B) in right ventricular trabeculae from three patients with heart failure and chronically administered with metoprolol. While the combination of cilostamide and rolipram potentiated the inotropic responses of (-)-noradrenaline and (-)-adrenaline, the degree of potentiation did not differ from that caused by cilostamide alone.