Background and purpose: beta(1)- and beta(2)-adrenoceptors coexist in rat heart but beta(2)-adrenoceptor-mediated inotropic effects are hardly detectable, possibly due to phosphodiesterase (PDE) activity. We investigated the influence of the PDE3 inhibitor cilostamide (300 nmol x L(-1)) and the PDE4 inhibitor rolipram (1 micromol x L(-1)) on the effects of (-)-catecholamines.
Experimental approach: Cardiostimulation evoked by (-)-noradrenaline (ICI118551 present) and (-)-adrenaline (CGP20712A present) through beta(1)- and beta(2)-adrenoceptors, respectively, was compared on sinoatrial beating rate, left atrial and ventricular contractile force in isolated tissues from Wistar rats. L-type Ca(2+)-current (I(Ca-L)) was assessed with whole-cell patch clamp.
Key results: Rolipram caused sinoatrial tachycardia. Cilostamide and rolipram did not enhance chronotropic potencies of (-)-noradrenaline and (-)-adrenaline. Rolipram but not cilostamide potentiated atrial and ventricular inotropic effects of (-)-noradrenaline. Cilostamide potentiated the ventricular effects of (-)-adrenaline but not of (-)-noradrenaline. Concurrent cilostamide + rolipram uncovered left atrial effects of (-)-adrenaline. Both rolipram and cilostamide augmented the (-)-noradrenaline (1 micromol x L(-1)) evoked increase in I(Ca-L). (-)-Adrenaline (10 micromol x L(-1)) increased I(Ca-L) only in the presence of cilostamide but not rolipram.
Conclusions and implications: PDE4 blunts the beta(1)-adrenoceptor-mediated inotropic effects. PDE4 reduces basal sinoatrial rate in a compartment distinct from compartments controlled by beta(1)- and beta(2)-adrenoceptors. PDE3 and PDE4 jointly prevent left atrial beta(2)-adrenoceptor-mediated inotropy. Both PDE3 and PDE4 reduce I(Ca-L) responses through beta(1)-adrenoceptors but the PDE3 component is unrelated to inotropy. PDE3 blunts both ventricular inotropic and I(Ca-L) responses through beta(2)-adrenoceptors.