Inotropy and L-type Ca2+ current, activated by beta1- and beta2-adrenoceptors, are differently controlled by phosphodiesterases 3 and 4 in rat heart.
OBJECTIVE
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.


METHODS
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.


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
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.
Christ
Torsten
T
Department of Pharmacology, Dresden University of Technology, Dresden, Germany.
Galindo-Tovar
Alejandro
A
Thoms
Marcus
M
Ravens
Ursula
U
Kaumann
Alberto J
AJ
D000818:Animals; D016275:Atrial Function / Q000187:drug effects; D020746:Calcium Channels, L-Type / Q000502:physiology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D020889:Rolipram / Q000494:pharmacology; D016276:Ventricular Function / Q000187:drug effects
D020746:Calcium Channels, L-Type; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D015363:Quinolones; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C021294:cilostamide; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D009638:Norepinephrine; D004837:Epinephrine