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Inotropy and L‐type Ca 2+ current, activated by β 1 ‐ and β 2 ‐adrenoceptors, are differently controlled by phosphodiesterases 3 and 4 in rat heart
Author(s) -
Christ Torsten,
GalindoTovar Alejandro,
Thoms Marcus,
Ravens Ursula,
Kaumann Alberto J.
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2008.00015.x
Subject(s) - rolipram , chronotropic , medicine , phosphodiesterase 3 , inotrope , phosphodiesterase , endocrinology , chemistry , sympatholytic , heart rate , enzyme , biochemistry , blood pressure
Background and purpose: β 1 ‐ and β 2 ‐adrenoceptors coexist in rat heart but β 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·L −1 ) and the PDE4 inhibitor rolipram (1 µmol·L −1 ) on the effects of (−)‐catecholamines. Experimental approach: Cardiostimulation evoked by (−)‐noradrenaline (ICI118551 present) and (−)‐adrenaline (CGP20712A present) through β 1 ‐ and β 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 µmol·L −1 ) evoked increase in I Ca‐L . (−)‐Adrenaline (10 µmol·L −1 ) increased I Ca‐L only in the presence of cilostamide but not rolipram. Conclusions and implications: PDE4 blunts the β 1 ‐adrenoceptor‐mediated inotropic effects. PDE4 reduces basal sinoatrial rate in a compartment distinct from compartments controlled by β 1 ‐ and β 2 ‐adrenoceptors. PDE3 and PDE4 jointly prevent left atrial β 2 ‐adrenoceptor‐mediated inotropy. Both PDE3 and PDE4 reduce I Ca‐L responses through β 1 ‐adrenoceptors but the PDE3 component is unrelated to inotropy. PDE3 blunts both ventricular inotropic and I Ca‐L responses through β 2 ‐adrenoceptors.