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Phosphodiesterase‐4 blunts inotropism and arrhythmias but not sinoatrial tachycardia of (−)‐adrenaline mediated through mouse cardiac β 1 ‐adrenoceptors
Author(s) -
GalindoTovar A,
Kaumann A J
Publication year - 2008
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 - 10.1038/sj.bjp.0707631
Subject(s) - chronotropic , rolipram , medicine , sinoatrial node , inotrope , ventricle , endocrinology , phosphodiesterase 3 , atrium (architecture) , phosphodiesterase , cardiology , heart rate , chemistry , atrial fibrillation , blood pressure , biochemistry , enzyme
Background and purpose: β 1 and β 2 ‐adrenoceptors coexist in murine heart but β 2 ‐adrenoceptor‐mediated effects have not been detected in atrial and ventricular tissues, possibly due to marked phosphodiesterase (PDE) activity. We investigated the influence of the PDE3 inhibitor cilostamide and PDE4 inhibitor rolipram on the effects of (−)‐adrenaline in three regions of murine heart. Experimental approach: (−)‐Adrenaline‐evoked cardiostimulation was compared on sinoatrial beating rate, left atrial and right ventricular contractile force in isolated tissues from 129SvxC57B1/6 cross mice. Ventricular arrhythmic contractions were also assessed. Key results: Both rolipram (1 μ M ) and cilostamide (300 n M ) caused transient sinoatrial tachycardia but neither enhanced the chronotropic potency of (−)‐adrenaline. Rolipram potentiated 19‐fold (left atrium) and 7‐fold (right ventricle) the inotropic effects of (−)‐adrenaline. (−)‐Adrenaline elicited concentration‐dependent ventricular arrhythmias that were potentiated by rolipram. All effects of (−)‐adrenaline were antagonized by the β 1 ‐adrenoceptor‐selective antagonist CGP20712A (300 n M ). Cilostamide (300 n M ) did not increase the chronotropic and inotropic potencies of (−)‐adrenaline, but administered jointly with rolipram in the presence of CGP20712A, uncovered left atrial inotropic effects of (−)‐adrenaline that were prevented by the β 2 ‐adrenoceptor‐selective antagonist ICI118551. Conclusions and implications: PDE4 blunts the β 1 ‐adrenoceptor‐mediated effects of (−)‐adrenaline in left atrium and right ventricle but not in sinoatrial node. Both PDE3 and PDE4 reduce basal sinoatrial rate in a compartment distinct from the β 1 ‐adrenoceptor compartment. PDE3 and PDE4, acting in concert, prevent left atrial β 2 ‐adrenoceptor‐mediated inotropy. PDE4 partially protects the right ventricle against (−)‐adrenaline‐evoked arrhythmias. British Journal of Pharmacology (2008) 153 , 710–720; doi: 10.1038/sj.bjp.0707631 ; published online 17 December 2007