Phosphodiesterase‐4 blunts inotropism and arrhythmias but not sinoatrial tachycardia of (−)‐adrenaline mediated through mouse cardiac β₁‐adrenoceptors

Abstract

Background and purpose: b 1 and b 2 -adrenoceptors coexist in murine heart but b 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 (À)-adrenaline in three regions of murine heart. Experimental approach: (À)-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 mM) and cilostamide (300 nM) caused transient sinoatrial tachycardia but neither enhanced the chronotropic potency of (À)-adrenaline. Rolipram potentiated 19-fold (left atrium) and 7-fold (right ventricle) the inotropic effects of (À)-adrenaline. (À)-Adrenaline elicited concentration-dependent ventricular arrhythmias that were potentiated by rolipram. All effects of (À)-adrenaline were antagonized by the b 1 -adrenoceptor-selective antagonist CGP20712A (300 nM). Cilostamide (300 nM) did not increase the chronotropic and inotropic potencies of (À)-adrenaline, but administered jointly with rolipram in the presence of CGP20712A, uncovered left atrial inotropic effects of (À)-adrenaline that were prevented by the b 2 -adrenoceptor-selective antagonist ICI118551. Conclusions and implications: PDE4 blunts the b 1 -adrenoceptor-mediated effects of (À)-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 b 1 -adrenoceptor compartment. PDE3 and PDE4, acting in concert, prevent left atrial b 2 -adrenoceptor-mediated inotropy. PDE4 partially protects the right ventricle against (À)-adrenaline-evoked arrhythmias.

Differential regulation of β2‐adrenoceptor‐mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non‐failing rat cardiac ventricle

“…Thus, PDE3 and PDE4 play prominent roles in the functional limitation of the cardiac b2-adrenoceptor signals. In the present study, the b1-adrenoceptor-mediated PIR was also found to be regulated by both PDE3 and PDE4, which is different from the findings by others that only PDE4 played such a role in non-failing mouse and rat right ventricle (Vargas et al 2006;Galindo-Tovar and Kaumann, 2008) and left ventricle (Christ et al, 2009). Interestingly, another study reported an increase in the inotropic potency of isoprenaline in non-failing rat right ventricle during PDE4 inhibition but not during PDE3 inhibition by 10 mM milrinone (Katano and Endoh, 1992), a concentration which inhibits approximately 97% of PDE3 (Shakur et al, 2002).…”

“…The b1-and b2-adrenoceptor-activated cAMP signals are differentially regulated by various PDE isoforms in cardiomyocytes (Nikolaev et al, 2006;Rochais et al, 2006;Galindo-Tovar and Kaumann, 2008). In nonfailing myocardium, PDE3 and PDE4 provide about 90% of total cAMP-PDE activity, and the b-adrenoceptor-mediated increase in cAMP is mainly limited by PDE4 (Mongillo et al, 2004).…”

The role of phosphodiesterase activity on the temperature-dependent responses of calf cardiac vein

“…However, different expressions and activities of PDE enzymes in the heart have been described among species, tissues, cells and subcellular compartments (28)(29)(30). In addition, effects of PDEs inhibitors on cardiac functions has been examined in basal and stimulated conditions in different experimental models (30)(31)(32)(33)(34).…”

Differential Effect of Phosphodiesterase-3 Inhibitors on Sympathetic Hyperinnervation in Healed Rat Infarcts

“…25 Increased PDE-4 activity has been shown to have an antiarrhythmic effect. 38 Previous studies have also shown that mice with PDE-4D deficiency show accelerated progression of heart failure following MI and that pharmacological PDE-4 inhibition was associated with exercise-induced cardiac arrhythmias. 39 Thus, it is possible, at least in theory, that the greater selectivity of cilostazol for PDE-3 may help prevent cardiac arrhythmias.…”