Small potentiation of the inotropic effects of catecholamines by PDE inhibitors is accompanied by dramatic increases of arrhythmias in rat right ventricular myocardium

Dr. Christ, Torsten1, Galindo-Tovar, Alejandro2, Prof. Dr. Ravens, Ursula1, Prof. Dr. Kaumann, Alberto3. 1Medical Faculty, Dresden University of Technology Pharmacology and toxicology, Fetscherstrasse 74, 01307 DRESDEN, Germany ; 2University of Murcia Department of Pharmacology, Avda. Teniente Flomesta, nº 5, 30003 Murcia, Spain; 3University of Cambridge Physiology, Development & Neuroscience, Downing Street, Cambridge, Great Britain.

Catecholamines can induce ventricular arrhythmias. PDE3 and PDE4 differently blunt the effects of β1- and β2-adrenoceptor (β1AR, β2AR) stimulation on L-type Ca2+ current and force generation, suggesting that PDEs not only limit overall cAMP but also generate compartmentation of cAMP. Accordingly inhibition of PDE activity is expected to abolish functional compartments. However, the relevance of PDE inhibition on electrical stability of the myocardium is unclear. Here we investigated the effects of PDE3 and PDE4 inhibitors on electrical stability in right ventricular strips paced at 1 Hz. The preparations were challenged with noradrenaline (NA) and adrenaline (Adr) to stimulate β1AR and β2AR respectively.

Under control conditions NA provoked arrhythmias in 8 out of 33 preparations (24%), which occurred at high concentrations that produced maximum inotropic responses (-logEC50(M) 5.2 for arrhythmia vs. 6.9 for inotropy). In the presence of the PDE4 inhibitor rolipram (1 µM) the incidence of NA-induced arrhythmias was dramatically increased of 19 out of 22 preparations (80%). The -logEC50 values for arrhythmia induction and inotropic response were no longer different (∼6.9 for both).

In contrast stimulation of β2AR by Adr elicited robust inotropic effects only in the concomitant presence of rolipram and cilostamide (300nM) to inhibit PDE4 and PDE3, but 11 out of 12 preparations (92%) became arrhythmic although maximum force generation tended to be smaller than with NA. This suggests that catecholamine-induced arrhythmias facilitated by PDE-inhibition are the result of loss of compartmentation for cAMP rather than caused by an increase in overall cAMP. Compartmented hydrolysis cAMP by PDE3 and PDE4 has an important impact on the electrical stability during catecholamine challenge in rat ventricular myocardium under in-vitro condition. We speculate that abolishing PDE-mediated compartments may lead to harmful arrhythmias.