Conserved expression and functions of PDE4 in rodent and human heart

PDE4 isoenzymes are critical in the control of cAMP signaling in rodent cardiac myocytes. Ablation of PDE4 affects multiple key players in excitation–contraction coupling and predisposes mice to the development of heart failure. As little is known about PDE4 in human heart, we explored to what extent cardiac expression and functions of PDE4 are conserved between rodents and humans. We find considerable similarities including comparable amounts of PDE4 activity expressed, expression of the same PDE4 subtypes and splicing variants, anchoring of PDE4 to the same subcellular compartments and macromolecular signaling complexes, and downregulation of PDE4 activity and protein in heart failure. The major difference between the species is a fivefold higher amount of non-PDE4 activity in human hearts compared to rodents. As a consequence, the effect of PDE4 inactivation is different in rodents and humans. PDE4 inhibition leads to increased phosphorylation of virtually all PKA substrates in mouse cardiomyocytes, but increased phosphorylation of only a restricted number of proteins in human cardiomyocytes. Our findings suggest that PDE4s have a similar role in the local regulation of cAMP signaling in rodent and human heart. However, inhibition of PDE4 has ‘global’ effects on cAMP signaling only in rodent hearts, as PDE4 comprises a large fraction of the total cardiac PDE activity in rodents but not in humans. These differences may explain the distinct pharmacological effects of PDE4 inhibition in rodent and human hearts

Concerted Regulation of cGMP and cAMP Phosphodiesterases in Early Cardiac Hypertrophy Induced by Angiotensin II

Left ventricular hypertrophy leads to heart failure and represents a high risk leading to premature death. Cyclic nucleotides (cAMP and cGMP) play a major role in heart contractility and cyclic nucleotide phosphodiesterases (PDEs) are involved in different stages of advanced cardiac diseases. We have investigated their contributions in the very initial stages of left ventricular hypertrophy development. Wistar male rats were treated over two weeks by chronic infusion of angiotensin II using osmotic mini-pumps. Left cardiac ventricles were used as total homogenates for analysis. PDE1 to PDE5 specific activities and protein and mRNA expressions were explored

Catecholamine-cAMP induces arrhythmias in the infarcting pig heart

[No abstract available

Cyclic AMP mediated arrhythmias induced in the ischaemic pig heart

Ligation of the anterior descending coronary artery two-thirds from its origin in the pig was found to precipitate ventricular arrhythmias and fibrillation, starting approximately 20 min post-ligation, which were associated with regional accumulation of myocardial cAMP in the ischaemic area. When the arrhythmias stopped, cyclic AMP levels in the ischaemic zone were decreased. Arrhythmias could then be induced by subepicardial infusion (10 μl/min) close to the visible edge of ischaemia of cAMP analogues [N6-monobutyryl cAMP, N6,O2'-dibutyryl cAMP to (5.10-2 M each)] or agents which increase the myocardial contents of cAMP. These agents were: isoproterenol (10-6 M), noradrenalin, adrenalin (10-5 M each), glucagon, histamine (10-3 M each), theophylline and caffeine (5.10-2 M). Also active were dopamine (10-3 M), oubain (10-5 M) and aconitine (10-6 M). The arrhythmias induced by infusion of catecholamines were dependent on Ca2+ and were abolished by beta-adrenoceptor blocking agents (pindolol, 10-6 M) and calcium antagonists (isoptin, D 600, 10-4 M each). Infusion of 150 mM sodium chloride or 100 mM sodium butyrate did not precipitate arrhythmias. It is concluded that myocardial cAMP may play an important role in the genesis of ventricular arrhythmias in the ischaemic heart, probably by augmenting the slow calcium inward current.Articl

Catecholamine-cAMP-Ca2+ induces arrhythmias in the healthy pig heart

[No abstract available

Cyclic AMP-arrhythmias. Myocardial maps and infusion

[No abstract available

Cyclic AMP-arrhythmias. Choline esters as anti-arrhythmic agents

[No abstract available