Decreased phosphodiesterase activities in cardiac hypertrophy

Abstract

There is limited information on the changes in cardiac cyclic nucleotide phosphodiesterases (PDE1 to PDE5) during hypertrophy and the functional consequences on the cAMP pathway. To address this, 3-week-old rats were subjected to aortic stenosis (H) or sham operated (S). Hypertrophy was assessed at 8 weeks of age. Cyclic nucleotide-gated (CNG) channels were used to monitor cAMP. The whole cell patch-clamp technique was used to record the associated CNG current (ICNG) and ICa,L. Increased heart weight (43%) in the H group was accompanied by a general decrease in PDE activities in LV and a ≈ 50% reduction in PDE3 and PDE4. The efficacy of isoprenaline (Iso) to increase ICNG was decreased in H myocytes vs. S, whereas the response to forskolin (100 μM) was unchanged. The transient increase in ICa,L elicited by a 15 s application of Iso (100 nM) was similar in both groups. In S myocytes, PDE3 inhibition had no effect on ICa,L time-course, whereas PDE4 inhibition prolonged the signal. In H myocytes, both PDE3 or PDE4 inhibition slowed down ICa,L decay. Thus, PDE activities follow β1-AR desensitization in hypertrophy. Termination of β-AR stimulation of ICa,L is unchanged in hypertrophy, but the PDEs involved in this process are different. The contribution of PDE3 in hypertrophy might be seen as compensatory for the reduction in PDE4.