Cyclic Nucleotide Phosphodiesterases and Compartmentation in Normal and Diseased Heart

International audienceCyclic nucleotide phosphodiesterases (PDEs) degrade the second messengers cAMP and cGMP, thereby regulating multiple aspects of cardiac function. This highly diverse class of enzymes encoded by 21 genes encompasses 11 families which are not only responsible for the termination of cyclic nucleotide signalling, but are also involved in the generation of dynamic microdomains of cAMP and cGMP controlling specific cell functions in response to various neurohormonal stimuli. In myocardium, the PDE3 and PDE4 families are predominant to degrade cAMP and thereby regulate cardiac excitation-contraction coupling. PDE3 inhibitors are positive inotropes and vasodilators in human, but their use is limited to acute heart failure and intermittent claudication. PDE5 is particularly important to degrade cGMP in vascular smooth muscle, and PDE5 inhibitors are used to treat erectile dysfunction and pulmonary hypertension. However, these drugs do not seem efficient in heart failure with preserved ejection fraction. There is experimental evidence that these PDEs as well as other PDE families including PDE1, PDE2 and PDE9 may play important roles in cardiac diseases such as hypertrophy and heart failure. After a brief presentation of the cyclic nucleotide pathways in cardiac cells and the major characteristics of the PDE superfamily, this chapter will present their role in cyclic nucleotide compartmentation and the current use of PDE inhibitors in cardiac diseases together with the recent research progresses that could lead to a better exploitation of the therapeutic potential of these enzymes in the future

A naturalistic study of grey matter volume increase after early treatment in anti-psychotic naïve, newly diagnosed schizophrenia

Background: Anti-psychotic treatment appears to be associated with striatal volume increase, but how early this change occurs is still unknown. Methods: A single prospective cohort of 20 anti-psychotic-naïve patients, newly diagnosed with schizophrenia, underwent magnetic resonance imaging brain scan at baseline. This was repeated following up to 8 weeks of anti-psychotic treatment. Ten patients had repeat scan within only 3 weeks. The choice of anti-psychotic medication was naturalistic, i.e., clinician-led. Well-matched healthy individuals were also scanned to control for non-specific changes over a 3-week period. Results: After 3 weeks of anti-psychotic treatment, significant grey matter volume increase in the right caudate, superior and inferior frontal gyrus, precentral gyrus, and left inferior parietal lobule was noted. However, after 8 weeks of anti-psychotic treatment, volume increase in the right thalamus and bilateral cerebellum was observed. Significant grey matter reduction was detected in the left medial frontal gyrus at both 3- and 8-week intervals. Conclusions: Early increase in striatal volume change occurs as early as 3 weeks after anti-psychotic treatment, whilst thalamic volume increase is apparent later, by 8 weeks of treatment. We speculate that drug-mediated neuroplasticity may provide a biomarker for clinical recovery. © 2009 Springer-Verlag.link_to_subscribed_fulltex