Synergic PDE3 and PDE4 control intracellular cAMP and cardiac excitation-contraction coupling in a porcine model

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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

Cyclic GMP regulation of the L-type Ca2+ channel current in human atrial myocytes

The cardiac L-type Ca2+ channel current (ICa) is an important determinant of myocardial contractility. Its regulation by neurotransmitters, hormones, and paracrine factors contributes to the control of cardiac output to meet the demands of the body. A large number of these extracellular first messengers, acting on specific membrane receptors in cardiac myocytes, regulate the activity of adenylyl cyclase which in turn controls the intracellular concentration of cAMP, the activity of the cAMPdependent protein kinase (PKA), and the degree of phosphorylation and stimulation of L-type Ca2+ channels (Hartzell, 1988; McDonald et al. 1994; Hove-Madsen et al. 1996; Striessnig, 1999). A typical example of such regulation is the control of heart function by the sympathetic and parasympathetic nervous systems, which act via adrenoceptors and muscarinic receptors (Brodde & Michel, 1999). In addition to the cAMP cascade, other factors regulate heart function by acting primarily on the cGMP cascade; these include atrial and brain natriuretic peptides (de Bold et al.1996) and nitric oxide (NO) (Paulus & Shah, 1999; Shah & MacCarthy, 2000)

Reconstruction of the anterior cruciate ligament:a clinical comparison of bone-patellar tendon-bone single bundle versus semitendinosus and gracilis double bundle technique

The study hypothesis was that the outcome of semitendinosus gracilis double bundle (STG-DB) anterior cruciate ligament (ACL) reconstruction is advantageous in terms of clinical results and restoration of anterior-posterior and rotational laxity in comparison to bone-patellar tendon-bone single-bundle (PTB-SB) ACL reconstruction. We analysed 41 PTB-SB and 51 STG-DB patients using the Tegner, IKDC and WOMAC scores preoperatively and at a minimum follow-up of two years. At follow-up, there was no significant difference in the clinical scores. The KT 1000 side-to-side measurement showed no significant difference between groups. The STG-DB group was significantly superior in terms of the pivot-shift sign and anterior knee pain. We conclude that the outcome of STG-DB reconstruction in the mid-term was not advantageous in terms of clinical scores and anterior-posterior laxity evaluated by the KT 1000. Nevertheless, the restored rotational laxity measured by the pivot shift test was significantly superior in the STG-DB technique