Levosimendan induces NO production through p38 MAPK,ERK and Akt in porcine coronary endothelial cells: role for mitochondrial KATP channel

Background and purpose:

Levosimendan acts as a vasodilator through the opening of ATP-sensitive K⁺ channels (K_ATP) channels. Moreover, the coronary vasodilatation caused by levosimendan in anaesthetized pigs has recently been found to be abolished by the nitric oxide synthase (NOS) inhibitor N^ω-nitro-L-arginine methyl ester, indicating that nitric oxide (NO) has a role in the vascular effects of levosimendan. However, the intracellular pathway leading to NO production caused by levosimendan has not yet been investigated. Thus, the purpose of the present study was to examine the effects of levosimendan on NO production and to evaluate the intracellular signalling pathway involved.

Experimental approach:

In porcine coronary endothelial cells (CEC), the release of NO in response to levosimendan was examined in the presence and absence of N^ω-nitro-L-arginine methyl ester, an adenylyl cyclase inhibitor, K_ATP channel agonists and antagonists, and inhibitors of intracellular protein kinases. In addition, the role of Akt, ERK, p38 and eNOS was investigated through Western blot analysis.

Key results:

Levosimendan caused a concentration-dependent and K⁺-related increase of NO production. This effect was amplified by the mitochondrial K_ATP channel agonist, but not by the selective plasma membrane K_ATP channel agonist. The response of CEC to levosimendan was prevented by the K_ATP channel blockers, the adenylyl cyclase inhibitor and the Akt, ERK, p38 inhibitors. Western blot analysis showed that phosphorylation of the above kinases lead to eNOS activation.

Conclusions and implications:

In CEC levosimendan induced eNOS-dependent NO production through Akt, ERK and p38. This intracellular pathway is associated with the opening of mitochondrial K_ATP channels and involves cAMP.     

Antiplatelet therapy in children: why so different from adults'?

Antiplatelet agents are administered in the treatment of a large number of adult diseases: coronary heart disease, ischemic stroke, peripheral arterial disease, arrhythmias with their thromboembolic complications, primary and secondary prevention. In childhood however, the situation is substantially different. The lack of large interventional trials on the use of antiplatelet drugs in children, has led to greater uncertainty, and a less extensive use of these drugs, limited to fewer indications. The purpose of this article was to review the studies conducted to date on the use of antiplatelet agents in children. A concerted effort has been made to identify which are the shared therapeutic indications of this class of compounds, the recommended dose, the contraindications and the possible side effects. In brief, an attempt has been made to ascertain the interesting potential of these drugs which are so often neglected in children.     

Evaluation of Regional Myocardial Function by Doppler Tissue Imaging in Univentricular Heart after Successful Fontan Repair

Background: The univentricular heart (UVH) corrected by Fontan repair is characterized by a single dilated pumping chamber, which is both hypertrophic and hypocontractile. The complex geometrical distortion and asynchronous contraction of this organ prevents assessment of systolic and diastolic function by traditional echocardiographic procedures. Methods: Sixteen children (10 males, 6 females) aged 12–31 years, who had undergone UVH Fontan repair were enrolled in the study. A transthoracic echocardiography was performed. Twelve different myocardial wall segments from single ventricles were studied by Doppler tissue imaging to measure peak systolic velocity (S), isovolumetric relaxation time (IRT), isovolumetric contraction time (ICT), and E′/A′ ratio. Results: S and E′/A′ ratio were significantly lower in the UVH group than in controls (P < 0.01 and P < 0.05, respectively). IRT and ICT were significantly longer in UVH than in controls (P < 0.001 and P < 0.005, respectively). In the UVH, both systolic and diastolic deficits were generally registered in the apical segments and also randomly distributed between the basal and middle segments of the single ventricle. Conclusions: It is an acknowledged fact that compared to normal children ventricular function is impaired in patients with UVH. Tissue Doppler imaging at multiple points of the single ventricle provides a complete, accurate assessment of systolic and diastolic function after Fontan repair, overcoming problems posed by geometrical distortion and limitations of conventional echocardiographic methods. (Echocardiography 2010;27:702‐708)