Involvement of MAP kinases in the control of cPLA(2) and arachidonic acid release in endothelial cells.

Cytosolic Phospholipase A(2) (cPLA(2)) has been implicated in receptor-mediated release of arachidonic acid from membrane phospholipids, the limiting step in prostacyclin and other eicosanoid production. Its activity is controlled by Ca(++) levels and enzymatically regulated phosphorylation. The purpose of this study was to assess the importance of phosphorylation of cPLA(2) in human umbilical vein endothelial cells and to identify the kinases involved. Inhibitors were used to study the pathways leading to phosphorylation and activation of mitogen activated protein kinases (MAP-kinases) and cPLA(2), as well as release of arachidonic acid and prostacyclin production after stimulation with different agonists. We have found that agonists that release arachidonic acid, including histamine, thrombin, AlF(4)(-), and pervanadate, all activate the MAP kinases ERK, p38 and JNK and cause phosphorylation of cPLA(2). Agonist specific differences in the signal transduction pathways included variable contribution of tyrosine phosphorylation, protein kinase C and ERK activity, and different effects of pertussis toxin. Treatment with PD98059 (inhibitor of ERK-activation) or SB203580 (inhibitor of p38) caused partial decrease in arachidonic acid release and cPLA(2) activity. In contrast the nonspecific protein kinase inhibitor staurosporin completely inhibited cPLA(2) activity. We conclude that in endothelial cells arachidonic acid release is largely mediated by cPLA(2) through agonist-specific pathways. The MAP kinases ERK and p38 both have demonstrable but not major effect on agonist stimulated arachidonic acid release and the data suggest that an additional unidentified kinase also has a role.

[Atrial fibrillation: therapeutic options at the turn of the century.].

Atrial fibrillation is an increasing health care problem and the incidence of this arrhythmia is expected to increase substantially in the next two decades. Atrial fibrillation can be seen in patients with structural heart disease as well as those who have a normal heart. A variety of underlying mechanisms can lead to atrial fibrillation, including parasympathetic stimulation causing vagal atrial fibrillation. Complications of atrial fibrillation include congestive heart failure and stroke. Atrial fibrillation is an independent risk factor for increased mortality. In recent years a number of new treatment options have emerged. Anticoagulation decreases the risk of stroke and new antiarrhythmic drugs have been developed which increase the likelihood of conversion to and subsequent maintenance of sinus rhythm. In addition there have been advances in the approach to electrical cardioversion. Radiofrequency ablation therapy is a promising option in the treatment of atrial fibrillation and could be increasingly utilized in the near future. This paper focuses on advances in the therapy of atrial fibrillation, including new pharmacological agents, radiofrequency ablation and electrical cardioversion.