Marcelo Auslender

PKC activity modulates availability and long openings of L-type Ca2+ channels in A7r5 cells.

The possibility that protein kinase C (PKC) could control the activity of L-type Ca2+ channels in A7r5 vascular smooth muscle-derived cells in the absence of agonist stimulation was investigated using the patch-clamp technique. Consistent with the possibility that L-type Ca2+ channels are maximally phosphorylated by PKC under these conditions, we show that 1) activation of PKC with the phorbol ester phorbol 12,13-dibutyrate was ineffective in modulating whole cell and single-channel currents, 2) inhibition of PKC activity with staurosporine or chelerythrine inhibited channel activity, 3) inhibition of protein phosphatases by intracellular dialysis of okadaic acid did not affect whole cell currents, and 4) the inhibitory effect of staurosporine was absent in the presence of okadaic acid. The inhibition of Ca2+ currents by PKC inhibitors was due to a decrease in channel availability and long open events, whereas the voltage dependence of the open probability and the single-channel conductance were not affected. The evidence suggests that in resting, nonstimulated A7r5 cells there is a high level of PKC activity that modulates the gating of L-type Ca2+ channels.

Pathophysiology of pediatric heart failure

Our understanding of the syndrome of heart failure has undergone several revisions, most importantly in the second half of the 20th century. New insights into the mechanisms of diseases offer new, challenging, controversial and sometimes counterintuitive forms of therapy. The development and progression of heart failure results from a complex interplay of hemodynamic and neurohormonal, cellular and genetic factors, rather than simply changes in cardiac function. It is because of this reason that our therapeutic focus can no longer be solely based on supply and demand models. Since the description of the pulsatile nature of the heart function and the flow of blood around a circuit by W. Harvey, numerous new paradigms have been put forward to explain the nature of heart failure. However, no single new model thus far proposed has been able to displace previous ones and successfully dictate therapy. It is the purpose of this manuscript to review the overall current understanding of the heart failure syndrome and how these new ideas may affect our therapeutic approach.

Management of heart failure in children

B dvances in our understanding of the pathophysiology and molecular basis of diseases offer new, challenging, controversial, and sometimes, counterintuitive forms of therapy. This is especially true with regard to the syndrome of heart failure. Therapeutic approaches to heart failure in adults have evolved rapidly during the past decade. Unfortunately, as with many other aspects of medicine, our concepts of heart failure in the pediatric population have been reduced to a simple extrapolation of the adult model. Pediatricians know that a child is not a small adult. Consequently, heart failure is perhaps a far more complex entity in the pediatric population with regard to pathophysiology and the possible courses of action. In this review we summarize recent advances in heart failure research in adults and attempt to integrate these findings in a pediatric context. The basic paradigm of hemodynamic derangement and the consequent symptoms have dominated our approach to congestive heart failure for most of this century (Fig 1). Despite constraint by this narrow viewpoint, the normalization of hemodynamics has an immediate positive effect on symptomatic improvement. Multiple clinical trials were conducted in the adult population with a variety of pharmacologic strategies aimed at enhancing systolic performance only. The clinical outcome of these trials was disappointing because of adverse effects on the heart in the long term, since the initial improvement in the standard measures of heart failure severity (such as exercise tolerance, symptoms, and hemodynamics) was not sustained. 1,2 Application of information available from recent heart failure research enables us to go beyond the concept of the heart as a simple pump and formulate a more comprehensive understanding of the syndrome of heart failure (Fig 2). We are now beginning to recognize the

New drugs in the treatment of heart failure.

New therapeutic strategies as well as the development of drugs with more specific targets have been fueled by disappointments in the treatment of adult heart failure. Calcium sensitizers, vesnarinone and angiotensin channel blockers will be addressed in this manuscript. The physiologic and pharmacologic principles that justify their use in the management of heart failure are reviewed. Calcium sensitizers increase myocardial contractility and in part they bypass the adenylyl cyclase cascade, which gives them a more favorable energy profile. Vesnarinone is a quinolinone derivative with ion channel modulation properties, which result in a positive inotropic effect and prolongation of the action potential. In addition vesnarinone has immunomodulatory properties. Angiotensin-converting enzyme inhibitors are the cornerstones for the treatment of heart failure. The discovery of some putative drawbacks to ACE inhibition has challenged this supremacy. Angiotensin receptor blockers have been developed hoping to overcome these deficiencies. Myocardial developmental differences highlight the shortcomings of attempting to extrapolate data on drugs and cellular physiology in adults to children. Studies are needed addressing standards of care, quality of life, morbidity and mortality, neurohumoral activation, its modulation and the consequences of these therapies in pediatric heart failure.

Vasodilators in the treatment of pediatric heart failure

The goals of heart failure therapy have shifted from purely hemodynamic manipulation to a combination of hemodynamic and neurohumoral modulation. Vasodilators with neurohumoral modulatory properties [such as ACE inhibitors (ACEi) and third generation beta-blockers] have become the cornerstone of chronic heart failure therapy. These newer agents have proven to improve morbidity and mortality in adults with chronic heart failure. Pure vasodilators still have a place in the treatment of acute decompensated heart failure and in patients who are intolerant to ACEi or beta-blocker therapy. In decompensated heart failure management, improvement of cardiac output is of paramount importance and restoration of normal hemodynamics takes priority over modulation of cardiac maladaptation. Under these circumstances agents that improve contractility and modify cardiac preload and afterload are used. In the intensive care unit setting inodilators offer the advantage of an added positive inotropic effect. NO donors play an important role when close titration of blood pressure is also needed. It is the purpose of this manuscript to address principles and current practice regarding the use of vasodilators in pediatric heart failure. ACE inhibitors and third generation beta-blockers due to their importance in todays therapeutic approach to heart failure are the focus of more detailed articles in this issue of Progress in Pediatric Cardiology.

Impact of a Surgical Pathway for the Postoperative Care of Children with Atrial Septal Defects

Impact of a Surgical Pathway for the Postoperative Care of Children with Atrial Septal Defects