Class Of Inotropic Agents Research Articles

Novel Therapeutic Targets in Heart Failure: The Phospholipase Cβ1b–Shank3 Interface

Inotropic agents are often used to improve the contractile performance of the failing myocardium, but this is often at a cost of increased myocardial ischemia and arrhythmia. Myocyte contractility depends on the release of Ca2+ from the sarcoplasmic reticulum, and this Ca2+ is subject to regulation by the phosphorylation status of phospholamban (PLN). Many currently used inotropic agents function by increasing the phosphorylation of PLN, but these also heighten the risk of ischemia. Another approach is to reduce the dephosphorylation of PLN, which can be achieved by inhibiting pathways upstream or downstream of the protein kinase Cα. Phospholipase Cβ1b is responsible for activating protein kinase Cα, and its activity is substantially heightened in failing myocardium. We propose phospholipase Cβ1b, a cardiac-specific enzyme, as a promising target for the development of a new class of inotropic agents. By reversing changes that accompany the transition to heart failure, it may be possible to provide well-tolerated improvement in pump performance.

Acute decompensated heart failure: current pharmacological approaches

Acute heart failure (AHF) represents a major burden in developed countries. However, pharmacological approaches have remained almost same for 30 years and are still based on consensus rather than evidence, given that no medical therapy has been shown to positively affect clinical outcomes. Current pharmacological approaches are still based on decongestion by using diuretics in almost all patients, plus either vasodilators or inotropic agents to hemodynamics according to perfusion status. The role of loop diuretics (furosemide) and nitrates (nitroglycerin and nitroprusside) is well established, but new agents such as vasopressin and adenosine antagonists, as well as nesiritide, have failed to show any additional value. In presence of hypoperfusion, use of inotropics must be considered despite lack of benefit in terms of survival, and use of phosphodiesterase inhibitors and levosimendan has not shown any significant advantages over catecholamines (dobutamine). AHF involves a wide spectrum of patients and syndromes, and this probably accounts for failure of trials set up to evaluate new therapeutic approaches for improving outcomes: therapies need to be tailored to specific patients. At this time, serelaxin represents a promising new agent which has a multifaceted effect, including organ protection, and has shown encouraging results when tailored for a well defined population. In addition, role of ularitide, a synthetic form of natriuretic peptide urodilatin, and new cardiac myosin activators, as a new class of inotropic agents, will be established in near future by ongoing trials. Therefore, AHF continues to be an unsolved problem and, in light of lessons learned, new pharmacological approaches should be tai- lored to well defined AHF populations, incorporating concepts such as the sooner better, improve and stabilize, and prevent organ damage, in order to be able to clinical outcomes, including both mortality and readmission rates.

Calcium sensitizer agents: A new class of inotropic agents in the treatment of decompensated heart failure

We have read with great interest the recent review article by Perrone SV and Kaplinsky EJ [1], entitled “Calcium sensitizer agents: A new class of inotropic agents in the treatment of decompensated heart failure”. They provided an excellent overview on the use of calcium sensitizer agents in the treatment of decompensated heart failure, but we were surprised that the authors state that no published reports exist about levosimendan’s use and profile in the context of cardiogenic shock.

Novel myofilament Ca2+-sensitizing property of xanthine oxidase inhibitors.

Antioxidants are known to mitigate the cardiac contractile dysfunction that follows brief periods of ischemia ("myocardial stunning"). Stunning decreases contractility at the level of the contractile proteins; therefore, we asked whether antioxidant treatment preserves myofilament Ca2+ responsiveness after global ischemia and reflow. Right ventricular trabeculae were dissected from rat hearts subjected either to 20 minutes ischemia and reperfusion in the absence of drugs (stunned group) or to the same protocol in the presence of allopurinol, an inhibitor of xanthine oxidase (XO), and mercaptopropionylglycine (MPG), a hydroxyl radical scavenger (antioxidant group). At 20 minutes of reflow, isovolumic developed pressure recovered completely in the antioxidant group, but in the stunned group it recovered by only 57%. [Ca2+]i and contractile force measurements in trabeculae revealed the expected depression of myofilament function in the stunned group, with no change in Ca2+ transients relative to nonischemic controls. In contrast, Ca2+ transients were smaller, but force was greater, in the antioxidant group relative to both the stunned group and to nonischemic controls. Steady-state [Ca2+]i-force relationships revealed a striking increase of maximal force and a modest shift of activation to a lower range of [Ca2+]i. The increase in maximal force was reproduced by allopurinol+MPG or by allopurinol alone under nonischemic conditions and also by oxypurinol (100 micromol/L), a potent inhibitor of XO. We conclude that allopurinol and oxypurinol sensitize the cardiac myofilaments to Ca2+. This Ca2+-sensitizing effect underlies the preservation of contractility observed with an allopurinol+MPG antioxidant cocktail in a model of stunned myocardium. These serendipitous findings identify allopurinol and oxypurinol as the lead compounds of a novel class of inotropic agents.