k201-compound and Heart-Diseases

At the start of a new decade (2011), heart failure and sudden cardiac death are still leading causes of mortality worldwide. There is a very obvious need for improved treatment strategies. Research over the past decade has focused on understanding and realising the therapeutic potential of molecular mechanisms that underlie the pathophysiology of cardiac dysfunction. There is now recognition that cell- and gene-based therapies could prove beneficial if aimed at the appropriate molecular targets. Two cardiac proteins that have received considerable attention over the last decade, have been identified as possible therapeutic targets. The cardiac sarcoplasmic reticulum Ca(2+) release channel (ryanodine receptor) and calcium/calmodulin dependent kinase II (CaMKIIδ) can act independently and in partnership, to regulate cardiac Ca(2+) handling. CaMKIIδ, by the very nature of its core function as a kinase, also modulates cardiac function globally, promoting effects on gene transcription and modulating inflammatory and proliferative responses, all events that are associated with both the functional and dysfunctional heart. In vivo approaches using genetic and pharmacologic strategies have revealed the prominent role of both proteins in cardiac dysfunction. More excitingly, they have also shown the potential for cardioprotection that modulation at the level of each protein can have. Translating these effects to the human heart is in its infancy. Whether intervention at these targets could result in clinical application is unknown at present, however current in vivo research has proved invaluable in revealing the potential that targeting of RyR and CaMKIIδ could have in limiting cardiac dysfunction.

Topics: Animals; Anti-Arrhythmia Agents; Calcium; Calcium Channel Blockers; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Flecainide; Heart Diseases; Humans; Myocardial Contraction; Ryanodine Receptor Calcium Release Channel; Thiazepines

K201 is a 1,4-benzothiazepine derivative that is a promising new drug with a strong cardioprotective effect. We initially discovered K201 as an effective suppressant of sudden cardiac cell death due to calcium overload. K201 is a non-specific blocker of sodium, potassium and calcium channels, and its cardioprotective effect is more marked than those of nicorandil, prazosine, propranolol, verapamil and diltiazem. Recently, K201 has also been shown to have activities indicated for treatment of atrial fibrillation, ventricular fibrillation, heart failure and ischemic heart disease, including action as a multiple-channel blocker, inhibition of diastolic Ca(2+) release from the sarcoplasmic reticulum, suppression of spontaneous Ca(2+) sparks and Ca(2+) waves, blockage of annexin V and provision of myocardial protection, and improvement of norepinephrine-induced diastolic dysfunction. Here, we describe the pharmacological characteristics and clinical applications of K201.

Topics: Animals; Calcium; Cardiotonic Agents; Cell Death; Heart Diseases; Humans; Sarcoplasmic Reticulum; Thiazepines