New cardioprotective agent K201 is natriuretic and glomerular filtration rate enhancing

Ondrej Lisy, John C Jr. Burnett

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background - K201 (JTV519) is a newly developed 1,4-benzothiazepine drug with antiarrhythmic and cardioprotective properties. It functions via stabilization of the ryanodine receptor-calcium release channel in the heart (RyR2). This receptor has been identified in the kidney, and in vitro studies suggest a role in the control of renal hemodynamics. To date, the in vivo function of this receptor is undefined. We hypothesized that this new drug, which is being developed for the treatment of heart failure for its myocardial actions, also possesses renal hemodynamic enhancing and excretory properties. We also used immunohistochemistry to identify RyR2 in the normal canine kidney. Methods and Results - We investigated the renal actions of K201 during intrarenal infusion in normal anesthetized dogs. K201 was infused after baseline measurements at 2 doses (0.1 and 0.5 mg·kg-1·min -1). Immunohistochemistry was used to identify RyR2 presence in the kidney not exposed to K201. K201 was potently natriuretic and diuretic, with glomerular filtration rate- and renal blood flow-enhancing actions. The excretory responses to K201 administration were associated with decreases in distal tubular reabsorption of sodium despite a mild decrease in mean arterial pressure, which returned to baseline levels after K201 discontinuation. Immunohistochemistry of the normal canine kidney revealed the presence of RyR2 in the medullary collecting duct cells. Conclusions - We report for the first time that the newly developed cardioprotective drug K201 possesses natriuretic, diuretic, glomerular filtration rate-enhancing, and vasodilating properties that go beyond myocardial actions and may support its therapeutic role in treatment of heart failure.

Original languageEnglish (US)
Pages (from-to)246-251
Number of pages6
JournalCirculation
Volume113
Issue number2
DOIs
StatePublished - Jan 2006

Fingerprint

Cardiotonic Agents
Glomerular Filtration Rate
Ryanodine Receptor Calcium Release Channel
Kidney
Immunohistochemistry
Treatment Failure
Diuretics
Canidae
Heart Failure
Hemodynamics
Renal Circulation
Anti-Arrhythmia Agents
Pharmaceutical Preparations
Arterial Pressure
Sodium
Dogs

Keywords

  • Drugs
  • Hemodynamics
  • Immunohistochemistry
  • Kidney
  • Receptors

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

New cardioprotective agent K201 is natriuretic and glomerular filtration rate enhancing. / Lisy, Ondrej; Burnett, John C Jr.

In: Circulation, Vol. 113, No. 2, 01.2006, p. 246-251.

Research output: Contribution to journalArticle

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