New cardioprotective agent K201 is natriuretic and glomerular filtration rate enhancing.
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.


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.
Lisy
Ondrej
O
Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic and College of Medicine, Rochester, MN 55905, USA. lisy.ondrej@mayo.edu
Burnett
John C
JC
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects; D004285:Dogs; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006334:Heart Function Tests; D006339:Heart Rate; D007668:Kidney / Q000737:chemistry / Q000502:physiology; D007677:Kidney Function Tests; D045283:Natriuretic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000032:analysis; D013841:Thiazepines / Q000008:administration & dosage / Q000494:pharmacology*
D002316:Cardiotonic Agents; D045283:Natriuretic Agents; D019837:Ryanodine Receptor Calcium Release Channel; D013841:Thiazepines; C109183:K201 compound