Lisy Ondrej, Burnett John C
Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic and College of Medicine, Rochester, MN 55905, USA.
Circulation. 2006 Jan 17;113(2):246-51. doi: 10.1161/CIRCULATIONAHA.105.558213. Epub 2006 Jan 9.
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.
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.
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.
K201（JTV519）是一种新开发的具有抗心律失常和心脏保护特性的1,4 - 苯并噻氮䓬类药物。它通过稳定心脏中的兰尼碱受体 - 钙释放通道（RyR2）发挥作用。该受体已在肾脏中被鉴定出来，体外研究表明其在肾血流动力学控制中起作用。迄今为止，该受体的体内功能尚不清楚。我们推测，这种因心肌作用而被开发用于治疗心力衰竭的新药，也具有增强肾血流动力学和排泄的特性。我们还使用免疫组织化学方法在正常犬肾中鉴定RyR2。
我们在正常麻醉犬肾内输注过程中研究了K201的肾脏作用。在基线测量后，以2种剂量（0.1和0.5mg·kg⁻¹·min⁻¹）输注K201。使用免疫组织化学方法鉴定未暴露于K201的肾脏中RyR2的存在。K201具有强大的利钠和利尿作用，同时具有增加肾小球滤过率和肾血流量的作用。尽管平均动脉压略有下降，但给予K201后的排泄反应与远端肾小管钠重吸收减少有关，在停用K201后平均动脉压恢复到基线水平。正常犬肾的免疫组织化学显示髓质集合管细胞中存在RyR2。
我们首次报道，新开发的心脏保护药物K201具有利钠、利尿、增加肾小球滤过率和血管舒张特性，这些特性超出了心肌作用，可能支持其在心力衰竭治疗中的治疗作用。
