The vascular barrier-protecting hawthorn extract WS® 1442 raises endothelial calcium levels by inhibition of SERCA and activation of the IP3 pathway

WS (R) 1442 has been proven as an effective and safe therapeutical to treat mild forms of congestive heart failure. Beyond this action, we have recently shown that WS (R) 1442 protects against thrombin-induced vascular barrier dysfunction and the subsequent edema formation by affecting endothelial calcium signaling. The aim of the study was to analyze the influence of WS (R) 1442 on intracellular calcium concentrations [Ca2+](i); in the human endothelium and to investigate the underlying mechanisms. Using ratiometric calcium measurements and a FRET sensor, we found that WS (R) 1942 concentration-dependently increased basal [Ca2+](i) by depletion of the endoplasmic reticulum (ER) and inhibited a subsequent histamine-triggered rise of [Ca2+](i). Interestingly, the augmented [Ca2+](i) did neither trigger an activation of the contractile machinery nor led to a barrier breakdown (macromolecular permeability). It also did not impair endothelial cell viability. As assessed by patch clamp recordings, WS (R) 1442 did only slightly affect endothelial Na+/K+-ATPase, but increased [Ca2+](i) by inhibiting the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) and by activating the inositol 1,4,5-trisphosphate (IP3) pathway. Most importantly, WS (R) 1442 did not induce store-operated calcium entry (SOCE), but even irreversibly prevented histamine-induced SOCE. Taken together, WS (R) 1442 prevented the deleterious hyperpermeability-associated rise of [Ca2+](i); by a preceding, non-toxic release of Ca2+ from the ER. WS (R) 1442 interfered with SERCA and the IP3 pathway without inducing SOCE. The elucidation of this intriguing mechanism helps to understand the complex pharmacology of the cardiovascular drug WS (R) 1442. (C) 2012 Elsevier Ltd. All rights reserved.