Blocking of the potassium current I(Kr) [human ether-a-go-go related gene (hERG)] is generally associated with an increased risk of long QT syndrome (LQTS). The 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, rosuvastatin, is a methanesulfonamide derivative, which shows structural similarities with several I(Kr) blockers. Hence, we assessed the effects of rosuvastatin on cardiac repolarization by using in vitro, ex vivo, and in vivo models. Patch clamp experiments on hERG-transfected human embryonic kidney (HEK) 293 cells established the potency of rosuvastatin to block hERG [half maximal inhibitory concentration (IC(50) ) = 195 nM]. We showed in isolated guinea pig hearts that 195 nM rosuvastatin prolonged (basic cycle length of 250 ms; p < 0.05) the monophasic action potential duration at 90% repolarization (MAPD(90) ) by 11 ± 1 ms. Finally, rosuvastatin (10 mg/kg, intraperitoneal) prolonged corrected QT interval (QTc) in conscious and unrestrained guinea pigs from 201 ± 1 to 210 ± 2 ms (p < 0.05). Thus, rosuvastatin blocks I(Kr) and prolongs cardiac repolarization. In additional experiments, we also show that hERG blockade in HEK 293 cells was modulated by coexpression of efflux [breast cancer resistance protein (BCRP), multidrug resistance gene (MDR1)] and influx [organic anion transporting polypeptide (OATP) 2B1] transporters involved in the disposition and cardiac distribution of the drug. Genetic polymorphisms observed for BCRP, MDR1, and OATP2B1, and IC(50) determined for hERG blocking lead us to propose that some patients may be at risk of rosuvastatin-induced LQTS.
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