Effects of mefloquine on cardiac contractility and electrical activity in vivo, in isolated cardiac preparations, and in single ventricular myocytes

To examine the possible cardiotoxicity of the antimalarial drug mefloquine, increasing doses (0.3–30 mg kg−1) were given i.v. to anaesthetized guinea‐pigs. Mefloquine did not alter ECG intervals significantly but gradually increased systolic blood pressure (at 3 mg kg−1) then had a depressor effect (at 10 mg kg−1). Death due to profound hypotension, probably resulting from cardiac contractile failure or AV block, occurred after either 10 mg kg−1 (2/6) or 30 mg kg−1 (4/6) mefloquine. In isolated cardiac preparations mefloquine (3–100 μM) did not alter the effective refractory period but at the higher concentrations resting tension increased. Developed tension was reduced by 100 μM mefloquine in left atria (from 5.8±1.7 to 2.2±0.4 mN) whereas in papillary muscles although 30 μM mefloquine reduced developed tension (from 2.6±0.5 to 1.1±0.1 mN) subsequent addition of 100 μM caused a marked, but not sustained, positive inotropic effect (from 1.2±0.1 to 3.8±0.8 mN). In single ventricular myocytes, mefloquine (10 μM) shortened action potential duration (e.g. APD90 from 285±29 to 141±12 ms) and reduced the amplitude of the systolic Ca2+ transient. These effects were accompanied by a decrease in the L‐type Ca2+ current. These results indicate that the main adverse effect of mefloquine on the heart is a negative inotropic action. This action can be explained by blockade of L‐type Ca2+ channels. British Journal of Pharmacology (2000) 129, 323–330; doi:10.1038/sj.bjp.0703060