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 μ M ) did not alter the effective refractory period but at the higher concentrations resting tension increased. Developed tension was reduced by 100 μ M mefloquine in left atria (from 5.8±1.7 to 2.2±0.4 mN) whereas in papillary muscles although 30 μ M mefloquine reduced developed tension (from 2.6±0.5 to 1.1±0.1 mN) subsequent addition of 100 μ M 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 μ M ) shortened action potential duration (e.g. APD 90 from 285±29 to 141±12 ms) and reduced the amplitude of the systolic Ca 2+ transient. These effects were accompanied by a decrease in the L‐type Ca 2+ 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 Ca 2+ channels.British Journal of Pharmacology (2000) 129 , 323–330; doi: 10.1038/sj.bjp.0703060