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. 2. In isolated cardiac preparations mefloquine (3 - 100 microM) did not alter the effective refractory period but at the higher concentrations resting tension increased. Developed tension was reduced by 100 microM mefloquine in left atria (from 5.8+/-1.7 to 2.2+/-0.4 mN) whereas in papillary muscles although 30 microM mefloquine reduced developed tension (from 2. 6+/-0.5 to 1.1+/-0.1 mN) subsequent addition of 100 microM caused a marked, but not sustained, positive inotropic effect (from 1.2+/-0.1 to 3.8+/-0.8 mN). 3. In single ventricular myocytes, mefloquine (10 microM) 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. 4. 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.
