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

1 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 mu M) did not alter the effective refractory period but at the higher concentrations resting tension increased. Developed tension was reduced by 100 mu M mefloquine in left atria (from 5.8 +/- 1.7 to 2.2 +/- 0.4 mN) whereas in papillary muscles although 30 mu M mefloquine reduced developed tension (from 2.6 +/- 0.5 to 1.1 +/- 0.1 mN) subsequent addition of 100 mu M 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 mu M) shortened action potential duration (e.g. APD(90) 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. 4 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.