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

Abstract

1 To examine the possible cardiotoxicity of the antimalarial drug me¯oquine, increasing doses (0.3 ± 30 mg kg 71 ) were given i.v. to anaesthetized guinea-pigs. Me¯oquine did not alter ECG intervals signi®cantly but gradually increased systolic blood pressure (at 3 mg kg 71 ) then had a depressor e ect (at 10 mg kg 71 ). Death due to profound hypotension, probably resulting from cardiac contractile failure or AV block, occurred after either 10 mg kg 71 (2/6) or 30 mg kg 71 (4/6) me¯oquine. 2 In isolated cardiac preparations me¯oquine (3 ± 100 mM) did not alter the e ective refractory period but at the higher concentrations resting tension increased. Developed tension was reduced by 100 mM me¯oquine in left atria (from 5.8+1.7 to 2.2+0.4 mN) whereas in papillary muscles although 30 mM me¯oquine reduced developed tension (from 2.6+0.5 to 1.1+0.1 mN) subsequent addition of 100 mM caused a marked, but not sustained, positive inotropic e ect (from 1.2+0.1 to 3.8+0.8 mN). 3 In single ventricular myocytes, me¯oquine (10 mM) 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 e ects were accompanied by a decrease in the L-type Ca 2+ current. 4 These results indicate that the main adverse e ect of me¯oquine on the heart is a negative inotropic action. This action can be explained by blockade of L-type Ca 2+ channels.

Potent block of Cx36 and Cx50 gap junction channels by mefloquine

“…Previous studies also indicate nonspecific actions: mefloquine has been shown to block L-type calcium channels and delayed rectifier channels in cardiac myocytes, volume-and calcium-activated chloride channels, and ATP-sensitive potassium channels. IC 50 values for blockade of these channels in single, dissociated cells, a situation similar to our studies on N2A cells, are 3-to 15-fold higher than those required for Cx36 blockade (23)(24)(25)(26). Because of these effects, use of mefloquine to study roles of Cx36 and Cx50 should be accompanied by proper controls.…”

Serotonin Evokes Endocannabinoid Release and Retrogradely Suppresses Excitatory Synapses

“…Although mefloquine slightly reduced the extent of the suppression (45 Ϯ 5% of baseline; n ϭ 4 cells) (Fig. 4 E) compared with control (20 Ϯ 4%of baseline; n ϭ 4 cells), this reduction in the extent of suppression might reflect the numerous nonspecific effects of mefloquine (Coker et al, 2000;Gribble et al, 2000;Kang et al, 2001;Cruikshank et al, 2004;Caridha et al, 2008).…”

Primaquine revisited six decades after its discovery

“…Several anti-malarial agents inhibit diverse types of voltagegated ionic channels [111][112][113], as well as acetylcholine (Ach) receptors that operate in potassium current (I KAch ) through muscarinic potassium channels, alone or linked to GTP-proteins (guanosine-5 0 -triphosphate-linked proteins) [111]. Distinct anti-malarials may exhibit anticholinergic activity via different molecular mechanisms; PQ and quinidine inhibit the potassium current by blockade of muscarinic receptors [111].…”