Biphasic inotropic effects of methamphetamine and methylphenidate on ferret papillary muscles

Methamphetamine and methylphenidate are structurally related agents that have direct negative inotropic (NIEs) and indirect positive inotropic effects (PIEs) in cardiac tissues. This study was designed to determine and compare cellular mechanisms of the NIEs of methamphetamine and methylphenidate by using a mammalian animal model. Isometric tension was measured in ferret papillary muscles in physiologic salt solution. A subset of muscles was loaded with the bioluminescent calcium indicator, aequorin. Further, to investigate the NIE of methamphetamine, the dose-response relations to isoproterenol, histamine, and calcium were measured with or without methamphetamine (2 x 10(-4) M), after adrenergic neuronal blockade with reserpine. Both methamphetamine and methylphenidate had direct NIEs at higher doses (>10(-4) M). A shift in the slope of the isoproterenol dose-response curve suggested involvement of the beta-adrenoceptor pathways. The direct NIE of methylphenidate was more prominent. Our results suggest that the negative inotropic effects of methamphetamine and methylphenidate may be important with clinically used and abused concentrations of these drugs and may be difficult to reverse with beta-adrenergic inotropic agents in cases of toxicity.