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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Inhibition of L-type Ca²⁺ channel current and negative inotropy induced by arachidonic acid in adult rat ventricular myocytes

Department of Pharmaceutical Sciences and Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Submitted 6 July 2007 ; accepted in final form 31 August 2007

We have previously shown an increase in arachidonic acid (AA) release in response to proinflammatory cytokines in adult rat ventricular myocytes (ARVM). AA is known to alter channel activities; however, its effects on cardiac L-type Ca²⁺ channel current (I_Ca,L) and excitation-contraction coupling remain unclear. The present study examined effects of AA on I_Ca,L, using the whole cell patch-clamp technique, and on cell shortening (CS) and the Ca²⁺ transient of ARVM. I_Ca,L was monitored in myocytes held at –70 mV and internally equilibrated and externally perfused with Na⁺- and K⁺-free solutions. Exposure to AA caused a voltage-dependent block of I_Ca,L concentration dependently (IC₅₀ 8.5 µM). The AA-induced inhibition of I_Ca,L is consistent with its hyperpolarizing shift in the voltage-dependent properties and reduction in maximum slope conductance. In the presence of AA, BSA completely blocked the AA-induced suppression of I_Ca,L and CS. Intracellular load with AA had no effect on the current density but caused a small depolarizing shift in the I_Ca,L activation curve, suggesting a site-specific action of AA. Moreover, intracellular AA had no effect on the extracellular AA-induced decrease in I_Ca,L. Pretreatment with indomethacin, an inhibitor of cyclooxygenase, or addition of nordihydroguaiaretic acid, an inhibitor of lipoxygenase, had no effect on AA-induced changes in I_Ca,L. Furthermore, AA suppressed CS and Ca²⁺ transients of intact ARVM with no significant effect on SR function and myofilament Ca²⁺ sensitivity. Therefore, these results suggest that AA inhibits contractile function of ARVM, primarily due to its direct inhibition of I_Ca,L at an extracellular site.

excitation-contraction coupling; cell shortening; contractility; Ca²⁺ transient