CARDIAC NORADRENERGIC MECHANISMS MEDIATE GABA-ENHANCED OUABAIN CARDIOTOXICITY

Peripherally administered gamma-aminobutyric acid (GABA) alters cardio vascular function and has been reported to enhance ouabain-induced car diotoxicity in vivo. Control and reserpinized rat hearts were perfused in vitro to determine if GABA directly evokes bradycardia by GABA(A) receptors, interacts with ouabain, and if noradrenergic mechanisms are required. Also, double-staining immunohistochemistry was employed to determine whether GABA-ergic and noradrenergic synthetic enzymes were juxtaposed within atrial tissue. The main results were as follows. GAB A produced a dose-dependent bradycardia (p < 0.05) by stimulating GABA (A) receptors in Langendorff-perfused hearts. Reserpinized hearts were unresponsive (p > 0.05) to GABA, except at the highest dose (20 mg/ml ). Oubain-induced cardiotoxicity was enhanced (p < 0.05) by GABA in is olated control, but not reserpinized hearts. Lastly, glutamic acid dec arboxylase and tyrosine hydroxylase immunoreactivities were in close p roximity in atrial slices. Collectively, the results document that GAB A causes bradycardia and enhances ouabain cardiotoxicity by modulating noradrenergic mechanisms in the isolated rat heart. Since the synthet ic enzymes for GABA and norepinephrine were in close proximity in atri al tissue, these transmitters may interact under physiological conditi ons.