Studies on the cardiotoxicity of noradrenaline in isolated rabbit hearts.
The concentration-dependent toxic effects of exogenous noradrenaline (NA, CAS 51-41-2) on acute regional myocardial ischemia (MI) was investigated with and without alpha- and beta-adrenoceptor blockade. Electrically-driven rabbit Langendorff-hearts with depleted catecholamine stores were used (reserpin 7.0 mg/kg i.p. 16-24 h before preparation, constant pressure: 70 cm H2O, Tyrode solution, Ca2+ 1.8 mmol/l). Repetitive MI, separated by a reperfusion period of 50 min, was induced by coronary artery branch ligature, and quantitated from epicardial NADH-fluorescence photography. Starting after a reperfusion period of 20 min, hearts were treated with exogenous NA (10(-7), 10(-6) or 10(-5) mol/l). Adrenoceptors were blocked by propranolol (10(-6) mol/l) and phentolamine (10(-6) mol/l). Without adrenoceptor blockers, NA 10(-6) mol/l induced an increase in left ventricular pressure and a reduction in the relative coronary flow. Concomitantly, MI was enhanced. After adrenoceptor blockade, NA 10(-7) or 10(-6) mol/l had no influence on functional parameters. MI was not affected by NA 10(-7) mol/l, but MI was significantly enhanced by NA 10(-6) mol/l. MI enhancement by NA 10(-6) mol/l was completely prevented by superoxide dismutase (30 U/ml). Functional effects of NA 10(-5) mol/l were not completely inhibited by adrenoceptor blockers at the concentrations used, and arrythmias were observed. MI was also enhanced by NA 10(-5) mol/l.


CONCLUSIONS
Deleterious effects on MI, that are independent on functional effects, are induced by NA in a micromolar concentration. These direct toxic effects are mediated by superoxide anion radicals. In lower concentrations (10(-7) mol/l), there is no evidence for direct toxic actions of NA independent of functional effects. MI enhancement by NA 10(-5), or 10(-6) mol/l without adrenoceptor blockers may have been caused in part by functional and arrythmogenic effects and/or through the generation of oxygen free radicals.
Institut für Pharmakologie, Universität zu Köln, Köln, Germany.
Alexis F E
AF
Rump
Jörg
J
Schierholz
Wolfgang
W
Klaus
D000316:Adrenergic alpha-Agonists / Q000633:toxicity*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004558:Electric Stimulation; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008856:Microscopy, Fluorescence; D017202:Myocardial Ischemia / Q000139:chemically induced / Q000473:pathology; D009243:NAD / Q000378:metabolism; D009638:Norepinephrine / Q000633:toxicity*; D010477:Perfusion; D010496:Pericardium / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D016277:Ventricular Function, Left / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D009243:NAD; D009638:Norepinephrine