Modulation of the negative inotropic effect of haloperidol by drugs with positive inotropic effects in isolated rabbit heart.
Haloperidol is a typical antipsychotic drug with inhibitory effects on dopamine and calcium homeostasis. In this study, the effect of haloperidol on the inotropism of rabbits' isolated heart was investigated by measuring the isovolumetric left ventricular pressure using a balloon in a modified Langendorff perfusion apparatus. Haloperidol at 0.01-0.3 micromol/l induced a negative inotropic effect (E(max) = 77.95 +/- 0.19; EC(50) = 0.043 +/- 0.002 micromol/l). The effect of haloperidol was decreased by Ca(2+) (E(max) = 42.93 +/- 3.22; EC(50) = 0.37 +/- 0.07 micromol/l; pD'(2) = 7.01 +/- 0.16), Bay K 8644 (E(max) = 30.75 +/- 1.33; EC(50) = 10.43 +/- 1.5 micromol/l, pD'(2) = 7.13 +/- 0.12), and digoxin (E(max ) = 42.03 +/- 3.72, EC(50) = 0.32 +/- 0.05 micromol/l, pD'(2) = 6.81 +/- 0.14). The effect of haloperidol was also reduced by norepinephrine (E(max) = 37.16 +/- 1.84; EC(50) = 1.73 +/- 0.24 micromol/l, pD'(2) = 6.97 +/- 0.08) and dopamine (E(max) = 35.68 +/- 2.78; EC(50) = 0.69 +/- 0.01 micromol/l, pD'(2 )7.48 +/- 0.15). However, the effect of haloperidol was nonsignificantly reduced by dobutamine (E(max) = 58.89 +/- 5.18; EC(50) = 0.15 +/- 0.06 micromol/l, pD'(2) = 5.88 +/- 0.47). These results show that the drugs that increase the influx of Ca(2+) into the cardiomyocyte decrease the negative inotropic effect of haloperidol, suggesting that the effect of haloperidol could be mediated via mechanisms involving actions on Ca(2+) entry into the cardiomyocyte. Haloperidol should be used carefully when prescribed for patients with cardiovascular disorders.
Hatip-Al-Khatib
Izzettin
I
Department of Pharmacology, Faculty of Medicine, Pamukkale University, Denizli, Turkey. izfunhatip2000@yahoo.com
Bolukbaşi-Hatip
Funda
F
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D003864:Depression, Chemical; D004077:Digoxin / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011817:Rabbits; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D014150:Antipsychotic Agents; D002120:Calcium Channel Agonists; D002316:Cardiotonic Agents; D004280:Dobutamine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D004077:Digoxin; D006220:Haloperidol; D002118:Calcium; D004298:Dopamine; D009638:Norepinephrine