The effects of sodium bicarbonate on thioridazine-induced cardiac dysfunction in the isolated perfused rat heart.
To determine the site of thioridazine-induced cardiotoxicity and investigate the effectiveness of sodium bicarbonate (NaHCO3) therapy, isolated rat hearts were perfused with Krebs-Henseleit-Bicarbonate buffer (KHB) at a constant coronary flow of 10 mL/min and electrically paced at 300 bpm. Experimental protocol included 15 min intervals of KHB, thioridazine (TDZ), TDZ + NaHCO3, KHB. Left ventricular (LV) pressure was measured with a balloon-tipped catheter placed in the LV via the mitral valve. Coronary perfusion pressure was monitored continuously as an index of coronary vascular resistance (CVR). LV generated pressure (LVGP) was used as our index of cardiac function and was calculated by subtracting LV end diastolic pressure (LVEDP) from LV peak systolic pressure (LVPSP). TDZ at 7,500 ng/mL was chosen as the toxic dose. NaHCO3 treatment was at an approximate sodium = 155 mM and pH = 7.60. Hearts perfused with TDZ resulted in a progressive decrease in LVGP. After 15 min of TDZ perfusion, LVGP decreased by 50%, and 75% at 30 min (n = 5). TDZ increased LVEDP and decreased LVPSP. TDZ perfusion increased CVR by 83%. In another experiment, hearts were perfused with TDZ for 15 min and then for an additional 15 min with TDZ + NaHCO3. NaHCO3 treatment transiently (approximately 5 min) increased LVGP by 23% (n=5). During NaHCO3 treatment, LVPSP increased and LVEDP and CVR decreased during the first 5 min. During the remainder of the NaHCO3 protocol, the hearts failed, similar to TDZ alone. TDZ diminished left ventricular function and promoted coronary artery vasoconstriction. NaHCO3 temporariy reversed these toxic effects.
Wang
R Y
RY
Division of Emergency Medicine, Brown University School of Medicine, Providence, RI 02903, USA.
Raymond
R M
RM
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017693:Sodium Bicarbonate / Q000494:pharmacology* / Q000627:therapeutic use; D013881:Thioridazine / Q000633:toxicity*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000517:prevention & control*
D002316:Cardiotonic Agents; D018492:Dopamine Antagonists; D017693:Sodium Bicarbonate; D013881:Thioridazine