The effect of hypertonic sodium and dantrolene on propranolol cardiotoxicity.
OBJECTIVE
To evaluate whether measures that lower cytosolic calcium (Ca) can reverse propranolol (PROP) toxicity in the isolated, perfused rat heart.


METHODS
Isolated rat hearts were perfused on a Langendorff apparatus with Krebs-Henseleit-bicarbonate (KHB) buffer solution. Toxicity was produced by perfusing the hearts with PROP (5 micrograms/mL) for 30 minutes. Subsequently, the hearts were treated for 30 minutes with buffer containing PROP plus experimental treatment. Three treatments were chosen: hypertonic sodium (Na) (160 mmol), to stimulate Na-Ca exchange, dantrolene (DAN) (10 mumol), to inhibit Ca release from sarcoplasmic reticulum, and combined hypertonic Na and DAN. The hearts were paced after 20 minutes of treatment. Heart rate (HR), left ventricular peak systolic pressure (LVP), the first derivative of LVP (dP/dt), and coronary flow were measured.


RESULTS
PROP decreased HR and rendered the hearts refractory to pacing. PROP did not alter dP/dt. PROP increased LVP consistent with increased cytosolic Ca. Combined hypertonic Na and DAN treatment restored the ability to pace PROP-toxic hearts to the basal HR. Individually, hypertonic Na or DAN treatment partially restored the ability to pace toxic hearts. As experimental treatments increased HR, dP/dt and LVP decreased, consistent with decreased cytosolic Ca availability.


CONCLUSIONS
These data are consistent with the hypothesis that bradycardia during beta-blocker cardiotoxicity is mediated by altered Ca homeostasis.
Kerns
W
W
Department of Emergency Medicine, Carolinas Medical Center, Charlotte, NC 28232-2861, USA.
Ransom
M
M
Tomaszewski
C
C
Raymond
R
R
D000319:Adrenergic beta-Antagonists / Q000009:adverse effects*; D000818:Animals; D002118:Calcium / Q000502:physiology; D002304:Cardiac Pacing, Artificial; D003600:Cytosol / Q000187:drug effects; D003620:Dantrolene / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D011433:Propranolol / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000494:pharmacology*; D017725:Ventricular Pressure / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D009125:Muscle Relaxants, Central; D012964:Sodium; D011433:Propranolol; D003620:Dantrolene; D002118:Calcium