Effect of pretreatment with atenolol and nifedipine on ZD6126-induced cardiac toxicity in rats.
Antivascular agents that act by destabilizing microtubules, such as ZD6126 (N-acetylcolchinol-O-phosphate), are associated with adverse cardiovascular effects, including transient hypertension, cardiac ischemia, myocardial infarction, and increases in circulating levels of markers of cardiac damage (e.g., troponins). We investigated mechanisms underlying these effects of ZD6126 in rats by continuously monitoring their heart rate and blood pressure and by assessing heart histopathology and plasma troponin T levels. ZD6126 induced acute transient hemodynamic changes (hypertension and delayed tachycardia), which were associated with statistically significant increases in circulating troponin T levels (median level 3 hours after treatment with vehicle or 12.5 mg/kg ZD6126: <9 pg/mL and 563 pg/mL, respectively; P <.001 [two-sided Wilcoxon rank sum test]) and in the incidence of left ventricular myocardial fiber necrosis (incidence 24 hours after treatment with vehicle or 12.5 mg/kg ZD6126: 0/10 rats and 9/10 rats, respectively; P <.001 [two-sided Wilcoxon rank sum test]). Pretreatment of rats with atenolol and nifedipine ameliorated the acute hemodynamic changes and prevented ZD6126-induced increases in both troponin T and myocardial necrosis but did not prevent ZD6126-induced tumor necrosis in an Hras5 tumor xenograft model in nude rats. Our findings suggest that ZD6126-induced acute hemodynamic changes are a prerequisite for cardiac damage in rats.
Gould
Sarah
S
AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, Cheshire, UK.
Westwood
F Russell
FR
Curwen
Jon O
JO
Ashton
Susan E
SE
Roberts
David W
DW
Lovick
Susan C
SC
Ryan
Anderson J
AJ
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001262:Atenolol / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000139:chemically induced / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy; D009543:Nifedipine / Q000494:pharmacology* / Q000627:therapeutic use; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000633:toxicity*; D011897:Random Allocation; D051381:Rats; D013610:Tachycardia / Q000139:chemically induced / Q000517:prevention & control*; D014183:Transplantation, Heterologous; D020107:Troponin T / Q000097:blood; D014665:Vasodilator Agents / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; D015415:Biomarkers; D002121:Calcium Channel Blockers; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D020107:Troponin T; D014665:Vasodilator Agents; D001262:Atenolol; D009543:Nifedipine