Cardiovascular Toxicity Induced by Chronic Vincristine Treatment

FIGURE 1. (A) Systolic arterial blood pressure (SBP), (B) diastolic blood pressure (DBP), and (C) heart rate (HR) of anesthetized animals chronically treated with saline (saline treatment) or vincristine (vincristine treatment) and two weeks post-treatment (sequelae saline and sequelae vincristine). Data represent the mean ± SEM, n = 6–13 animals per experimental group. A one-way ANOVA followed by Bonferroni’s multiple comparison test was used for statistical analysis.

FIGURE 2. Basal values of (A) left ventricular developed pressure (LVDP), (B) end-diastolic pressure (EDP), and (C) coronary perfusion pressure (CPP) of isolated hearts from animals chronically treated with saline (saline treatment) or vincristine (vincristine treatment) and two weeks post-treatment (sequelae saline and sequelae vincristine). Data represent the mean ± SEM, n = 8–12 preparations per experimental group. A one-way ANOVA followed by Bonferroni’s multiple comparison test was used for statistical analysis.

FIGURE 3. (A) Concentration-response curve of phenylephrine (10−9 M–10−5 M), (B) concentration-response curve of carbachol (10−9 M–10−4 M), and (C) concentration-response curve of sodium nitroprusside (SNP) (10−9 M–10−6 M) in isolated rat aorta rings from animals chronically treated with saline (saline treatment, white squares) or vincristine (vincristine treatment, black squares). Values are expressed as mean ± SEM, n = 11–21 preparations per experimental group. A two-way ANOVA followed by the Bonferroni test was used for statistical analysis (***p < 0.001, *p < 0.05, vincristine treatment vs. saline treatment).

FIGURE 4. (A) Concentration-response curve of phenylephrine (10−9 M–10−5 M), (B) concentration-response curve of carbachol (10−9 M–10−4 M), and (C) concentration-response curve of sodium nitroprusside (SNP) (10−9 M–10−6 M) in isolated rat aorta rings from animals two weeks post-treatment with saline (sequelae saline, white circles) or vincristine (sequelae vincristine, black circles). Values are expressed as mean ± SEM, n = 9–12 preparations per experimental group. A two-way ANOVA followed by the Bonferroni test was used for statistical analysis.

FIGURE 5. (A) Concentration-response curve of phenylephrine (10–80 nmol), (B) concentration-response curve of carbachol (3·10−10 mol–3·10−5 mol), and (C) concentration-response curve of sodium nitroprusside (SNP) (3·10−11 mol–3·10−6 mol) in perfused mesenteric bed from animals chronically treated with saline (saline treatment, white squares) or vincristine (vincristine treatment, black squares). Values are expressed as mean ± SEM, n = 9–13 preparations per experimental group. A two-way ANOVA followed by the Bonferroni test was used for statistical analysis (***p < 0.001, **p < 0.01, vincristine treatment vs. saline treatment).

FIGURE 6. (A) Concentration-response curve of phenylephrine (10–80 nmol), (B) concentration-response curve of carbachol (3·10−10 mol–3·10−5 mol), and (C) concentration-response curve of sodium nitroprusside (SNP) (3·10−11 mol–3·10−6 mol) in perfused mesenteric bed from animals two weeks post-treatment with saline (sequelae saline, white circles) or vincristine (sequelae vincristine, black circles). Values are expressed as mean ± SEM, n = 6–8 preparations per experimental group. A two-way ANOVA followed by the Bonferroni test was used for statistical analysis.

FIGURE 7. Effect of vincristine treatment and two weeks post-treatment (sequelae) on TNFα (A), eNOS (B), connexin 43 (C), and iNOS (D) protein expression in the left ventricle. Representative western blots show bands during vincristine treatment and 2 weeks post-treatment (sequelae). Densitometric evaluations of protein levels were obtained from 4–6 different animals. Data represent the mean ± SEM. Saline vs. vincristine (*p < 0.05, *p < 0.05 and ***p < 0.001).

FIGURE 8. Effects of vincristine treatment and two-week suspension of the treatment (sequelae) on TNFα (A), eNOS (B), connexin 43 (C), and iNOS (D) protein expression in the aorta. Representative western blots show bands during vincristine treatment and 2 weeks after treatment (sequelae). Densitometric evaluations of protein levels were obtained from 5–6 different animals. Data represent the mean ± SEM. Saline vs. vincristine (*p < 0.05), sequelae saline vs. sequelae vincristine (+ p < 0.05).

FIGURE 9. Immunohistochemistry of mesenteric vessels. Expression of TNFα (A–C), eNOS (D–F), and connexin 43 (G–I) and iNOS (J–L). Animals treated with saline (A, D, G, J), vincristine (B, E, H, K), and 2 weeks after vincristine administration (C, F, I, L). Bar: 100 μm.

FIGURE 10. Effect of vincristine in the structure of the heart (A–C), mesenteric vessels (D–F), and aorta (G–I). Masson’s trichrome stain of saline (A, D, G), animals treated with vincristine (B, E, H) or vincristine-treated animals 2 weeks after treatment (C, F). Bar: 100 μm. Mean thickness of the aortic tunica media (I), obtained from 4–6 different animals. Data represent the mean ± SEM. Saline vs. vincristine (***p < 0.001).

FIGURE 11. Effect of vincristine treatment and 2-week suspension of treatment (sequelae) on malondialdehyde (MDA) in plasma. Data represent the mean ± SEM, n = 4–6 animals per experimental group. A one-way ANOVA followed by Bonferroni’s multiple comparison test was used for statistical analysis.