A new animal model of continuous catheterization for investigating mechanisms of arteritis associated with chemotherapy.

Although superselective continuous intra-arterial infusion has advantages for cancer therapy, intra-arterial chemotherapy is often interrupted by arterial damage due to arteritis. Therefore, an animal model must be developed to elucidate the mechanism of arteritis associated with continuous anti-cancer drug infusion. We developed a new rat model with which to investigate the causal mechanism(s) of vascular damage associated with continuous catheterization chemotherapy. Chemotherapeutic agents (fluorouracil (5-FU) or peplomycin (PEP)) were continuously administered for 7 days into the abdominal aorta of male Sprague-Dawley rats through a catheter fixed in situ. We found that the incidence of apoptotic endothelial cells of the aorta was higher nearer the tip of the catheter. The incidence of apoptosis was higher in the group treated with 5-FU than with PEP. This animal model will be useful to improve arterial damage among patients undergoing chemotherapy using continuous catheterization.

Effects of angiotensin-II receptor blocker candesartan cilexetil in rats with dilated cardiomyopathy.

We examined effects of an angiotensin-II receptor blockers, candesartan cilexetil, in rats with dilated cardiomyopathy after autoimmune myocarditis. Candesartan cilexetil showed angiotensin-II blocking action in a dose-dependent manner in rats with dilated cardiomyopathy. Twenty-eight days after immunization, surviving Lewis rats were divided into four groups and given candesartan cilexetil at 0.05 mg/kg, 0.5 mg/kg or 5 mg/kg per day (Group-C0.05, n = 15, Group-C0.5, n = 15 and Group-C5, n = 15, respectively) or vehicle alone (Group-V, n = 15). After oral administration for 1 month, the left ventricular end-diastolic pressure and heart weight/body weight ratio were lower in Group-C0.05 (13.3+/-1.1 mmHg and 3.7+/-0.2 g/kg, respectively), in Group-C0.5 (8.0+/-0.9 mmHg and 3.3+/-0.1 g/kg, respectively) and in Group-C5 (5.5+/-1 mmHg and 3.1+/-0.1 g/kg, respectively) than in Group-V (13.5+/-1.0 mmHg and 3.8+/-0.2 g/kg, respectively). The area of myocardial fibrosis was also lower in Group-C0.05 (25+/-3%), in Group-C0.5 (20+/-3%), and in Group-C5 (12+/-1%) than in Group-V (32+/-4%). Furthermore, expressions of transforming growth factor-beta1 and collagen-III mRNA were suppressed in Group-C0.05 (349+/-23% and 395+/-22%, respectively), Group-C0.5 (292+/-81% and 364+/-42%, respectively) and in Group-C5 (204+/-63% and 259+/-33%, respectively) compared with those in Group-V (367+/-26% and 437+/-18%, respectively). These results suggest that candesartan cilexetil can improve the function of inefficient heart.

Comparative effects of angiotensin II receptor blockade (candesartan) with angiotensin-converting enzyme inhibitor (quinapril) in rats with dilated cardiomyopathy.

Angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors have been shown to reduce morbidity and mortality in patients with heart failure, but their inhibitory actions on angiotensin I-induced increases in blood pressure in heart failure are not clear. Angiotensin I blocking and cardioprotective properties of the angiotensin II receptor blocker candesartan and the angiotensin-converting enzyme inhibitor quinapril were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Low-dose candesartan (0.5 mg/kg) showed the same angiotensin I blocking action as high-dose quinapril (20 mg/kg) in rats with heart failure. Twenty-eight days after immunization, surviving Lewis rats (43/58, 74%) were divided into three groups and given quinapril at 20 mg/kg per day (group Q, n = 14), candesartan at 0.5 mg/kg per day (group C, n = 14) or vehicle alone (group V, n = 15). After oral administration for 1 month, four of 15 (27%) rats in group V and two of 14 (14%) in group C died. None of the animals in group Q died. Although angiotensin II levels of the blood and the left ventricle in group V [367 +/- 26 and 437 +/- 18% versus normal rats (group N)] were significantly higher than those in group N (both p < 0.01), they were reduced in group Q (88 +/- 32 and 169 +/- 53%, both p < 0.01). The left ventricular end-diastolic pressure and the area of myocardial fibrosis were lower, and the first derivative +/-dP/dt was higher in group Q (7.0 +/- 1.7 mmHg, 9 +/- 3% and +3451+/- 170/-3182 +/- 186 mmHg/s, respectively) than in group V (16.7 +/- 1.3 mmHg, 36 +/- 6% and +2601 +/- 235/-2156 +/- 257 mmHg/s, respectively) and in group C (11.2 +/- 2.0 mmHg, 26 +/- 4% and +3063 +/- 164/-2734 +/- 174 mmHg/s, respectively). Although levels of expression of transforming growth factor beta1 and collagen III mRNA in groupV (367 +/- 26 and 437 +/- 18% versus group N) were significantly higher than those in group N (both p < 0.01), they were reduced in group Q (88 +/- 32 and 169 +/- 53%, both p < 0.01). These results suggested that although low-dose candesartan can block increases in blood pressure with circulating angiotensin I to the same extent as high-dose quinapril, it does not confer sufficient protection against injury from the renin-angiotensin system in heart failure.

Betaxolol improves the survival rate and changes natriuretic peptide expression in rats with heart failure.

The cardioprotective effects of betaxolol were studied in a rat model with heart failure induced by autoimmune myocarditis. Twenty-eight days after immunization, Lewis rats were divided into four groups; 0.1 mg/kg betaxolol per day (group 0.1), 1.0 mg/kg betaxolol per day (group 1), 10 mg/kg betaxolol per day (group 10), and vehicle (0.5% methylcellulose, group V) (all groups, n = 13). After oral administration for 1 month, the heart weight, the mRNA expression of atrial natriuretic peptide and brain natriuretic peptide in the left ventricle, the plasma atrial natriuretic peptide concentration, the mean blood pressure, the heart rate, the central venous pressure, the peak left ventricular pressure, the left ventricular end-diastolic pressure and its first derivative +/-dP/dt, and the area of myocardial fibrosis were measured. Betaxolol reduced the heart rate, the levels of atrial natriuretic peptide and brain natriuretic peptide mRNA expression and the atrial natriuretic peptide concentration [group N (normal rats), 367 +/- 4 beats/min, 100%, 100% and 78 +/- 7 pg/ml, respectively; group V, 391 +/- 9 beats/min, 761 +/- 68% versus group N, 317 +/- 42% versus group N and 4374 +/- 312 pg/ml, respectively; group 0.1, 387 +/- 10 beats/min, 621 +/- 78%, 288 +/- 41% and 2875 +/- 331 pg/ml, respectively; group 1, 323 +/- 9 beats/min, 442 +/- 84%, 148 +/- 12% and 884 +/- 51 pg/ml, respectively; and group 10, 312 +/- 8 beats/min, 97 +/- 18%, 92 + 9% and 453 +/- 53 pg/ml, respectively], and increased survival (group V, 62%; group 0.1, 69%; groups N, 1 and 10, 100%). Betaxolol did not significantly alter the heart weight, the hemodynamic parameters or the area of fibrosis. These observations suggest that betaxolol may improve the survival rate by reducing sudden death and changing the atrial natriuretic peptide and brain natriuretic peptide mRNA expression in patients with heart failure.