Dose-dependent prevention of fibrosis in aorta of salt-loaded stroke-prone spontaneously hypertensive rats by combined delapril and indapamide treatment.
Combined treatment with the angiotensin-converting enzyme (ACE) inhibitor delapril and the diuretic indapamide prevented vascular damage in vital organs of salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp). Whether the changes occurring after long-term hypertension could also be modulated in large arteries was investigated. Two-month-old SHRsp were salt loaded and treated with the drug regimen until they reached 50% mortality or around midlife. In a first experiment, delapril (12 mg/kg) and indapamide (1 mg/kg) were administered daily separately or in combination. In the second dose-finding experiment, delapril (6, 3, 1.5 mg/kg) and indapamide (0.5, 0.25, 0.125 mg/kg) in decreasing dose combinations were analyzed. Ultrastructural, histomorphometric, and biochemical studies were performed on the thoracic aorta. When compared with delapril (12 mg/kg) or indapamide (1 mg/kg) administered individually for 5 months, the combination 12 + 1 mg/kg was able to prevent the increase in extracellular matrix deposition observed in other treatment groups, as assessed by histomorphometry or 4-OH-proline biochemical determination. In the second experiment, a half-dose (delapril 6 mg/kg + indapamide 0.5 mg/kg) combination was similarly effective in counteracting fibrosis, but the other doses progressively failed. In the first experiment, the combination had a stabilizing effect on hypertension and stimulated diuresis. In the second experiment, arterial blood pressure values and sodium balance were not consistently affected by the treatments that antagonized fibrosis (i.e., delapril 6 mg/kg + indapamide 0.5 mg/kg and, less efficiently, delapril 3 mg/kg + indapamide 0.25 mg/kg). These results suggest that indapamide interacts with ACE inhibitors to limit aortic fibrosis independent of any well-established mechanism.
Department of Biomedical Sciences, University of Modena and Reggio Emilia, Italy.
Miranda Baccarani
MB
Contri
Francesca
F
Taparelli
Monica
M
Miselli
Giada
G
Pedrazzi
Barbara
B
Bacchelli
Giuseppe
G
Biagini
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005355:Fibrosis; D006973:Hypertension / Q000473:pathology / Q000517:prevention & control*; D007189:Indans / Q000008:administration & dosage*; D007190:Indapamide / Q000008:administration & dosage*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology
D007189:Indans; D007190:Indapamide; C047759:delapril