Inhibition of experimental abdominal aortic aneurysm progression by nifedipine.
Agents to inhibit the renin-angiotensin system have been reported to suppress the progression of abdominal aortic aneurysm (AAA). However, the effects of calcium channel blockers (CCBs) are still unclear in terms of the inhibition of the progression of AAA. Recently, several effects of CCBs beyond those associated with blood pressure lowering have attracted much interest. In this study, we examined the effects of nifedipine on AAA progression. AAA was induced in rats by transient aortic perfusion with elastase. Then, nifedipine (10 mg/kg/day) and saline (control) were administered to rats by osmotic mini-pump. At 2 and 4 weeks, the size of the AAA, blood pressure and heart rate were measured. Then, to further explore the mechanisms of the progression of AAA, we used human vascular smooth muscle cells (VSMCs). Especially, we focused on NF-kappaB and matrix metalloproteinase-9 (MMP-9). Treatment with nifedipine resulted in a significant inhibition of the progression of AAA such as aneurismal dilation at 14 and 28 days compared to the control (week 2: control, 2.98+/-0.71 mm; nifedipine, 2.37+/-0.64 mm; p<0.05 and week 4: control, 3.28+/-0.98 mm; nifedipine, 2.41+/-0.17 mm; p<0.05). Neither nifedipine nor saline changed blood pressure and heart rate, significantly. Nifedipine (1 microM) significantly suppressed angiotensin II-induced (10(-6) M) NF-kappaB activity in VSMCs by reporter assay (p<0.01). Furthermore, nifedipine (1 microM) inhibited MMP-9 protein expression and activity. Saline did not show such inhibitory effects. Taken together, these results indicated that nifedipine inhibits the progression of experimental AAA possibly through suppression of NF-kappaB and MMP-9 activity, leading to protective effects against AAA beyond those associated with blood pressure lowering.
Tomita
Naruya
N
Division of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita 565-0871, Japan. tomita@med.kawasaki-m.ac.jp
Yamasaki
Keita
K
Izawa
Keiko
K
Kunugiza
Yasuo
Y
Osako
Mariana K
MK
Ogihara
Toshio
T
Morishita
Ryuichi
R
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D024202:Electrophoretic Mobility Shift Assay; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012965:Sodium Chloride / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014463:Ultrasonography
D002121:Calcium Channel Blockers; D016328:NF-kappa B; D012965:Sodium Chloride; D009543:Nifedipine