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AMLODIPINE PREVENTS MONOCROTALINE‐INDUCED PULMONARY ARTERIAL HYPERTENSION AND PROLONGS SURVIVAL IN RATS INDEPENDENT OF BLOOD PRESSURE LOWERING
Author(s) -
Mawatari Eiichiro,
Hongo Minoru,
Sakai Akio,
Terasawa Fumiko,
Takahashi Masafumi,
Yazaki Yoshikazu,
Kinoshita Osamu,
Ikeda Uichi
Publication year - 2007
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2007.04618.x
Subject(s) - amlodipine , blood pressure , medicine , cardiology , pulmonary arterial pressure , pulmonary hypertension , anesthesia
SUMMARY1 The present study was designed to examine the role of amlodipine in preventing and reversing monocrotaline (MCT)‐induced pulmonary arterial hypertension (PAH) in rats. 2 Rats were injected with MCT (40 mg/kg, s.c.) and randomly given either 6 mg/kg per day of amlodipine in drinking water or placebo for 3 weeks. Any animals treated with MCT that survived for 3 weeks were given either amlodipine or placebo for the next 3 weeks. 3 Blood pressure was not different between the groups. Amlodipine immediately following MCT markedly inhibited PAH with severe pulmonary vascular remodelling. The survival rate at 3 weeks after treatment was increased significantly in the amlodipine group compared with the placebo group (77% vs 43%; P < 0.01). The placebo group showed markedly diminished expression of endothelial nitric oxide synthase (eNOS) protein and mRNA levels, increased numbers of proliferating cell nuclear antigen‐positive cells, enhanced mRNA expression of matrix metalloproteinase‐2 and pro‐inflammatory cytokines in the lung tissue and upregulation of P‐selectin on the endothelium of the pulmonary arteries, whereas these effects were suppressed in the amlodipine‐treated group. Furthermore, late treatment with amlodipine did not palliate PAH or improve survival. 4 Amlodipine inhibited the development of PAH and improved survival in rats independent of its effect on lowering blood pressure. These effects were associated with marked inhibition of the downregulation of eNOS and improvement of pulmonary vascular endothelial activation, as well as anti‐inflammatory, antiproliferative and antifibrotic effects in the lung tissue. However, amlodipine failed to reverse established PAH. This study may provide an insight into therapeutic strategy of amlodipine in PAH.