Effects of cilnidipine on nitric oxide and endothelin-1 expression and extracellular signal-regulated kinase in hypertensive rats

• Published in: European journal of pharmacology 2001-06, Vol.422 (1), p.149-157
• Main Authors: Kobayashi, Naohiko, Mori, Yousuke, Mita, Shin-ichiro, Nakano, Shigefumi, Kobayashi, Tsutomu, Tsubokou, Yusuke, Matsuoka, Hiroaki
• Format: Article
• Language: English
• Subjects: Animals; Antianginal agents. Coronary vasodilator agents; Biological and medical sciences; Blotting, Western; Body Weight - drug effects; Ca 2+ channel antagonist; Calcium Channel Blockers - pharmacology; Cardiovascular system; Coronary Vessels - drug effects; Dihydropyridines - pharmacology; Endothelin-1; Endothelins - genetics; Extracellular signal-regulated kinase; Gene Expression Regulation - drug effects; Heart Ventricles - growth & development; Heart Ventricles - metabolism; Hemodynamics - drug effects; Hypertension - enzymology; Hypertension - genetics; Hypertension - physiopathology; Male; Medical sciences; Mitogen-Activated Protein Kinase 1 - drug effects; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - drug effects; Mitogen-Activated Protein Kinases - metabolism; Nitric oxide (NO); Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type III; Organ Size - drug effects; Pharmacology. Drug treatments; Protein Precursors - genetics; Rat; Rats; Rats, Wistar; Receptor, Endothelin A; Receptors, Endothelin - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(01)01067-6

We evaluated the effects of cilnidipine, a long-acting Ca 2+ channel antagonist, on endothelial nitric oxide synthase (eNOS), preproendothelin-1 and endothelin ET A receptor expression in the left ventricle, and evaluated the relations between these effects and coronary microvascular remodeling and extracellular signal-regulated kinases belonging to one subfamily of mitogen-activated protein kinases in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Cilnidipine (DOCA-cilnidipine, 1 mg/kg/day, subdepressor dose) or vehicle (DOCA-vehicle) was given after induction of DOCA-salt hypertension for 5 weeks. The eNOS mRNA and protein expression in the left ventricle was significantly lower in DOCA-vehicle than in control rats and significantly higher in DOCA-cilnidipine than in DOCA-vehicle rats. Preproendothelin-1 and endothelin ET A receptor expression levels and phospho-p42/p44 extracellular signal-regulated kinase activities were significantly increased in DOCA-vehicle compared with control rats and significantly suppressed in DOCA-cilnidipine compared with DOCA-vehicle rats. DOCA-vehicle rats showed a significant increase in the wall-to-lumen ratio, perivascular fibrosis and myocardial fibrosis, with all these parameters being significantly improved by cilnidipine. These results led us to conclude that phospho-p42/p44 extracellular signal-regulated kinase activities may contribute to the coronary microvascular remodeling of DOCA rats and that protective effects of cilnidipine on cardiovascular remodeling may be at least in part mediated by an increased eNOS expression and a decreased endothelin-1 and endothelin ET A receptor expression in the left ventricle.