Felodipine inhibits free-radical production by cytokines and glucose in human smooth muscle cells.
An imbalance between nitric oxide (NO) and superoxide is importantly involved in the pathogenesis of vascular disease. Inflammatory stimuli and risk factors contribute to these alterations. Calcium antagonists and angiotensin-converting enzyme inhibitors are commonly used cardiovascular drugs. To clarify the effect of felodipine and ramiprilat on the balance of these free radicals, we stimulated human aortic smooth muscle cells (HASCs) with cytokines (human interleukin-1beta, tumor necrosis factor-alpha, lipopolysaccharide, and/or interferon-gamma) or high glucose in the presence and absence of these compounds. Felodipine, but not ramiprilat, concentration-dependently inhibited cytokine-induced NO production and NO synthase (NOS) mRNA induction. The antioxidant N-acetylcysteine also inhibited cytokine-induced NO production and induction of inducible NOS mRNA. Moreover, felodipine inhibited cytokine-induced superoxide production both in the presence and absence of an NOS inhibitor, suggesting that it acted as a superoxide scavenger and not as an inhibitor of inducible NOS induction. High glucose treatment (22 mmol/L for 48 hours) also significantly increased superoxide production in HASCs, and this increase was inhibited in a concentration-dependent manner by felodipine but not by ramiprilat. These results suggest that felodipine may exert vascular protective effects by suppressing free radical generation in human smooth muscle cells during activation of inflammatory mechanisms and diabetic conditions.
Hishikawa
K
K
Cardiology Division and Institute of Clinical Pharmacology, University Hospitals, Bern and Zürich, and Cardiovascular Research, Institute of Physiology, University Zürich, Switzerland.
Lüscher
T F
TF
D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D015736:Felodipine / Q000494:pharmacology*; D005609:Free Radicals / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis; D017257:Ramipril / Q000031:analogs & derivatives / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
D002121:Calcium Channel Blockers; D016207:Cytokines; D005609:Free Radicals; D012333:RNA, Messenger; D013481:Superoxides; D009569:Nitric Oxide; C052549:ramiprilat; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D005947:Glucose; D017257:Ramipril; D015736:Felodipine