Calcium channel blockades exhibit anti-inflammatory and antioxidative effects by augmentation of endothelial nitric oxide synthase and the inhibition of angiotensin converting enzyme in the N(G)-nitro-L-arginine methyl ester-induced hypertensive rat aorta: vasoprotective effects beyond the blood pressure-lowering effects of amlodipine and manidipine.
Long-acting dihydropyridine calcium channel blockades have been shown to limit the progression of atherosclerosis and decrease the incidence of cardiovascular events in humans and animals. To investigate the vasoprotective effects beyond the blood pressure-lowering effects of these agents, amlodipine (20 mg/kg/ day) and manidipine (10 mg/kg/day) were administered by gavage to N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats for 2 weeks. L-NAME treatment (0.7 mg/ml in drinking water) significantly decreased the gene and protein expression of endothelial nitric oxide synthase (eNOS) and increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) mRNA levels in the aorta, as determined by Western blotting and reverse transcription (RT)-polymerase chain reaction (PCR). Amlodipine and manidipine normalized the decreased expression of eNOS gene and protein, and attenuated the overexpression of NADPH oxidase, VCAM-1, and MCP-1 mRNA. Furthermore, amlodipine and manidipine prevented the L-NAME-induced increase in the angiotensin converting enzyme (ACE) mRNA content, thereby restoring control levels in the aorta. On the other hand, hydralazine treatment had no such effect in L-NAME treated rats. Furthermore, the increased expression of manganese superoxide dismutase (Mn-SOD) by L-NAME treatment was not affected by amlodipine, manidipine, or hydralazine. We concluded that the direct anti-inflammatory and antioxidative effects of calcium channel blockades in the aorta of rats with L-NAME-induced hypertension were not likely to have been mediated by the blood pressure-lowering action of these agents, but instead these beneficial effects appear to have been mediated by an augmentation of eNOS expression and by the inhibition of the expression of ACE.
Toba
Hiroe
H
Department of Clinical Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan. toba@mb.kyoto-phu.ac.jp
Nakagawa
Yoshitsugu
Y
Miki
Shunsuke
S
Shimizu
Takahiro
T
Yoshimura
Akiko
A
Inoue
Riyako
R
Asayama
Jun
J
Kobara
Miyuki
M
Nakata
Tetsuo
T
D017311:Amlodipine / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001011:Aorta / Q000737:chemistry / Q000201:enzymology* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000032:analysis / Q000235:genetics; D004095:Dihydropyridines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D019255:NADPH Oxidases / Q000032:analysis / Q000235:genetics; D019331:NG-Nitroarginine Methyl Ester; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D009578:Nitrobenzenes; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000032:analysis / Q000235:genetics; D010879:Piperazines; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics
D000806:Angiotensin-Converting Enzyme Inhibitors; D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D000975:Antioxidants; D002121:Calcium Channel Blockers; D018932:Chemokine CCL2; D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D009578:Nitrobenzenes; D010879:Piperazines; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D017311:Amlodipine; C054218:manidipine; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; D019331:NG-Nitroarginine Methyl Ester