title: Dual actions of cilnidipine in human internal thoracic artery: inhibition of calcium channels and enhancement of endothelial nitric oxide synthase.
abstract: OBJECTIVE
  Cilnidipine is a novel, long-action L/N-type dihydropyridine calcium channel blocker that has recently been used for antihypertensive therapy. We investigated the vasorelaxation effect of cilnidipine with regard to its calcium channel blockage and nitric oxide-cyclic guanosine monophosphate-dependent mechanism in human internal thoracic artery.
  
  
  METHODS
  Fresh human internal thoracic arteries taken from discarded tissues of patients undergoing coronary artery bypass surgery were studied. Concentration-relaxation curves for cilnidipine in comparison with nifedipine were studied. The expression level of endothelial nitric oxide synthase mRNA was assayed by quantitative real-time polymerase chain reaction, and the phosphorylation of endothelial nitric oxide synthase at Ser(1177) was determined by Western blotting analysis.
  
  
  RESULTS
  Cilnidipine and nifedipine caused nearly full relaxation in potassium-precontracted internal thoracic artery. Pretreatment with cilnidipine at the clinical plasma concentration significantly depressed the maximal contraction. Endothelium denudation (47.7% ± 7.0%, P < .05) and inhibition of endothelial nitric oxide synthase (48.6% ± 6.1%, P < .05) or guanylate cyclase (41.6% ± 3.8%, P < .01) significantly reduced the cilnidipine-induced endothelium-dependent relaxation (73.9% ± 6.4%). Cilnidipine increased the expression of endothelial nitric oxide synthase mRNA by 42.4% (P < .05) and enhanced phosphorylation level of endothelial nitric oxide synthase at Ser(1177) by 37.0% (P < .05).
  
  
  CONCLUSIONS
  The new generation of calcium channel antagonist cilnidipine relaxes human arteries through calcium channel antagonism and increases production of nitric oxide by enhancement of endothelial nitric oxide synthase. The dual mechanisms of cilnidipine in human arteries demonstrated in this study may prove particularly important in vasorelaxing therapy in cardiovascular diseases.
authors.affiliation: Cardiovascular Research, Starr Academic Center, Providence Heart and Vascular Institute, Department of Surgery, Oregon Health and Science University, Portland, Ore, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.forename: Xiao-Qiu
authors.initials: XQ
authors.lastname: Xiao
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Grove
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.forename: Zhi-Wu
authors.initials: ZW
authors.lastname: Chen
authors.forename: Anthony
authors.initials: A
authors.lastname: Furnary
authors.forename: Guo-Wei
authors.initials: GW
authors.lastname: He
mesh_terms: D000368:Aged; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008323:Mammary Arteries / Q000187:drug effects* / Q000201:enzymology; D008875:Middle Aged; D009543:Nifedipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D012694:Serine; C065927:cilnidipine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP; D009543:Nifedipine