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J Thorac Cardiovasc Surg 2011;141:1063-1069
© 2011 The American Association for Thoracic Surgery

Evolving Technology/Basic Science

Dual actions of cilnidipine in human internal thoracic artery: Inhibition of calcium channels and enhancement of endothelial nitric oxide synthase

Li Fan, MD, PhDa,b, Qin Yang, MD, PhDc, Xiao-Qiu Xiao, MDd, Kevin L. Grove, PhDd, Yu Huang, PhDe, Zhi-Wu Chen, PhDb, Anthony Furnary, MDa, Guo-Wei He, MD, PhD, DSca,c,f,*

a Cardiovascular Research, Starr Academic Center, Providence Heart and Vascular Institute, Department of Surgery, Oregon Health and Science University, Portland, Ore
b Department of Pharmacology, Anhui Medical University, Hefei, Anhui, China
c Department of Physiology, The Chinese University of Hong Kong, Hong Kong
d Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Ore
e Department of Surgery, The Chinese University of Hong Kong, Hong Kong
f TEDA International Cardiovascular Hospital, Medical College, Nankai University, Tianjin, China

Received for publication September 10, 2009; revisions received December 11, 2009; accepted for publication January 15, 2010.

* Address for reprints: Guo-Wei He, MD, PhD, DSc, Professor of Surgery, TEDA International Cardiovascular Hospital, Medical College, Nankai University, No. 61, the 3rd Ave, TEDA, Tianjin, China, 300457. (Email: gwhe{at}cuhk.edu.hk; heguowei{at}nankai.edu.cn).

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 Ser1177 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 Ser1177 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.




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