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Acute Activation of α7-Nicotinic Receptors by Nicotine Improves Rodent Skin Flap Survival Through Nitrergic System

Abbaszadeh-kasbi, Ali MD*; Haddadi, Nazgol-Sadat MD, MPH*; Dehdashtian, Amir MD, MPH*; Afshari, Khashayar MD, MPH*; Jazaeri, Seyedeh Zarifeh MD*; Khodaei, Naser MD*; Momeni, Majid PhD; Dehpour, Ahmad-Reza PharmD, PhD*‡

doi: 10.1097/SAP.0000000000001809
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Background Recent reports have identified angiogenic, anti-inflammatory, and antioxidant properties of acute treatment with nicotine via activation of nicotinic acetylcholine receptors (nAChRs). In addition, the nitric oxide (NO) pathway is involved in ischemic reperfusion injuries.

Objectives We investigated the effects of acute pretreatment with nicotine in a rat model of random-pattern skin flap and the potential role of the NO pathway.

Methods The Sprague-Dawley rats received increasing doses of (−)-nicotine (0.5, 1, 1.5, 2, and 3 mg/kg) before the procedure. Dorsal skin flaps with caudal pedicles were elevated at the midline, and flap survival was evaluated 7 days after surgery. In addition, animals received an α7-nAChR antagonist, methyllycaconitine, with nicotine. Quantitative reverse transcription polymerase chain reaction was also applied to measure the dermal expression of α7-nAChR. Next, a nonselective NO synthase inhibitor, N-nitro-L-arginine methyl ester hydrochloride; a selective inducible NO synthase inhibitor, aminoguanidine; and an NO precursor, L-arginine, were administered with nicotine.

Results Nicotine at doses of 1, 1.5, and 2 mg/kg significantly increased flap survival, whereas the protective effects of nicotine disappeared at higher doses. Methyllycaconitine completely reversed the protective effects of nicotine and the elevated cutaneous expression of α7-nAChR in nicotine-pretreated rats. In addition, systemic administration of N-nitro-L-arginine methyl ester hydrochloride or aminoguanidine with an effective dose of nicotine caused a significant decrease in flap survival. Conversely, coinjection of a subeffective dose of L-arginine with the subeffective dose of nicotine significantly boosted its protective effects.

Conclusions Acute pretreatment with nicotine by stimulating the expression and activation of cutaneous α7-nAChR improves skin flap survival, which is partially mediated through modulation of the NO pathway.

From the *Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; and

Cancer Cell Signaling, Turku Center for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; and

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Abbaszadeh-kasbi and Haddadi have contributed equally to this project.

Conflicts of interest and sources of funding: The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article. The study was supported by a grant (96002757) from Iran National Science Foundation.

Reprints: Ahmad-Reza Dehpour, PharmD, PhD, Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Poorsina St, Enghelab Ave, Tehran 13145-784, Iran. E-mail: dehpour@yahoo.com.

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