Nicorandil Increased the Cerebral Blood Flow Via Nitric Oxide Pathway and ATP-sensitive Potassium Channel Opening in Mice

Overview

Journal J Anesth

Specialty Anesthesiology

Date 2018 Mar 7

PMID 29508065

Citations 9

Authors

Masakazu Kotoda

Tadahiko Ishiyama

Kazuha Mitsui

Sohei Hishiyama

Takashi Matsukawa

Affiliations

Soon will be listed here.

Abstract

Purpose: Nicorandil has dual properties and acts as a nitric oxide donor and an ATP-sensitive potassium (K) channel opener. Considering its pharmacological profile, nicorandil might exert protective effects on the brain as well as on the heart. The purpose of this study was to directly evaluate the effect of nicorandil on cerebral blood flow (CBF) in mice using a transcranial Doppler method.

Methods: Under general anesthesia, the nicorandil groups received a single-bolus intraperitoneal injection of the respective doses of nicorandil (1, 5, or 10 mg/kg), while the control group received vehicle only. CBF was measured using a transcranial Doppler flowmeter. N-nitro-L-arginine methyl ester and glibenclamide were used to elucidate the underlying mechanisms.

Results: A single-bolus injection of 1 mg/kg of nicorandil increased the CBF (11.6 ± 3.6 vs. 0.5 ± 0.7%, p < 0.001) without affecting the heart rate and blood pressure. On the contrary, 5 and 10 mg/kg of nicorandil significantly decreased the cerebral blood flow by decreasing the mean blood pressure below the cerebral autoregulation range. The positive effect of 1 mg/kg of nicorandil on the cerebral blood flow was inhibited by co-administration of either N-nitro-L-arginine methyl ester or glibenclamide.

Conclusions: A clinical dose of nicorandil increases CBF without affecting systemic hemodynamics. The positive effect of nicorandil on CBF is most likely caused via both the nitric oxide pathway and K channel opening.

Citing Articles

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References

Gulati P, Singh N . Pharmacological evidence for connection of nitric oxide-mediated pathways in neuroprotective mechanism of ischemic postconditioning in mice. J Pharm Bioallied Sci. 2014; 6(4):233-40. PMC: 4231382. DOI: 10.4103/0975-7406.142951. View

. Impact of nicorandil in angina: subgroup analyses. Heart. 2004; 90(12):1427-30. PMC: 1768587. DOI: 10.1136/hrt.2003.026310. View

Shushrutha Hedna V, Ansari S, Shahjouei S, Cai P, Ahmad A, Mocco J . Validity of Laser Doppler Flowmetry in Predicting Outcome in Murine Intraluminal Middle Cerebral Artery Occlusion Stroke. J Vasc Interv Neurol. 2015; 8(3):74-82. PMC: 4535598. View

Kobayashi S, Yamaguchi S, Okada K, Suyama N, Bokura K, Murao M . Effects of nicorandil on regional cerebral blood flow in patients with chronic cerebral infarction. Preliminary communication. Arzneimittelforschung. 1992; 42(9):1086-9. View

Akai K, Wang Y, Sato K, Sekiguchi N, Sugimura A, Kumagai T . Vasodilatory effect of nicorandil on coronary arterial microvessels: its dependency on vessel size and the involvement of the ATP-sensitive potassium channels. J Cardiovasc Pharmacol. 1995; 26(4):541-7. DOI: 10.1097/00005344-199510000-00006. View

Tarkin J, Kaski J . Vasodilator Therapy: Nitrates and Nicorandil. Cardiovasc Drugs Ther. 2016; 30(4):367-378. PMC: 5658472. DOI: 10.1007/s10557-016-6668-z. View

Seino S, Miki T . Physiological and pathophysiological roles of ATP-sensitive K+ channels. Prog Biophys Mol Biol. 2003; 81(2):133-76. DOI: 10.1016/s0079-6107(02)00053-6. View

Phillips S, Whisnant J . Hypertension and the brain. The National High Blood Pressure Education Program. Arch Intern Med. 1992; 152(5):938-45. View

Heron-Milhavet L, Xue-Jun Y, Vannucci S, Wood T, Willing L, Stannard B . Protection against hypoxic-ischemic injury in transgenic mice overexpressing Kir6.2 channel pore in forebrain. Mol Cell Neurosci. 2004; 25(4):585-93. DOI: 10.1016/j.mcn.2003.10.012. View

10.

Niwa K, Kazama K, Younkin L, Younkin S, Carlson G, Iadecola C . Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein. Am J Physiol Heart Circ Physiol. 2002; 283(1):H315-23. DOI: 10.1152/ajpheart.00022.2002. View

11.

Yu D, Fan C, Zhang W, Wen Z, Hu L, Yang L . Neuroprotective effect of nicorandil through inhibition of apoptosis by the PI3K/Akt1 pathway in a mouse model of deep hypothermic low flow. J Neurol Sci. 2015; 357(1-2):119-25. DOI: 10.1016/j.jns.2015.07.010. View

12.

Ishiyama T, Dohi S, Iida H, Akamatsu S, Ohta S, Shimonaka H . Mechanisms of vasodilation of cerebral vessels induced by the potassium channel opener nicorandil in canine in vivo experiments. Stroke. 1994; 25(8):1644-50. DOI: 10.1161/01.str.25.8.1644. View

13.

Kaneko T, Saito Y, HIKAWA Y, Yasuda K, Makita K . Dose-dependent prophylactic effect of nicorandil, an ATP-sensitive potassium channel opener, on intra-operative myocardial ischaemia in patients undergoing major abdominal surgery. Br J Anaesth. 2001; 86(3):332-7. DOI: 10.1093/bja/86.3.332. View

14.

Greene N, Lee L . Modern and Evolving Understanding of Cerebral Perfusion and Autoregulation. Adv Anesth. 2017; 30(1):97-129. PMC: 5339023. DOI: 10.1016/j.aan.2012.08.003. View

15.

Brodmann M, Lischnig U, Lueger A, Stark G, Pilger E . The effect of the K+ agonist nicorandil on peripheral vascular resistance. Int J Cardiol. 2005; 111(1):49-52. DOI: 10.1016/j.ijcard.2005.06.053. View

16.

Nielsen-Kudsk J, Boesgaard S, Aldershvile J . K+ channel opening: a new drug principle in cardiovascular medicine. Heart. 1996; 76(2):109-16. PMC: 484456. DOI: 10.1136/hrt.76.2.109. View

17.

Wolf D, FERRY J, Hearron A, Froeschke M, Luderer J . The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers. Eur J Clin Pharmacol. 1993; 44(1):27-33. DOI: 10.1007/BF00315276. View

18.

Nakagawa I, Alessandri B, Heimann A, Kempski O . MitoKATP-channel opener protects against neuronal death in rat venous ischemia. Neurosurgery. 2005; 57(2):334-40. DOI: 10.1227/01.neu.0000166681.88736.86. View

19.

Sun H, Feng Z, Miki T, Seino S, French R . Enhanced neuronal damage after ischemic insults in mice lacking Kir6.2-containing ATP-sensitive K+ channels. J Neurophysiol. 2005; 95(4):2590-601. DOI: 10.1152/jn.00970.2005. View

20.

Matsuo H, Watanabe S, Segawa T, Yasuda S, Hirose T, Iwama M . Evidence of pharmacologic preconditioning during PTCA by intravenous pretreatment with ATP-sensitive K+ channel opener nicorandil. Eur Heart J. 2003; 24(14):1296-303. DOI: 10.1016/s0195-668x(03)00202-1. View