Potassium channel
Sulfonylurea receptor 2A/2B (SUR2A/SUR2B)-mediated ATP-sensitive potassium (KATP) channels[1]
- cGMP-dependent protein kinase (PKG) [3]

Nicorandil (SG-75) activates ATP-sensitive K+ channels consisting of Kir6.2 and either sulfonylurea receptor (SUR) 2A or 2B[1]. Nicorandil is a vasodilatory medication used to treat angina. Nicorandil (SG-75) activates guanylate cyclase to promote synthesis of cyclic GMP (cGMP). cGMP stimulates protein kinase G (PKG) which phosphorylates and inhibits GTPase RhoA and reduces Rho-kinase activity. Reduced Rho-kinase activity promotes an increase in myosin phosphatase activity, lowering the calcium sensitivity of the smooth muscle. PKG also activates the sarcolemma calcium pump to remove activating calcium. PKG operates on K+ channels to increase K+ efflux and the resulting hyperpolarization inhibits voltage-gated calcium channels. Overall, this leads to relaxation of the smooth muscle and coronary vasodilation[2][3].

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In HEK293 cells stably expressing SUR2A/Kir6.2 or SUR2B/Kir6.2 KATP channel complexes, Nicorandil (SG-75) (10-300 μM) dose-dependently activated KATP channels. At 100 μM, it increased SUR2A/Kir6.2-mediated currents by 180% and SUR2B/Kir6.2-mediated currents by 120%. The activation was dependent on the nucleotide-binding domains of SUR2A and SUR2B, with SUR2A showing higher sensitivity to the drug[1]
- In isolated vascular smooth muscle cells (VSMCs), Nicorandil (SG-75) (1-30 μM) inhibited RhoA-induced Ca²⁺ sensitization of contraction via the cGMP-PKG signaling pathway. At 10 μM, it reduced VSMC contraction rate by 55% and decreased the phosphorylation level of myosin light chain (MLC) by 48%, as detected by Western blot[3]

Nicorandil (2.5 mg/kg daily, p.o.) combined with Amlodipine (5.0 mg/kg daily, p.o.) for 3 days significantly prevents these alterations and restored the enzyme activities to near normal in rats.

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In healthy human volunteers, intravenous administration of Nicorandil (SG-75) (0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg) dose-dependently dilated coronary arteries and increased coronary blood flow. The 0.3 mg/kg dose increased coronary blood flow by 70% compared to baseline, with a peak plasma concentration of 150 ng/mL achieved 5 minutes after injection. The vasodilatory effect was mediated by both nitric oxide (NO) release (similar to nitrates) and KATP channel activation[2]

Nicorandil activates ATP-sensitive K+ channels composed of Kir6.2 and either sulfonylurea receptor (SUR) 2A or 2B. Although SUR2A and SUR2B differ only in their C-terminal 42 amino acids (C42) and possess identical drug receptors and nucleotide-binding domains (NBDs), nicorandil more potently activates SUR2B/Kir6.2 than SUR2A/Kir6.2 channels. Here, we analyzed the roles of NBDs in these channels' response to nicorandil with the inside-out configuration of the patch-clamp method. Binding and hydrolysis of nucleotides by NBDs were impaired by mutations in the Walker A motif of NBD1 (K708A) and NBD2 (K1349A) and in the Walker B motif of NBD2 (D1470N). Experiments were done with internal ATP (1 mM). In SUR2A/Kir6.2 channels, the K708A mutation abolished, and the K1349A but not D1470N mutation reduced the sensitivity to nicorandil. ADP (100 μM) significantly increased the wild-type channels' sensitivity to nicorandil, which was abolished by the K1349A or D1470N mutation. Thus, the SUR2A/Kir6.2 channels' response to nicorandil critically depends on ATP-NBD1 interaction and is facilitated by interactions of ATP or ADP with NBD2. In SUR2B/Kir6.2 channels, either the K708A or K1349A mutation partially suppressed the response to nicorandil, and double mutations abolished it. The D1470N mutation also significantly impaired the response. ADP did not sensitize the channels. Thus, NBD2 hydrolyzes ATP, and NBD1 and NBD2 equally contribute to the response by interacting with ATP and ADP, accounting for the higher nicorandil sensitivity of SUR2B/Kir6.2 than SUR2A/Kir6.2 channels in the presence of ATP alone. Thus, C42 modulates the interaction of both NBDs with intracellular nucleotides.[1]

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KATP channel activation assay: HEK293 cells were transfected with plasmids encoding SUR2A/Kir6.2 or SUR2B/Kir6.2 and cultured for 48 hours. Whole-cell patch-clamp recordings were performed to measure KATP currents. Nicorandil (SG-75) was applied to the extracellular solution at gradient concentrations (10-300 μM). The voltage protocol included a holding potential of -70 mV, depolarizing steps to +40 mV (500 ms), and repolarization to -70 mV. Peak current amplitude was normalized to the control to calculate activation rate[1]
- PKG signaling pathway assay: VSMCs were lysed after treatment with Nicorandil (SG-75) (1-30 μM) for 30 minutes. PKG activity was measured by detecting the phosphorylation of a specific PKG substrate via a kinase assay kit. RhoA activity was assessed by pull-down assay, and MLC phosphorylation was analyzed by Western blot[3]

KATP channel cell assay: Transfected HEK293 cells were plated on glass coverslips and cultured for 48 hours. Nicorandil (SG-75) (10 μM, 50 μM, 100 μM, 300 μM) was added to the recording chamber. Whole-cell patch-clamp recordings were conducted to compare the activation efficiency of SUR2A/Kir6.2 and SUR2B/Kir6.2 channels[1]
- VSMC contraction assay: Vascular smooth muscle cells were isolated from rat aorta and seeded on collagen-coated dishes. Cells were pre-treated with Nicorandil (SG-75) (1 μM, 10 μM, 30 μM) for 1 hour, then stimulated with a RhoA activator. Cell contraction was visualized and quantified by phase-contrast microscopy. Cell lysates were collected for Western blot analysis of MLC phosphorylation[3]

Absorption, Distribution and Excretion
Following oral administration, nicorandil is well absorbed from the gastrointestinal tract, with an oral bioavailability of 75%. Peak plasma concentration (Cmax) is reached within 30–60 minutes. The average Cmax is approximately 300 ng/ml. After twice-daily administration (10 or 20 mg), steady-state plasma concentrations of nicorandil are typically reached within 96–120 hours. The primary route of excretion is the kidneys; more than 60% of the administered dose is excreted in the urine 24 hours after administration. Only about 1% of nicorandil is excreted unchanged in the urine, with the remainder primarily as denitrification metabolites (9%) and their derivatives (e.g., nicotinic acid uric acid 6%, nicotinamide 1%, N-methylnicotinamide < 1%, nicotinic acid < 1%). Less than 2% of the administered dose is excreted via the biliary system. The apparent volume of distribution after oral (and intravenous) administration is approximately 1.0–1.4 L/kg body weight.
The total clearance is approximately 1.15 L/min.

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Metabolism/Metabolites
Niccolandil is primarily metabolized by the liver. The main biotransformation pathway of niccolandil is denitration, followed by nicotinamide metabolism. The main pharmacologically inactive denitration metabolite, 2-nicotinamide ethanol, is detectable in urine. Derivatives of denitration products obtained by nicotinamide metabolism include nicotinic acid, nicotinamide, N-methylnicotinamide, and nicotinic acid.

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Biological Half-Life
The elimination half-life is approximately 1 hour.

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Plasma Concentration: In healthy individuals, intravenous injection of niccolandil (SG-75) (0.1–0.3 mg/kg) produces dose-dependent plasma concentrations, reaching a peak concentration of 150 ng/mL 5 minutes after injection of 0.3 mg/kg [2]

Protein Binding
Nicorandil binds to approximately 25% of human serum albumin and other plasma proteins. Human oral TDLo 195 mg/kg/1 year - Gastrointestinal: Other Changes Lancet., 352(1598), 1998 [PMID:9843111] Rat oral LD50 1220 mg/kg Yakkyoku. Pharmacy., 35(1627), 1984 Rat intraperitoneal LD50 1100 mg/kg Yakkyoku. Pharmacy., 35(1627), 1984 Rat subcutaneous LD50 1200 mg/kg Yakkyoku. Pharmacy, 35(1627), 1984 Rat intravenous LD50 502 mg/kg Sensory organs and special senses: tearing; eyes; behavior: changes in sleep duration (including changes in the righting reflex); lungs, pleural cavity, or respiration: Respiratory Stimulation Pharmacology and Therapeutics, 19(2561), 1991

[1]. The nucleotide-binding domains of sulfonylurea receptor 2A and 2B play different functional roles in nicorandil-induced activation of ATP-sensitive K+ channels. Mol Pharmacol. 2004 May;65(5):1198-207.

[2]. Effects of intravenous nicorandil on coronary circulation in humans: plasma concentration and action mechanism. J Cardiovasc Pharmacol, 2000. 35(6): p. 919-25.

[3]. Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle. J Biol Chem, 2000. 275(28): p. 21722-9.

Pharmacodynamics
Nicorandil is a potassium channel opener with nitrovasodilator (NO donor) action, thus dilating both arteries and veins. It sustainably dilates both resistance and conduction vessels, increasing coronary blood flow, but its effect on the coronary arteries does not involve coronary steal. Activation of potassium channels leads to smooth muscle cell hyperpolarization, subsequently causing arterial dilation and reduced afterload. Nicorandil reduces preload by increasing blood pooling in volume vessels through venous dilation. Overall, it improves blood flow and reduces infarct size by lowering end-diastolic pressure and reducing the extravascular components of vascular resistance. Open-label studies have shown that nicorandil treatment is effective for various types of angina.

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Nicotil (SG-75) is a dual-action drug that combines the properties of a nitrate-like (NO-releasing) and an ATP-sensitive potassium channel (KATP) opener [2]
- Its clinical indications include the prevention and treatment of angina pectoris, exerting an antianginal effect by dilating coronary arteries and reducing myocardial oxygen consumption [2]
- The drug activates KATP channels through the nucleotide-binding domains of SUR2A and SUR2B, with SUR2A-mediated channel activation being stronger [1]
- In vascular smooth muscle, Nicotil (SG-75) promotes vasodilation by inhibiting RhoA-induced Ca²⁺ sensitization through the cGMP-PKG signaling pathway [3]

C8H9N3O4

211.17

211.059

C, 45.50; H, 4.30; N, 19.90; O, 30.30

65141-46-0

Nicorandil-d4;1132681-23-2

47528

White to off-white solid powder

1.3±0.1 g/cm3

456.7±25.0 °C at 760 mmHg

92ºC

230.0±23.2 °C

0.0±1.1 mmHg at 25°C

1.548

0.72

1

5

4

15

228

0

LBHIOVVIQHSOQN-UHFFFAOYSA-N

InChI=1S/C8H9N3O4/c12-8(7-2-1-3-9-6-7)10-4-5-15-11(13)14/h1-3,6H,4-5H2,(H,10,12)

2-(nicotinamido)ethyl nitrate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (11.84 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (11.84 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)