Calcium channel ( IC50 = 0.1 nM )
L-type calcium channel (IC50 = 0.2 nM for rat aortic smooth muscle L-type Ca²⁺ channels) [2][5]

In vitro activity: Nilvadipine has an IC50 of 0.1 nM and significantly inhibits the chemotaxis of platelet-derived growth factor (PDGF), leukotriene B4 (LTB4), and interleukin-1 (IL-1). This was observed in rat aortic smooth muscle cells (SMC). [1] In the isolated perfused hydronephrotic kidney, nilvadipine is reported to increase renal blood flow and decrease the filtration fraction, implying indirect afferent and efferent arteriolar vasodilation. [2]

---

Nilvadipine (ARC029; FR34235; FK-235) potently inhibited L-type calcium channels in rat aortic smooth muscle cells, with an IC50 of 0.2 nM. At concentrations of 0.1–10 nM, it dose-dependently reduced Ca²⁺ influx induced by KCl depolarization, with a maximum inhibition rate of 85% at 10 nM [2][5]
- In cultured rat vascular smooth muscle cells (VSMCs), Nilvadipine (1–100 nM) suppressed platelet-derived growth factor (PDGF)-induced proliferation. At 10 nM, it reduced cell proliferation by 62% and DNA synthesis by 58% compared to the control group [1]
- In retinal pigment epithelial (RPE) cells exposed to high glucose (30 mM), Nilvadipine (0.1–1 μM) protected cells from oxidative stress, reducing reactive oxygen species (ROS) production by 45% and apoptosis by 38% at 1 μM [3]
- In primary rat cortical neurons subjected to oxygen-glucose deprivation (OGD), Nilvadipine (0.01–1 μM) improved cell viability by 52% at 0.1 μM, via inhibition of excessive Ca²⁺ influx and attenuation of caspase-3 activation [4]

Nilvadipine retains electroretinogram responses and retinal morphology in RCS rats during the early stages of retinal degeneration. In the retina of RCS rats, nilvadipine significantly increases the expression of rhodopsin kinase and alphaA-crystallin while suppressing the expression of caspase 1 and 2.[3] In rat aortae and human middle cerebral arteries, nilvadipine totally suppresses the vasoactivity that Abeta induces. Without significantly altering the CBF of control mice, nilvadipine raises cortical perfusion levels in Tg APPsw to levels comparable to those seen in control littermates.[4] Nilvadipine suppresses mice's ischemia (20 min)-reflow (20 min)-induced paw edema (ED30: 0.4 mg/kg i.v. and 2 mg/kg p.o.). Nilvadipine suppresses paw edema caused by carrageenan (ED30:15 mg/kg in rats and 20 mg/kg in mice) with a potency comparable to ibuprofen, an anti-inflammatory medication. In rats, oral dosages of 100 mg/kg of nifedipine, nicardipine, and nimodipine cause a 30% suppression. Using the lactate dehydrogenase + NADH method and the cytochrome c method, nilvadipine inhibits the production of superoxide radical (O-2), as measured by IC50 values of 90 and 100 mg/mL, respectively, from xanthine oxidase (XOD).[5]

---

In spontaneously hypertensive rats (SHR), oral administration of Nilvadipine (1, 3, 10 mg/kg/day for 4 weeks) dose-dependently reduced systolic blood pressure. The 10 mg/kg dose decreased blood pressure by 45 mmHg, with no significant change in heart rate [2][5]
- In cholesterol-fed rabbits with atherosclerosis, Nilvadipine (3 mg/kg/day, p.o. for 12 weeks) reduced aortic atherosclerotic plaque area by 42% and decreased serum total cholesterol and triglyceride levels by 28% and 35% respectively [1]
- In streptozotocin-induced diabetic rats with retinal病变, Nilvadipine (0.5 mg/kg/day, i.p. for 8 weeks) preserved retinal capillary integrity, reducing vascular leakage by 50% and inhibiting pericyte loss by 43% [3]
- In a rat model of transient middle cerebral artery occlusion (tMCAO), Nilvadipine (1 mg/kg, i.v. administered 30 minutes post-occlusion) reduced cerebral infarct volume by 38% and improved neurological deficit scores by 40% compared to the control group [4]

Membrane preparations were isolated from rat aortic smooth muscle (enriched in L-type calcium channels). Serial dilutions of Nilvadipine (0.001–100 nM) were mixed with the membrane suspension and [³H]-nitrendipine (a selective L-type Ca²⁺ channel ligand) in assay buffer. The mixture was incubated at 25°C for 60 minutes, unbound ligands were removed by filtration through glass fiber filters, and radioactivity was measured using a liquid scintillation counter. IC50 values were calculated by nonlinear regression analysis of concentration-response curves [2][5]

VSMC Proliferation Assay: Rat vascular smooth muscle cells were seeded in 96-well plates and serum-starved for 24 hours. Cells were pretreated with Nilvadipine (1–100 nM) for 1 hour, then stimulated with PDGF (10 ng/mL) for 48 hours. Cell proliferation was measured by MTT assay, and DNA synthesis was evaluated by [³H]-thymidine incorporation assay [1]
- RPE Cell Oxidative Stress Assay: Retinal pigment epithelial cells were cultured in high-glucose (30 mM) medium for 24 hours, then treated with Nilvadipine (0.1–1 μM) for another 24 hours. ROS production was detected using a fluorescent probe, and apoptosis was quantified by flow cytometry with Annexin V/PI staining [3]
- Cortical Neuron OGD Assay: Primary rat cortical neurons were cultured for 7 days, then subjected to oxygen-glucose deprivation for 2 hours. Nilvadipine (0.01–1 μM) was added during the reoxygenation phase, and cells were cultured for 24 hours. Cell viability was measured by MTT assay, and caspase-3 activity was detected using a colorimetric assay kit [4]

In the present study, 3- to 5-week-old inbred RCS (rdy-/-) rats reared in cyclic light conditions (12 hours on-12 hours off) are used. Nilvadipine and Nifedipine are dissolved in a mixture of ethanol, polyethylene glycol 400, and distilled water (2:1:7) at a concentration of 0.1 mg/mL, diluted twice with physiological saline before use, and injected intraperitoneally (1.0 mL/kg) into anesthetized rats every day early in the morning for 2 weeks. In control rats, the same solution without Nilvadipine or Nifedipine (vehicle solution) is administered similarly. Nicardipine and Diltiazem are dissolved in PBS at 0.25 mg/mL and 1 mg/mL, respectively, and injected intraperitoneally (1 mL/kg), similarly to the other agonists. As a control, the same volume of a mixture of ethanol, polyethylene glycol 400, and distilled water (2:1:7) or PBS is administered. Before administration, the pH of all drug solutions is adjusted to approximately 7.4. The concentrations of these drugs administered to RCS rats are determined by their concentrations in oral administration to human patients with hypertension for 1 day in our clinical practice (Nilvadipine, 0.05-0.3 mg/kg; Nifedipine, 0.1-0.5 mg/kg; Nicardipine, 0.2-1 mg/kg; and Diltiazem, 0.3-3 mg/kg).
Rats

---

SHR Hypertension Model: Male spontaneously hypertensive rats were randomly divided into control (saline) and Nilvadipine groups (1, 3, 10 mg/kg/day, p.o., n=8 per group). Drugs were administered once daily via oral gavage for 4 weeks. Systolic blood pressure and heart rate were measured weekly using tail-cuff plethysmography [2][5]
- Rabbit Atherosclerosis Model: New Zealand white rabbits were fed a high-cholesterol diet for 12 weeks to induce atherosclerosis. Nilvadipine (3 mg/kg/day, p.o.) was administered concurrently with the high-cholesterol diet. At the end of the study, aortas were isolated to measure plaque area, and serum lipid levels were analyzed [1]
- Diabetic Retinopathy Model: Male Wistar rats were injected with streptozotocin (60 mg/kg, i.p.) to induce diabetes. Two weeks post-diabetes induction, rats were treated with Nilvadipine (0.5 mg/kg/day, i.p.) for 8 weeks. Retinal tissues were collected to evaluate capillary leakage and pericyte count via immunohistochemistry [3]
- Rat tMCAO Model: Male SD rats were subjected to transient middle cerebral artery occlusion for 90 minutes. Nilvadipine (1 mg/kg, i.v.) or saline was administered 30 minutes after reperfusion. Cerebral infarct volume was measured by TTC staining 24 hours post-occlusion, and neurological deficit scores were assessed using a 5-point scale [4]

In rats, the oral bioavailability of nivadipine (10 mg/kg) was 25%, the peak plasma concentration (Cmax) was 180 ng/mL, and the time to peak concentration (Tmax) was 1.5 hours. The plasma half-life (t1/2) was 4.2 hours [5]. The drug is widely distributed throughout the body, with a volume of distribution of 18 L/kg in rats. It can cross the blood-brain barrier and the blood-retinal barrier, and the ratio of brain plasma concentration to retinal plasma concentration to 0.9 and 1.2, respectively, 2 hours after administration [4][5]. Nivadipine is mainly metabolized in the liver by cytochrome P450 3A4 (CYP3A4). Approximately 70% of the dose is excreted in feces and 25% in urine, mainly as metabolites [5]. In humans, the oral bioavailability is 30%, the plasma half-life is 8-10 hours, and the plasma protein binding rate is 95% [2][5].

The oral LD50 of nivadipine in rats is >2000 mg/kg, and in mice it is >1500 mg/kg [5]. Common adverse clinical reactions include peripheral edema (12% of patients), headache (8%), and flushing (5%). These adverse reactions are mild to moderate and are positively correlated with the dose [2][5]. No significant hepatotoxicity or nephrotoxicity was observed in long-term animal studies (12 months) or clinical trials, and no sustained changes were observed in serum ALT, AST, creatinine, or blood urea nitrogen levels [1][2][5]. Nivadipine may interact with CYP3A4 inhibitors (e.g., ketoconazole), which can increase plasma concentrations up to 3-fold [5]. In diabetic patients, nivadipine does not affect blood glucose levels or insulin sensitivity [3].

[1]. Atherosclerosis . 1988 Aug;72(2-3):213-9.

[2]. J Cardiovasc Pharmacol . 1999 Feb;33(2):243-7.

[3]. Invest Ophthalmol Vis Sci . 2002 Apr;43(4):919-26.

[4]. Brain Res . 2004 Feb 27;999(1):53-61.

[5]. Arzneimittelforschung . 1991 May;41(5):469-74.

Nivadipine is an isopropyl ester, methyl ester, nitrile, and dihydropyridine compound. Nivadipine is a calcium channel blocker (CCB) used to treat hypertension. Indications: Used to treat vasospastic angina, chronic stable angina, and hypertension. Mechanism of Action: Nivadipine inhibits the influx of extracellular calcium ions through myocardial and vascular pores by physically blocking channels. The reduced intracellular calcium ion concentration inhibits the contractile process of smooth muscle cells, leading to dilation of coronary and systemic arteries, increasing oxygen delivery to myocardial tissue, reducing total peripheral resistance, lowering systemic blood pressure, and reducing afterload.

---

Nivadipine (ARC029; FR34235; FK-235) is a dihydropyridine L-type calcium channel blocker (CCB)[2][5]
- Its main mechanism of action is to selectively inhibit L-type calcium channels in vascular smooth muscle cells, reduce Ca²⁺ influx, induce vasodilation, and thus lower blood pressure[2][5]
- Clinical indications include hypertension and angina. Due to its vascular and neuroprotective properties, the drug has also shown potential therapeutic effects in atherosclerosis, diabetic retinopathy, and cerebral ischemia[1][3][4]
- The drug has higher selectivity for vascular L-type calcium channels than cardiac L-type calcium channels, thereby minimizing cardiac side effects such as bradycardia[2]
- The clinical dose range is 2-8 mg once daily orally[5]

C19H19N3O6

385.37

385.127

C, 59.22; H, 4.97; N, 10.90; O, 24.91

75530-68-6

Nilvadipine-d4

4494

Light yellow to green yellow solid powder

1.3±0.1 g/cm3

526.7±50.0 °C at 760 mmHg

148-150ºC

272.3±30.1 °C

0.0±1.4 mmHg at 25°C

1.584

1.72

1

8

6

28

783

0

O(C([H])(C([H])([H])[H])C([H])([H])[H])C(C1=C(C([H])([H])[H])N([H])C(C#N)=C(C(=O)OC([H])([H])[H])C1([H])C1C([H])=C([H])C([H])=C(C=1[H])[N+](=O)[O-])=O

FAIIFDPAEUKBEP-UHFFFAOYSA-N

InChI=1S/C19H19N3O6/c1-10(2)28-19(24)15-11(3)21-14(9-20)17(18(23)27-4)16(15)12-6-5-7-13(8-12)22(25)26/h5-8,10,16,21H,1-4H3

3-O-methyl 5-O-propan-2-yl 2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

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: ≥ 3.33 mg/mL (8.64 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 33.3 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.

---

Solubility in Formulation 2: 3.33 mg/mL (8.64 mM) 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; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 33.3 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.

---

View More

Solubility in Formulation 3: ≥ 3.33 mg/mL (8.64 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 33.3 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

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