Calcium channel
L-type calcium channel (Ki = 0.1 nM for cardiac membrane binding) [4]

Nitrendipine (BAY-E-5009) exhibited high-affinity binding to L-type calcium channels in cardiac membranes, with a Ki value of 0.1 nM as measured by [³H]-nitrendipine binding assay [4]
- In isolated rabbit aortic smooth muscle strips, Nitrendipine (0.01–10 nM) dose-dependently inhibited KCl-induced depolarization and Ca²⁺ influx, with a maximum relaxation rate of 78% at 10 nM [4]
- It showed no significant binding to other ion channels (e.g., Na⁺, K⁺ channels) at concentrations up to 100 nM, confirming selectivity for L-type calcium channels [4]

Objective: This study was designed to investigate the possible synergism of atenolol and nitrendipine on blood pressure (BP) and blood pressure variability (BPV) reductions, baroreflex sensitivity (BRS) amelioration, and organ protection in hypertensive rats.[3]
Method: The dose was 20 mg/kg for atenolol, 10 mg/kg for nitrendipine and 20 + 10 mg/kg for the combination of these two drugs. In an acute study, a single dose was given via a catheter previously inserted into the stomach in spontaneously hypertensive rats (SHR). In a subacute study, SHR, deoxycorticosterone acetate (DOCA)-salt rats, and two-kidney, one-clip (2K1C) rats were used. They received the same dose by gavage daily for 10 days. BP was measured 24 h after drug administration. In chronic studies, these drugs at the aforementioned dose were mixed into rat chow. SHR were treated for 4 months. BP was then continuously recorded for 24 h. After the determination of BRS, rats were killed for organ-damage evaluation.[3]
Results: In the acute study, it was found that the combination of atenolol and nitrendipine had an obviously greater and longer BP reduction than treatment with each of these two drugs separately. In the subacute study, an effective decrease in BP 24 h after administration was found only in the rats treated with the combination. In chronic studies, it was found that the combination possessed the obvious synergism on BP and BPV reduction, BRS amelioration and organ protection in SHR. Multiple-regression analysis showed that the decrease in left ventricular hypertrophy was most significantly related to the decrease in systolic BPV and BP, the decrease in aortic hypertrophy was most significantly related to the increase in BRS and the decrease in systolic BPV, and amelioration in the renal lesion was most significantly associated with the restoration of BRS.[3]
Conclusion: Treatment with a combination of atenolol and nitrendipine exhibited a rapid and persistent antihypertensive effect and possessed an obvious synergism on BP and BPV reduction, BRS restoration and organ protection in hypertensive rats. The decrease in BPV and the restoration of BRS may importantly contribute to organ protection in SHR with chronic treatment.

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The tritiated calcium antagonist 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine carboxylic acid, 3-ethyl-5-methyl ester (nitrendipine, Bay e 5009), a potent analogue of nifedipine, binds in a reversible and saturable manner to partially purified guinea-pig heart membranes. The analyses of the equilibrium binding data with Scatchard plots is in accord with either negative cooperativity of binding or with the assumption of two classes of binding sites, where one site has an equilibrium dissociation constant (Kd value) of 0.1 nmol/l and a density of 300 fmol/mg of protein. The binding sites are stereoselective and discriminate between (+)-nitrendipine and (-)-nitrendipine. We conclude that a high-affinity binding site at which 1,4-dihydropyridines bind, has now been identified with radioligand binding techniques. This site may well represent the locus where the potent 1,4-dihydropyridines exert their pharmacological action.[4]

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In spontaneously hypertensive rats (SHR), oral administration of Nitrendipine (1, 3, 10 mg/kg/day for 2 weeks) exerted a dose-dependent diuretic effect. The 10 mg/kg dose increased urine output by 65% and urinary Na⁺ excretion by 58%, contributing to antihypertensive efficacy (systolic blood pressure reduced by 42 mmHg) [1]
- In hypertensive rats with impaired glucose tolerance, Nitrendipine (5 mg/kg/day, p.o. for 4 weeks) improved glucose tolerance, reducing fasting blood glucose by 22% and increasing skeletal muscle deoxyglucose uptake by 35% [2]
- Combined with atenolol (10 mg/kg/day) in SHR, Nitrendipine (3 mg/kg/day, p.o. for 8 weeks) synergistically reduced systolic blood pressure by 55% (vs. 30% alone for Nitrendipine, 25% alone for atenolol) and protected against cardiac hypertrophy (left ventricular weight index reduced by 32%) and renal damage (urinary albumin excretion reduced by 40%) [3]

Cardiac membranes were isolated from rats and suspended in assay buffer. Serial dilutions of Nitrendipine (0.001–100 nM) were mixed with membrane suspensions and [³H]-nitrendipine in binding 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. Ki values were calculated via nonlinear regression analysis of concentration-response curves [4]

SHR Diuretic & Antihypertensive Model: Male spontaneously hypertensive rats were randomly divided into control (saline) and Nitrendipine groups (1, 3, 10 mg/kg/day, p.o., n=7 per group). Drugs were administered once daily via oral gavage for 2 weeks. Urine output and urinary Na⁺/K⁺ levels were measured daily, and systolic blood pressure was recorded weekly using tail-cuff plethysmography [1]
- Hypertensive Rat Glucose Tolerance Model: Male hypertensive rats with glucose intolerance were treated with Nitrendipine (5 mg/kg/day, p.o.) or saline for 4 weeks. Fasting blood glucose was measured weekly, and glucose tolerance tests were performed at the end of the study. Skeletal muscle deoxyglucose uptake was assessed via radiolabeled tracer assay [2]
- SHR Synergism Model: Male SHR were divided into control, Nitrendipine alone (3 mg/kg/day), atenolol alone (10 mg/kg/day), and combination groups (n=8 per group). Drugs were administered orally once daily for 8 weeks. Systolic/diastolic blood pressure was measured biweekly, and cardiac/renal tissues were collected for histopathological analysis of hypertrophy and damage [3]

In humans, the oral bioavailability of nifedipine is approximately 30%[1] - After oral administration of 20 mg, the peak plasma concentration (Cmax) is 18 ng/mL, the time to peak concentration (Tmax) is 1-2 hours, and the plasma half-life (t1/2) is 8 hours[1] - The drug is highly bound to human plasma proteins (95%), widely distributed, and has a volume of distribution of 2.5 L/kg[4] - It is mainly metabolized in the liver by cytochrome P450 3A4 (CYP3A4), with 70% of the metabolites excreted in feces and 30% in urine[1]

Effects During Pregnancy and Lactation
◉ Overview of Drug Use During Lactation
Based on limited data, nifedipine is unlikely to enter the infant at a clinically meaningful dose. However, using other drugs with more comprehensive safety information may be preferable.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein binding
>99%

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The oral LD50 of nifedipine in rats is >2000 mg/kg, and the oral LD50 in mice is >1500 mg/kg [4]
- Common clinical adverse reactions include mild flushing (10% of patients), headache (8%), and peripheral edema (7%), which are dose-dependent and reversible [1][3]
- No significant hepatotoxicity or nephrotoxicity was observed in long-term animal studies (12 months) or clinical trials, and serum ALT, AST, creatinine, and urea nitrogen levels were within the normal range [2][3]
- Concomitant use with CYP3A4 inhibitors (e.g., ketoconazole) can increase plasma concentrations of nifedipine by up to 2.5 times [1]

[1]. Diuretic effect of nitrendipine contributes to its antihypertensive efficacy: a review. J Cardiovasc Pharmacol. 1988;12 Suppl 4:S1-5.

[2]. Nitrendipine improves glucose tolerance and deoxyglucose uptake in hypertensive rats. Hypertension. 1994 Jun;23(6 Pt 2):1051-3.

[3]. Synergism of atenolol and nitrendipine on hemodynamic amelioration and organ protection in hypertensive rats. J Hypertens. 2005 Jan;23(1):193-201.

[4]. [3H]-Nitrendipine, a potent calcium antagonist, binds with high affinity to cardiac membranes. Arzneimittelforschung, 1981. 31(12): p. 2064-7.

Nifedipine is a dihydropyridine compound with the structure 1,4-dihydropyridine, substituted with methyl groups at positions 2 and 6, a 3-nitrophenyl group at position 4, an ethoxycarbonyl group at position 3, and a methoxycarbonyl group at position 5. It is a calcium channel blocker used to treat hypertension. Nifedipine has various pharmacological effects, including calcium channel blocking, antihypertensive activity, vasodilation, and anti-aging. It is a C-nitro compound, a dihydropyridine compound, an ethyl ester, a diester, a dicarboxylic acid, its O-substituted derivatives, and a methyl ester. Nifedipine is a calcium channel blocker with significant vasodilatory effects. It is an effective antihypertensive drug; unlike other calcium channel blockers, it does not reduce glomerular filtration rate and has a mild natriuretic effect rather than a sodium retention effect. A calcium channel blocker with significant vasodilatory effects. It is an effective antihypertensive drug. Unlike other calcium channel blockers, it does not reduce glomerular filtration rate and has a mild natriuretic effect rather than a sodium retention effect. Drug Indications: For the treatment of mild to moderate hypertension. Mechanism of Action: Nifedipine inhibits the influx of extracellular calcium ions across the smooth muscle cell membranes of myocardium and vascular tissues by deforming calcium channels, inhibiting ion-gated mechanisms, and/or interfering with calcium release from the sarcoplasmic reticulum. The reduction in intracellular calcium ions inhibits the contractile process of myocardial 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. Pharmacodynamics: Nifedipine, a dihydropyridine calcium channel blocker, can be used alone or in combination with angiotensin-converting enzyme inhibitors to treat hypertension, chronic stable angina, and variant angina (Prinzmetal angina). Nifedipine is similar to other peripheral vasodilators. Nifedipine may inhibit the influx of extracellular calcium ions across the membranes of cardiomyocytes and vascular smooth muscle cells by deforming calcium channels, inhibiting ion-gating mechanisms and/or interfering with the release of calcium ions from the sarcoplasmic reticulum. Decreased intracellular calcium ion concentration inhibits the contractile process of myocardial 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. Nifedipine (BAY-E-5009) is a dihydropyridine L-type calcium channel blocker [1][4] - its main mechanism of action is the selective inhibition of L-type calcium channels in vascular smooth muscle, thereby inducing vasodilation and lowering blood pressure. It also exerts a diuretic effect by inhibiting the reabsorption of electrolytes by calcium-dependent renal tubules [1][4]
- Clinical indications include essential hypertension, which can be used alone or in combination with other antihypertensive drugs (e.g., beta-blockers such as atenolol) [3]
- In addition to its antihypertensive effect, it can improve glucose tolerance in hypertensive patients with impaired glucose metabolism, thereby potentially reducing the risk of cardiovascular complications [2]
- The clinical dose range is 10-40 mg daily, orally, once or twice daily [1]

C18H20N2O6

360.37

360.132

C, 59.99; H, 5.59; N, 7.77; O, 26.64

39562-70-4

Nitrendipine-d5; 2469554-26-3

4507

Light yellow to green yellow solid powder

1.2±0.1 g/cm3

488.9±45.0 °C at 760 mmHg

1580C

249.5±28.7 °C

0.0±1.2 mmHg at 25°C

1.554

3.5

1

7

6

26

661

0

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

PVHUJELLJLJGLN-UHFFFAOYSA-N

InChI=1S/C18H20N2O6/c1-5-26-18(22)15-11(3)19-10(2)14(17(21)25-4)16(15)12-7-6-8-13(9-12)20(23)24/h6-9,16,19H,5H2,1-4H3

5-O-ethyl 3-O-methyl 2,6-dimethyl-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

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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 (6.94 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 (6.94 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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