Calcium channel

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.

---

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]

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Based on limited data, it is unlikely that nitrendipine will reach the infant in clinically important amounts. However, it may be preferable to use another agent drug for which more safety information is available.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
> 99%

[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.

Nitrendipine is a dihydropyridine that is 1,4-dihydropyridine substituted by methyl groups at positions 2 and 6, a 3-nitrophenyl group at position 4, a ethoxycarbonyl group at position 3 and a methoxycarbonyl group at position 5. It is a calcium-channel blocker used in the treatment of hypertension. It has a role as a calcium channel blocker, an antihypertensive agent, a vasodilator agent and a geroprotector. It is a C-nitro compound, a dihydropyridine, an ethyl ester, a diester, a member of dicarboxylic acids and O-substituted derivatives and a methyl ester.
Nitrendipine is a calcium channel blocker with marked vasodilator action. It is an effective antihypertensive agent and differs from other calcium channel blockers in that it does not reduce glomerular filtration rate and is mildly natriuretic, rather than sodium retentive.
A calcium channel blocker with marked vasodilator action. It is an effective antihypertensive agent and differs from other calcium channel blockers in that it does not reduce glomerular filtration rate and is mildly natriuretic, rather than sodium retentive.

---

Drug Indication
For the treatment of mild to moderate hypertension

---

Mechanism of Action
By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Nitrendipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload.

---

Pharmacodynamics
Nitrendipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Nitrendipine is similar to other peripheral vasodilators. Nitrendipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload.

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.

---

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.

---

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