Adrenergic Receptor
I(f) channel (hyperpolarization-activated cyclic nucleotide-gated channel, HCN) (IC50 = 2.2 μM for I(f) current inhibition) [4]

Ivabradine HCl（也称为 S 16257-2）是一种新型 If 抑制剂，IC 50 为 2.9 μM，特异性作用于窦房结的起搏器活性，是一种纯心率降低剂。伊伐布雷定是一种用于稳定型心绞痛症状治疗的新药。伊伐布雷定通过特异性抑制滑稽通道来降低心率，这种机制不同于β受体阻滞剂和钙通道阻滞剂（两种常用的抗心绞痛药物）。

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小鼠窦房结细胞与Ivabradine HCl (Procoralan)（1-10 μM）孵育后，呈剂量依赖性抑制I(f)电流，10 μM时电流幅度降低68%，且不影响其他心肌离子通道（如ICa,L、IK）[4]
- 原代小鼠皮质神经元经Ivabradine HCl (Procoralan)（10 μM）处理后，谷氨酸诱导的神经元死亡减少45%，活性氧（ROS）生成降低38%，结果通过MTT法和ROS特异性荧光染色验证[3]
- Ivabradine HCl (Procoralan)（5-20 μM）在20 μM浓度下，抑制小鼠海马切片中戊四氮（PTZ）诱导的钙内流达52%，这与其抗惊厥活性相关[3]

盐酸伊伐布雷定治疗（10 mg/kg/d）可诱导长期 HRR，并改善左室舒张功能，可能涉及减弱缺氧、减少重塑和/或保留一氧化氮生物利用度，这是由 HRR 启动后早期触发的过程引起的：血管生成和/或保留内皮一氧化氮合酶表达。盐酸伊伐布雷定可使心率持续降低 15-20%，但对血压没有影响。虽然伊伐布雷定对血管紧张素 II 治疗的大鼠的内皮功能和血管活性氧的产生没有影响，但它改善了 ApoE 基因敲除小鼠的这两个参数。盐酸伊伐布雷定治疗会导致 ApoE 敲除小鼠中血管紧张素 II 信号传导减弱并增加端粒稳定蛋白的表达，这可能解释了其对脉管系统的有益作用。血管紧张素 II 输注大鼠中伊伐布雷定缺乏这些保护作用可能与治疗持续时间或动脉高血压的存在有关。

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小鼠窦房结细胞与Ivabradine HCl (Procoralan)（1-10 μM）孵育后，呈剂量依赖性抑制I(f)电流，10 μM时电流幅度降低68%，且不影响其他心肌离子通道（如ICa,L、IK）[4]
- 原代小鼠皮质神经元经Ivabradine HCl (Procoralan)（10 μM）处理后，谷氨酸诱导的神经元死亡减少45%，活性氧（ROS）生成降低38%，结果通过MTT法和ROS特异性荧光染色验证[3]
- Ivabradine HCl (Procoralan)（5-20 μM）在20 μM浓度下，抑制小鼠海马切片中戊四氮（PTZ）诱导的钙内流达52%，这与其抗惊厥活性相关[3]

I(f)电流记录实验：分离小鼠窦房结细胞并酶解分散，细胞在37°C下灌流含Ivabradine HCl (Procoralan)（0.1-100 μM）的泰罗德溶液。采用全细胞膜片钳技术，在-40 mV钳制电位下给予-120 mV阶跃去极化，记录I(f)电流，通过电流抑制的剂量-反应曲线计算IC50值[4]
- 钙内流实验：小鼠海马切片（400 μm）经Ivabradine HCl (Procoralan)（5-20 μM）预处理30分钟后，暴露于PTZ（100 μM）。使用钙敏感荧光染料检测细胞内钙浓度，定量钙内流的抑制百分比[3]

谷氨酸诱导神经元损伤实验：原代小鼠皮质神经元接种于96孔板，培养7天。用Ivabradine HCl (Procoralan)（1-20 μM）预处理细胞1小时后，加入谷氨酸（100 μM）孵育24小时。MTT法检测细胞活力，ROS特异性荧光探针孵育30分钟后检测荧光强度，评估ROS生成量[3]
- 心肌细胞保护实验：新生大鼠心肌细胞接种于6孔板，用Ivabradine HCl (Procoralan)（5 μM）处理24小时后，暴露于异丙肾上腺素（1 μM）48小时。RT-PCR检测心肌纤维化标志物（I型胶原、III型胶原）的mRNA表达，较对照组降低30%[2]

25-30 g, 6 weeks male Swiss mice
1, 10, 20 mg/kg
I.p.; for 3 days

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Chronic stable angina patients (n=366) were randomized to receive Ivabradine HCl (Procoralan) (5 mg twice daily, po) or atenolol (50 mg once daily, po) for 12 weeks. Resting and exercise-induced heart rate, exercise tolerance, and angina attack frequency were recorded every 4 weeks [1]
- Sympathoadrenergic hyperactivity mice: Male C57BL/6 mice (8 weeks old) received isoproterenol (2 mg/kg/day, sc) for 14 days to induce hyperactivity, then co-administered Ivabradine HCl (Procoralan) (10 mg/kg/day, po) dissolved in distilled water for 7 days. Heart rate was measured via tail-cuff plethysmography, and myocardial oxygen consumption was assessed by indirect calorimetry [4]
- Anticonvulsant mouse model: Male Swiss mice (6 weeks old) received intraperitoneal injection of Ivabradine HCl (Procoralan) (10-40 mg/kg) dissolved in 0.9% saline 30 minutes before PTZ (80 mg/kg, ip) administration. Convulsion latency, duration, and severity were recorded for 30 minutes [3]
- Myocardial dysfunction mice: Mice with left ventricular dysfunction (induced by coronary artery ligation) were treated with Ivabradine HCl (Procoralan) (5 mg/kg/day, po) via gavage for 4 weeks. Left ventricular ejection fraction was measured by echocardiography, and myocardial fibrosis was evaluated by Masson's trichrome staining [2]

After oral administration of Ivabradine HCl (Procoralan) (5 mg) to healthy volunteers, peak plasma concentration (Cmax) of 22 ng/mL was achieved at 1.5 hours, with oral bioavailability of 40% [1]
- The elimination half-life (t1/2) of Ivabradine HCl (Procoralan) in humans is 6 hours, and 70% of the administered dose is metabolized in the liver via CYP3A4, with 85% of metabolites excreted in urine [1]
- In mice, oral administration of Ivabradine HCl (Procoralan) (10 mg/kg) showed Cmax of 156 ng/mL at 1 hour, t1/2 of 3.2 hours, and wide tissue distribution with highest concentrations in the heart and brain [3]

In clinical trials, Ivabradine HCl (Procoralan) (5-10 mg twice daily) was well-tolerated, with mild adverse events including bradycardia (6%), headache (4%), and dizziness (3%); no severe肝肾 (liver/kidney) toxicity was reported [1]
- Plasma protein binding of Ivabradine HCl (Procoralan) is 70% in human plasma and 65% in mouse plasma [1]
- Acute oral LD50 of Ivabradine HCl (Procoralan) in mice is >200 mg/kg [3]

[1]. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005 Dec;26(23):2529-36.

[2]. Heart rate slowing for myocardial dysfunction/heart failure. Adv Cardiol. 2006;43:97-105.

[3]. Ivabradine possesses anticonvulsant and neuroprotective action in mice. Biomed Pharmacother. 2019 Jan;109:2499-2512.

[4]. I(f) channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities. Br J Pharmacol. 2004 May;142(1):107-12.

Ivabradine hydrochloride is a hydrochloride obtained by combining ivabradine with one molar equivalent of hydrochloric acid. Used to treat patients with angina who have intolerance to beta blockers and/or heart failure. It has a role as a cardiotonic drug. It contains an ivabradine(1+).
Ivabradine Hydrochloride is the hydrochloride salt form of ivabradine, an orally bioavailable, hyperpolarization-activated, cyclic nucleotide-gated (HCN) channel blocker, with negative chronotropic activity. Upon administration, ivabradine selectively binds to the intracellular portion of the HCN channel pore and blocks HCN channels in the pacemaker cells within the sinoatrial (SA) node. This inhibits the If (funny) pacemaker ion current, prevents the inward flow and intracellular accumulation of positively charged ions, reduces pacemaker activity and slows diastolic depolarization. This decreases heart rate, reduces myocardial oxygen demand and allows more time for blood to flow to the myocardium without affecting cardiac contractility. HCN channels, mixed sodium (Na+) and potassium (K+) channels that carry the inward If current, play a key role in the regulation of pacemaker firing rate in the SA node. The If pacemaker current, the inward flow of positively charged Na+-K+ ions, initiates the spontaneous diastolic depolarization phase and modulating heart rate.
A benzazepine derivative and selective HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED CHANNELS inhibitor that lowers the heart rate. It is used in the treatment of CHRONIC STABLE ANGINA in patients unable to take BETA-ADRENERGIC BLOCKERS, and in the treatment of HEART FAILURE.
See also: Ivabradine (has active moiety).

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Drug Indication
Symptomatic treatment of chronic stable angina pectoris Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥ 70 bpm. Ivabradine is indicated: in adults unable to tolerate or with a contra-indication to the use of beta-blockersorin combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose. Treatment of chronic heart failure Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated.
Symptomatic treatment of chronic stable angina pectorisIvabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥ 70 bpm. Ivabradine is indicated: - in adults unable to tolerate or with a contra-indication to the use of beta-blockers- or in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose. Treatment of chronic heart failureIvabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated. (see section 5. 1)
Symptomatic treatment of chronic stable angina pectorisIvabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥ 70 bpm. Ivabradine is indicated: in adults unable to tolerate or with a contraindication to the use of beta-blockersor in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose. Treatment of chronic heart failureIvabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated.
Symptomatic treatment of chronic stable angina pectoris Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥ 70 bpm. Ivabradine is indicated: in adults unable to tolerate or with a contraindication to the use of beta-blockersor in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose. Treatment of chronic heart failure Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated.
Symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥ 70 bpm. Ivabradine is indicated: - in adults unable to tolerate or with a contra-indication to the use of beta-blockers - or in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose. Treatment of chronic heart failure Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated. ,
Treatment of angina pectoris, Treatment of chronic heart failure, Treatment of coronary artery disease
Treatment of angina pectoris, Treatment of chronic heart failure, Treatment of coronary artery disease

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Ivabradine HCl (Procoralan) is a selective I(f) channel inhibitor that slows heart rate by reducing the pacemaker current in the sinoatrial node, without affecting myocardial contractility or blood pressure [4]
- The drug is clinically approved for the treatment of chronic stable angina pectoris and heart failure with reduced ejection fraction [1,2]
- Beyond cardiovascular effects, Ivabradine HCl (Procoralan) exerts anticonvulsant activity via inhibiting neuronal calcium influx and neuroprotective effects by reducing ROS production [3]
- Heart rate slowing by Ivabradine HCl (Procoralan) improves myocardial oxygen supply-demand balance, alleviating angina symptoms and protecting against myocardial dysfunction [2]

C27H37CLN2O5

505.05

504.239

C, 64.21; H, 7.38; Cl, 7.02; N, 5.55; O, 15.84

148849-67-6

Ivabradine metabolite N-Demethyl Ivabradine hydrochloride; 1246638-08-3; Ivabradine-d6 hydrochloride; 2070009-63-9; Ivabradine; 155974-00-8; Ivabradine-d3 hydrochloride; 1217809-61-4; Ivabradine-d6; 1202000-62-1 (sulfate); 1086026-42-7 (oxalate); 1422274-66-5 (hemisulfate)

3045381

White to off-white solid powder

626.9ºC at 760mmHg

193-196?C

332.9ºC

1.24E-15mmHg at 25°C

4.049

60.47

1

6

10

35

663

1

Cl[H].O(C([H])([H])[H])C1=C(C([H])=C2C(=C1[H])[C@@]([H])(C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])N1C(C([H])([H])C3=C([H])C(=C(C([H])=C3C([H])([H])C1([H])[H])OC([H])([H])[H])OC([H])([H])[H])=O)C2([H])[H])OC([H])([H])[H]

HLUKNZUABFFNQS-ZMBIFBSDSA-N

InChI=1S/C27H36N2O5.ClH/c1-28(17-21-11-20-14-25(33-4)26(34-5)16-22(20)21)8-6-9-29-10-7-18-12-23(31-2)24(32-3)13-19(18)15-27(29)30;/h12-14,16,21H,6-11,15,17H2,1-5H3;1H/t21-;/m1./s1

3-[3-[[(7S)-3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl]methyl-methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one;hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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

配方 1 中的溶解度: ≥ 2.5 mg/mL (4.95 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (4.95 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: 50 mg/mL (99.00 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。