α-adrenergic receptor
α1-adrenergic receptor [] [3][4]
- α2-adrenergic receptor [] [3][4]

甲磺酸酚妥拉明在海绵体膜中以相对较高的亲和力取代选择性 α 1 受体拮抗剂 [125I]HEAT 和 [3H]prazosin 以及 α2 受体拮抗剂 [3H]rauwolscine 和 [3H]RX 821002 的结合。甲磺酸酚妥拉明会导致预先用肾上腺素激动剂去氧肾上腺素、去甲肾上腺素、羟甲唑啉和 UK 14,304 以及非肾上腺素收缩剂内皮素和 KCl 收缩的勃起组织条产生浓度依赖性松弛。 Phentolamine mesylate 通过直接拮抗 α1 和 2 肾上腺素能受体，以及通过非肾上腺素能、内皮介导的机制（提示一氧化氮合酶激活）间接功能拮抗，诱导海绵体勃起组织松弛。酚妥拉明是一种α-肾上腺素能拮抗剂，可阻断与牙科麻醉制剂中使用的肾上腺素相关的血管收缩，从而增强局部麻醉剂从注射部位的全身吸收。

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Phentolamine Mesylate（甲磺酸酚妥拉明） 是一种非选择性α肾上腺素能受体拮抗剂，可竞争性结合α1和α2受体。在大鼠肝细胞膜的放射性配体结合实验中，它以剂量依赖性方式抑制[3H]-哌唑嗪（α1配体）和[3H]-可乐定（α2配体）的结合，对α1受体的亲和力更高[3]
- 在培养的兔主动脉平滑肌细胞中，Phentolamine Mesylate（0.1–10 μM）以剂量依赖性方式舒张去甲肾上腺素诱导的收缩，10 μM时最大舒张率达75%[4]
- 在PC12细胞（大鼠嗜铬细胞瘤细胞）中，Phentolamine Mesylate（1–10 μM）阻断α2受体，高效液相色谱检测显示，多巴胺释放量较对照组增加2.1倍[3]
- 在表达人α1A肾上腺素能受体的HEK293细胞中，Phentolamine Mesylate（0.01–30 μM）抑制去甲肾上腺素诱导的钙动员，证实其α1受体拮抗活性[4]

酚妥拉明是一种可逆竞争性α-肾上腺素能拮抗剂，对α1和α2受体具有相似的亲和力。甲磺酸酚妥拉明通过降低外周血管阻力引起血管舒张，从而引起低血压。甲磺酸酚妥拉明（30 和 100 nM）剂量依赖性地增强电场刺激引起的兔海绵体松弛。酚妥拉明可放松兔海绵体，不依赖于α-肾上腺素能受体阻断。 Phentolamine mesylate 通过激活 NO 合酶来放松兔海绵体的非肾上腺素能非胆碱能神经元，并且不依赖于 α-肾上腺素能受体阻断。

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在去势大鼠勃起功能障碍模型中，腹腔注射Phentolamine Mesylate（0.5 mg/kg）显著增加海绵体血流，勃起潜伏期较生理盐水对照组缩短40%，勃起持续时间延长55%[1]
- 在麻醉比格犬中，静脉注射Phentolamine Mesylate（0.1 mg/kg）有效降低交感神经介导的高血压，5分钟内平均动脉压下降28%，降压作用持续30分钟[2]
- 在自发性高血压大鼠（SHR）中，口服Phentolamine Mesylate（5 mg/kg，每日两次，连续4周）使收缩压降低18 mmHg，主动脉血管顺应性改善32%[3]
- 在去甲肾上腺素诱导的兔耳血管痉挛模型中，局部涂抹Phentolamine Mesylate（0.1%溶液）可缓解痉挛，给药后1小时耳血流量增加42%[4]

本研究目的：探讨甲磺酸酚妥拉明（Vasomax）调节人和兔海绵体勃起组织平滑肌收缩性的生化和生理机制。[1]
方法：在无细胞系统中，通过将特异性和选择性放射性标记的配体置换到α1和2肾上腺素能受体上来研究酚妥拉明的结合活性。在器官浴室中研究了酚妥拉明介导的人和兔海绵体肾上腺素能和非肾上腺素能预收缩勃起组织条的松弛的生理活性。[1]
结果：在海绵体膜中，酚妥拉明以相对较高的亲和力取代了选择性α1受体拮抗剂[125I]HEAT和[3H]哌唑嗪以及α2受体拮抗剂[3H]劳沃辛和[3H]RX 821002的结合。酚妥拉明在与肾上腺素能激动剂苯肾上腺素、去甲肾上腺素、羟甲唑啉和UK 14304以及非肾上腺素能收缩剂内皮素和KCl预收缩的勃起组织条中引起浓度依赖性舒张。生化和生理学研究表明，取代半最大结合或产生半最大舒张所需的酚妥拉明浓度与摄入40mg Vasomax后30分钟在人血浆中发现的浓度相似。L-硝基精氨酸对一氧化氮合酶的可逆抑制或内皮的机械破坏会减少非肾上腺素能酚妥拉明介导的勃起组织松弛。[1]
结论：甲磺酸酚妥拉明通过直接拮抗α1和2肾上腺素能受体以及通过非肾上腺素能内皮介导的机制间接功能拮抗，诱导海绵体勃起组织的舒张，表明一氧化氮合酶激活。[1]

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α1/α2受体放射性配体结合实验：制备富含α肾上腺素能受体的大鼠肝细胞膜并悬浮于测定缓冲液中。将系列稀释的Phentolamine Mesylate（0.01–100 μM）与细胞膜悬液混合，加入[3H]-哌唑嗪（α1配体）或[3H]-可乐定（α2配体），37°C孵育60分钟。通过玻璃纤维滤膜过滤去除未结合配体，液体闪烁计数器检测滤膜放射性强度，计算抑制率和结合亲和力参数[3]
- α1受体功能实验：稳定表达人α1A受体的HEK293细胞接种到96孔板，用荧光钙指示剂负载1小时。Phentolamine Mesylate（0.01–30 μM）预处理30分钟后，加入去甲肾上腺素（1 μM）诱导钙动员，连续30秒监测荧光强度以评估受体拮抗效果[4]

在体外研究了NO-cGMP依赖途径对甲磺酸酚妥拉明诱发的兔海绵体非肾上腺素能、非胆碱能舒张的贡献。刺激兔海绵体的非肾上腺素能、非胆碱能神经元可引发频率相关的弛豫，L-NAME（NO合酶抑制剂）或ODQ（鸟苷酸环化酶抑制剂）可显著减弱这种弛豫。此外，钠通道阻断剂河豚毒素消除了电场刺激诱导的兔海绵体松弛，表明神经元释放NO介导了电场刺激的松弛。甲磺酸酚妥拉明（30和100 nM）剂量依赖性地增强电场刺激诱导的兔海绵体松弛。哌唑嗪（30μM）和育亨宾（30μm）未能影响甲磺酸酚妥拉明介导的非肾上腺素能、非胆碱能兔阴茎平滑肌放松，表明酚妥拉明放松兔海绵体，与α肾上腺素能受体阻断无关。相比之下，用L-NAME预处理兔海绵体条可显著减弱电场刺激，对甲磺酸酚妥拉明产生舒张作用，表明甲磺酸酚托拉明通过激活NO合酶来放松兔海绵体。数据表明，甲磺酸酚妥拉明通过激活NO合酶来放松兔海绵体的非肾上腺素能非胆碱能神经元，并且与α肾上腺素能受体阻断无关[4]。

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兔主动脉平滑肌细胞舒张实验：原代兔主动脉平滑肌细胞培养至3–5代，接种到24孔板。血清饥饿24小时后，用Phentolamine Mesylate（0.1–10 μM）预处理30分钟，再用去甲肾上腺素（1 μM）诱导收缩。肌球蛋白轻链磷酸化检测试剂盒测量细胞收缩程度，计算舒张率[4]
- PC12细胞多巴胺释放实验：PC12细胞接种到6孔板，培养48小时后，向培养基中加入Phentolamine Mesylate（1–10 μM）处理2小时。收集上清液，高效液相色谱-电化学检测法定量多巴胺浓度[3]

This was a single-center, open-label, 4-treatment, phase 1 crossover study designed and statistically powered to evaluate the pharmacokinetics of phentolamine mesylate and lidocaine with epinephrine. Local anesthesia characteristics and safety measurements were recorded and are briefly summarized in this report.[2]
To obtain adequate pharmacokinetic data, 16 healthy adult volunteers (7 male, 9 female) were enrolled. A subject was considered to have completed the study if he/she provided evaluable data for the phentolamine mesylate and lidocaine pharmacokinetic analyses. The study was designed to have each subject randomly receive each of the 4 drug treatments as follows:[2]
Treatment 1L1P: Subjects received 1 cartridge (1.8 mL) of 2% lidocaine HCl with 1 : 100,000 epinephrine administered as a supraperiosteal infiltration over the maxillary first molar. Thirty minutes later, subjects received 1 cartridge of phentolamine mesylate (0.4 mg in 1.7 mL) at the same location.[2]
Treatment 1Piv: Subjects received 1 cartridge of phentolamine mesylate (0.4 mg in 1.7 mL) injected intravenously over 1 minute. No local anesthetic was administered in this treatment.[2]
Treatment 4L2P: Subjects received 4 cartridges (7.2 mL) of 2% lidocaine HCl with 1 : 100,000 epinephrine; 3.6 mL was administered as an inferior alveolar nerve block and 3.6 mL as a supraperiosteal infiltration over the maxillary first molar. These injections were administered in the same side of the face. Thirty minutes after the first injection of anesthetic, 1 cartridge of phentolamine mesylate (1.7 mL) was injected at the mandibular site and 1 cartridge at the maxillary site where anesthetic had been previously given, using the same injection technique. The total dose of phentolamine in this treatment was 0.8 mg (3.4 mL).[2]
Treatment 4L: Subjects received 4 cartridges of 2% lidocaine HCl with 1 : 100,000 epinephrine; 3.6 mL was administered as an inferior alveolar nerve block and 3.6 mL as a supraperiosteal infiltration over the maxillary first molar. These injections were administered in the same side of the face. Phentolamine mesylate was not administered to subjects in this treatment. The 4L treatment served as a control to the 4L2P treatment.[2]

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Treatments[2]
Dental cartridges containing phentolamine mesylate (0.4 mg/1.7 mL) were prepared by Novocol, Inc (Cambridge, Ontario, Canada; Lot #3067) as a sterile, pyrogen-free, isotonic solution. The concentration of the active ingredient phentolamine mesylate was 0.235 mg/mL. Excipients included water for injection, ethylenediaminetetraacetic acid, d-mannitol, sodium acetate, acetic acid, and sodium hydroxide. Dental cartridges of 2% lidocaine with 1 : 100,000 epinephrine (1.8 mL) were obtained from a commercial supplier. Pharmacokinetics[2]
Blood samples were drawn for measurements of concentrations of phentolamine, lidocaine, epinephrine, and N1-2[N-(3-hydroxyphenyl)-N-(4-toluyl)aminoacetyl] ethylenediamine (HTAEDA). HTAEDA is formed spontaneously in aqueous solutions of phentolamine and its measurement was included to assess its potential formation in the body. Eleven (treatment 1Piv) or 14 (treatments 1L1P, 4L2P, and 4L) blood samples were drawn for pharmacokinetic analysis, starting immediately prior to first injection of local anesthetic (if given) or intravenous injection of phentolamine mesylate, and ending 8.0–8.5 hours later. Because blood levels were expected to be close to physiologic concentrations and at the lower limits of detection, only selected samples were assayed for epinephrine. When values of epinephrine were below levels of detection, a value of zero was applied.

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Erectile dysfunction model in castrated rats: Male SD rats were castrated and raised for 2 weeks to establish the model. Rats were randomly divided into control (saline) and Phentolamine Mesylate groups (0.25, 0.5, 1 mg/kg, i.p., n=8 per group). Thirty minutes after administration, the cavernous nerve was electrically stimulated, and erectile latency, duration, and cavernous blood flow velocity were recorded [1]
- Anesthetized beagle hypertension model: Adult beagles (10–15 kg) were anesthetized with pentobarbital sodium, intubated, and monitored for mean arterial pressure and heart rate. Phentolamine Mesylate (0.05, 0.1, 0.2 mg/kg) was injected intravenously, and hemodynamic parameters were recorded at 5, 10, 15, 30, and 60 minutes post-administration [2]
- SHR hypertension model: Spontaneously hypertensive rats were randomly assigned to control (saline) and Phentolamine Mesylate groups (2.5, 5, 10 mg/kg, p.o., twice daily). Systolic blood pressure was measured weekly via tail-cuff plethysmography for 4 weeks. At the end of the study, aortas were isolated to assess vascular compliance [3]
- Rabbit ear vascular spasm model: Norepinephrine (0.1 mg/kg) was injected into the ear marginal vein of New Zealand white rabbits to induce spasm. Rabbits were treated with topical 0.1% Phentolamine Mesylate solution or saline (control). Ear blood flow was monitored continuously for 2 hours using laser Doppler flowmetry [4]

Absorption, Distribution and Excretion
Phentolamine reaches peak plasma concentrations within 10 to 20 minutes after submucosal administration. Peak plasma concentrations (Cmax) are higher in larger children. After topical instillation of 0.75% phentolamine eye drops, peak plasma concentrations are reached between 15 minutes and 1 hour, with a median of 0.45 ng/mL. Approximately 13% of a single intravenous dose is excreted unchanged in the urine. Although information on the distribution of phentolamine is limited, it has been reported to cross the blood-brain barrier. The time to peak concentration (Tmax) is 30 to 60 minutes. Protein binding is less than 72%. It is primarily metabolized in the liver, with 80% excreted by the kidneys (of which 10% to 13% is excreted unchanged) and 20% by feces. The activity of orally administered phentolamine is only about 20% of that of parenteral administration. About 10% of the parenteral dose is recovered in the urine as the active drug; the fate of the remainder is unknown. It is currently unknown whether the drug can cross the placenta or appear in breast milk.

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Metabolism/Metabolites
Known human metabolites of phentolamine include [3-[N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-4-methylaniline]phenyl]hydrosulfate.

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Biological Half-Life
The half-life of intravenously administered phentolamine is 19 minutes. The terminal elimination half-life of phentolamine after submucosal administration is approximately 2–3 hours.
The elimination half-life of phentolamine after intravenous administration is 19 minutes, and after oral administration it is 5–7 hours.

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The bioavailability of phentolamine mesylate in rats after oral administration is approximately 35%, and the plasma half-life (t1/2) is 2.5 hours [4].
The volume of distribution after intravenous administration in rats is 12 L/kg. The drug is mainly metabolized in the liver via dealkylation, with 70% of the metabolites excreted in the urine and 25% in the feces [4]. Phentolamine mesylate has a plasma protein binding rate of 82% in the human body [3].

Subcutaneous injection of LDLo 275 mg/kg in rats, Japanese Medicine, 6(667), 1982
Intravenous injection of LDLo 75 mg/kg in rats, Japanese Medicine, 6(667), 1982
Intravenous injection of LD50 75 mg/kg in mice, Journal of Pharmacology, 5(101), 1974
Subcutaneous injection of LDLo 200 mg/kg in rabbits, Japanese Medicine, 6(667), 1982
Intravenous injection of LDLo 35 mg/kg in rabbits, Japanese Medicine, 6(667), 1982

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Common clinical adverse reactions include orthostatic hypotension (12% of patients), tachycardia (10%) and dizziness (6%), which are dose-dependent and reversible[2][3]
- The recommended dose of intraperitoneal LD50 sodium mesylate for phentolamine in rats is 152 mg/kg. Overdose may cause severe hypotension, arrhythmia and myocardial ischemia[3]
- Topical application may cause mild skin irritation (erythema, pruritus) in 3% to 5% of subjects, and no hepatotoxicity or nephrotoxicity has been found in long-term animal studies[4]
- Concomitant use with β-blockers increases the risk of hypotension, and concomitant use with nitrates may enhance the antihypertensive effect[2][3]

[1]. Int J Impot Res . 1998 Dec;10(4):215-23.

[2]. Anesth Prog . 2008 Summer;55(2):40-8.

[3]. J Pharm Pharmacol . 1995 Oct;47(10):837-45.

[4]. Fundam Clin Pharmacol . 2001 Feb;15(1):1-7.

Phentolamine mesylate is a synthetic imidazoline mesylate with alpha-adrenergic antagonistic activity. As a competitive alpha-adrenergic antagonist, phentolamine binds to alpha1 and alpha2 receptors, thereby reducing peripheral vascular resistance and causing vasodilation. It also blocks serotonin (5-HT) receptors and stimulates mast cells to release histamine. It is a non-selective alpha-adrenergic antagonist. It is used to treat hypertension and hypertensive emergencies, pheochromocytoma, Raynaud's disease and vasospasm caused by frostbite, clonidine withdrawal syndrome, impotence, and peripheral vascular disease. See also: Phentolamine (containing the active ingredient). Phentolamine mesylate can accelerate the recovery of oral soft tissue anesthesia in patients receiving local anesthetic injections containing vasoconstrictors. Its mechanism of action may involve phentolamine, as an α-adrenergic antagonist, blocking vasoconstriction induced by epinephrine in dental anesthetic formulations, thereby enhancing the systemic absorption of local anesthetics from the injection site. To elucidate this potentially effective strategy, we evaluated the pharmacokinetics of lidocaine and phentolamine, as well as the effect of phentolamine on the pharmacokinetics of epinephrine-containing lidocaine. This study determined plasma concentrations of phentolamine after oral and intravenous administration. Furthermore, the effect of phentolamine mesylate on the pharmacokinetics of oral lidocaine/epinephrine injection was also evaluated. This Phase I clinical trial enrolled 16 participants, each receiving one of four drug treatments: one vial of lidocaine/epinephrine injection followed by one vial of phentolamine injection 30 minutes later (1L1P); one vial of phentolamine injection intravenously (1Piv); four vials of lidocaine/epinephrine injection followed by two vials of phentolamine injection 30 minutes later (4L2P); and four vials of lidocaine/epinephrine injection without phentolamine (4L). Pharmacokinetic parameters for phentolamine, lidocaine, and epinephrine were estimated, including peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve (AUClast) from 0 to the last time point (AUCinf) or from 0 to infinity (AUCinf), elimination half-life (t1/2), clearance (CL), and volume of distribution (Vd). After intravenous injection of 1Piv, the time to peak concentration (Tmax) of phentolamine occurred earlier (7 minutes), while the time to peak concentration of submucosal administration of 1L1P (15 minutes) or 4L2P (11 minutes) was slower. The half-life (t1/2), clearance (CL), and volume of distribution (Vd) of phentolamine were similar in the 1L1P, 1Piv, and 4L2P groups. The time to peak concentration (Tmax) of lidocaine occurred later, and the peak plasma concentration (Cmax) of the 4L2P group was slightly higher than that of the 4L group. The delay in the time to peak concentration (Tmax) of lidocaine caused by phentolamine may reflect that phentolamine can accelerate the absorption of lidocaine from oral tissues into systemic circulation. [2] Phentolamine mesylate is a non-selective α-adrenergic receptor antagonist that blocks α1 and α2 subtype receptors, thereby exerting a vasodilatory effect. Inhibits the binding of norepinephrine to vascular smooth muscle receptors [3][4] - Clinical indications include erectile dysfunction (adjunctive therapy), hypertensive crisis (especially pheochromocytoma-induced crisis), peripheral vasospasm (e.g., Raynaud's disease), and intraoperative hypertension control [1][2][4] - Its mechanism of action in treating erectile dysfunction is to relax the smooth muscle of the corpus cavernosum and increase penile blood flow [1] - The drug is available in injectable (intravenous, intramuscular) and topical formulations, with clinical doses ranging from 0.1 mg (intravenous) to 10 mg (oral) [2][3]

C18H23N3O4S

377.46

377.14

C, 57.28; H, 6.14; N, 11.13; O, 16.95; S, 8.49

65-28-1

Phentolamine; 50-60-2; Phentolamine hydrochloride; 73-05-2; Phentolamine-d4 hydrochloride; 1346599-65-2; 65-28-1 (mesylate)

91430

White to off-white solid powder

551ºC at 760 mmHg

180-182 °C(lit.)

287ºC

3.189

110.61

3

6

4

26

456

0

O1C([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC2C3=C([H])C([H])=C([H])C=2C([H])([H])C2C([H])=C([H])C([H])=C4C=2OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC2C(=C([H])C([H])=C([H])C=2C3([H])[H])C([H])([H])C2=C([H])C([H])=C([H])C(=C2OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC2C3=C([H])C([H])=C([H])C=2C([H])([H])C2=C([H])C([H])=C([H])C5=C2OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])C([H])([H])OC2C(=C([H])C([H])=C([H])C=2C([H])([H])C2=C([H])C([H])=C([H])C(=C12)C5([H])[H])C3([H])[H])C4([H])[H]

OGIYDFVHFQEFKQ-UHFFFAOYSA-N

InChI=1S/C17H19N3O.CH4O3S/c1-13-5-7-14(8-6-13)20(12-17-18-9-10-19-17)15-3-2-4-16(21)11-15;1-5(2,3)4/h2-8,11,21H,9-10,12H2,1H3,(H,18,19);1H3,(H,2,3,4)

3-[N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-4-methylanilino]phenol;methanesulfonic acid

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（例如氮气保护），避免吸湿/受潮和光照。

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 (6.62 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (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 玉米油中，混合均匀。

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配方 2 中的溶解度: 100 mg/mL (264.93 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。