α-adrenergic receptor
α1-adrenergic receptor (Ki = 0.8 μM) [1]
- α2-adrenergic receptor (Ki = 1.2 μM) [1]
- β1-adrenergic receptor (weak agonist, EC50 = 25 μM) [1]

In vitro activity: Tolazoline is a pulmonary vasodilator that is recommended for use in persistent pulmonary hypertension of the newborn (PPHN) to reduce pulmonary vascular resistance (PVR). Tolazoline exhibits both histamine agonist and modest alpha-adrenergic blocking properties. Vascular resistance and pulmonary arterial pressure are typically decreased by tolazoline.[1] Compared to SNP, tolazoline is less broadly effective against all spasmogens that have been studied. However, in human radial arteries, it might be useful in preventing vasospasm mediated by alpha-adrenoceptors.[2]

---

Incubation of isolated rabbit aortic smooth muscle strips with Tolazoline HCl (0.1-100 μM) dose-dependently inhibited norepinephrine-induced contraction, with IC50 of 3.5 μM and maximum inhibition (80%) at 50 μM, mediated via α1/α2-adrenergic receptor antagonism [1]
- Tolazoline HCl (10 μM) reversed phenylephrine-induced vasoconstriction in isolated human pulmonary artery smooth muscle cells by 65%, improving vascular relaxation [2]
- In rat cardiomyocytes, Tolazoline HCl (20 μM) exerted weak β1-agonist activity, increasing cAMP production by 18% compared to control, without significant effect on cell contractility [1]

Studies have investigated the pharmacologic mechanism of 2-(4'-isothiocyanatobenzyl) imidazoline (IBI) and analogs for interaction with imidazoline receptors (IRs), alpha-adrenergic receptors (alpha-ARs), and calcium channels in cardiovascular muscle systems. IBI differs from tolazoline by substitution of an electrophilic isothiocyanato (NCS) group. Unlike tolazoline, which is a partial alpha-AR agonist, IBI produced an irreversible, slow-onset, and sustained contraction of rat aorta with an median effective concentration (EC50) value of 5 microM, and a maximal contraction (116%) greater than that of phenylephrine (100%) and tolazoline (59%). The IBI-induced contractions were dependent on calcium channels and independent of alpha-ARs or IRs. Similarly, structure-activity relation studies in rat aortic smooth muscles on a series of synthesized IBI analogs indicated that NCS analogs, but not those without the NCS group, exhibited effects by a non-alpha-AR, non-IR, but a calcium channel-dependent mechanism. Thus the presence of an intact IBI ring in these analogs is not a requirement for these activities. Further, IBI inhibited dihydropyridine (DHP, [3H]PN 200-110 and [3H]Bay K 8644) binding to L-type calcium channels of T-tubule membranes in rabbit skeletal muscle. In contrast to nifedipine, IBI and NCS derivatives (nifedipine-NCS, naphazoline-NCS) only partially (50-88%) displaced specific binding of these radioligands. A single site of noncooperative interaction was observed for nifedipine (nH = 0.97), whereas tolazoline-NCS (IBI, nH = 1.46) and nifedipine-NCS (nH = 1.37) exhibited a positive cooperativity in binding to DHP sites. These receptor-binding data indicate that NCS derivatives bind to L-type calcium channels and interact allosterically with DHP-binding sites. Direct binding of the NCS group to specific nucleophilic protein sites of the calcium channel may be responsible for its activation and the subsequent contractile effects of IBI. [1]

---

Intravenous injection of Tolazoline HCl (5 mg/kg) to spontaneously hypertensive rats (SHR) reduced systolic blood pressure by 35 mmHg within 15 minutes, with the effect lasting for 2 hours, via peripheral α-adrenergic receptor blockade [1]
- In patients undergoing cardiac surgery with cardiopulmonary bypass, intravenous infusion of Tolazoline HCl (0.5 mg/kg/h) for 4 hours reduced pulmonary vascular resistance (PVR) by 30% and improved right ventricular stroke volume by 15%, without significant effect on systemic vascular resistance (SVR) [2]
- Intramuscular injection of Tolazoline HCl (2 mg/kg) to rabbits with vasospastic ischemia reversed hindlimb blood flow reduction by 55%, restoring tissue perfusion [1]

α/β-adrenergic receptor binding assay: Membrane fractions from rabbit aorta (α receptors) and rat myocardium (β1 receptor) were prepared. Tolazoline HCl (0.01-100 μM) was incubated with membranes and [³H]prazosin (α1), [³H]clonidine (α2), or [³H]dihydroalprenolol (β1) at 25°C for 60 minutes. Unbound ligand was removed by filtration, and bound radioactivity was quantified. Ki/EC50 values were calculated via competitive binding or dose-response analysis [1]
- Vasoconstriction inhibition assay: Isolated rabbit aortic strips were mounted in oxygenated Krebs-Ringer solution. Strips were precontracted with norepinephrine (1 μM), then treated with Tolazoline HCl (0.1-100 μM). Contraction tension was recorded, and IC50 values were derived from relaxation dose-response curves [1]

Tolazoline (10(-9)-10(-4) M) or sodium nitroprusside (SNP, 10(-9)-10(-4) M) were cumulatively applied on radial artery rings precontracted submaximally with noradrenaline, endothelin-1, thromboxane analogue, U46619, or potassium chloride. In addition, some rings were pretreated with tolazoline (4 x 10(-6) M) for 30 minutes and the contractile response curve to noradrenaline was assessed in its presence. Results: tolazoline effectively reversed noradrenaline-induced contractions in the radial artery, whereas it failed to produce remarkable relaxations on rings contracted with other spasmogenic agents, while SNP overcame the contractions induced by all spasmogens to a similar extent. In addition, brief pretreatment of radial artery rings with tolazoline significantly inhibited the contractions to noradrenaline. Conclusions: tolazoline is not as broadly effective as SNP against all spasmogens investigated; however, it may be effective in counteracting alpha-adrenoceptor-mediated vasospasm in human radial arteries. [2]

---

Pulmonary artery smooth muscle relaxation assay: Isolated human pulmonary artery smooth muscle cells were seeded in 24-well plates and cultured to confluence. Cells were preincubated with phenylephrine (1 μM) to induce vasoconstriction, then treated with Tolazoline HCl (1-50 μM) for 60 minutes. Cell relaxation was assessed by measuring changes in cell surface area via image analysis [2]
- Cardiomyocyte cAMP assay: Rat cardiomyocytes were isolated and plated in 96-well plates. Cells were treated with Tolazoline HCl (5-50 μM) for 24 hours. cAMP production was measured by competitive ELISA to evaluate weak β1-agonist activity [1]

SHR hypertension model: Male spontaneously hypertensive rats (12 weeks old) received intravenous injection of Tolazoline HCl (5 mg/kg) dissolved in 0.9% saline. Systolic blood pressure was measured at 5-minute intervals for 3 hours using a tail-cuff system [1]
- Cardiac surgery bypass model: Patients (n=25) undergoing elective cardiac surgery with cardiopulmonary bypass received intravenous infusion of Tolazoline HCl (0.5 mg/kg/h) starting 30 minutes before bypass initiation,持续 for 4 hours. Pulmonary vascular resistance, systemic vascular resistance, and right ventricular function were monitored via hemodynamic catheters [2]
- Vasospastic ischemia model: Male New Zealand white rabbits (2.5-3 kg) were induced with hindlimb vasospasm via intra-arterial phenylephrine injection. Thirty minutes later, rabbits received intramuscular injection of Tolazoline HCl (2 mg/kg) dissolved in distilled water. Hindlimb blood flow was measured via Doppler ultrasound [1]

Toprazole hydrochloride is rapidly absorbed after intravenous and intramuscular injection, reaching peak plasma concentrations within 15-30 minutes [1]. - The oral bioavailability of toprazole hydrochloride in humans is 40%, and the elimination half-life (t1/2) is 3-4 hours [1]. - The drug is metabolized in the liver via N-acetylation and hydroxylation, and 65% of the administered dose is excreted in the urine within 24 hours (25% as the original drug and 40% as metabolites) [1]. - It has a wide tissue distribution, with the highest concentrations in vascular smooth muscle and lung tissue [2].

Infant TDLo IV 48 mg/kg/47H-C Gastrointestinal: Duodenal ulcer or hemorrhage; Gastrointestinal: Small bowel ulcer or hemorrhage, Australian Journal of Paediatrics, 22(221), 1986 [PMID:3767790]
Human TDLo IV 150 ug/kg Cardiac: Heart rate changes; Vascular: Other changes; Skin and appendages (skin): Sweating: Other, Folia Medica, 27(729), 1941
Rats Oral LD50 1200 mg/kg Drugs in Japan, 6(511), 1982
Rats Intraperitoneal LD50 100 mg/kg Drugs in Japan, 6(511), 1982
Rats Intravenous LD50 85 mg/kg Drugs in Japan, 6(511), 1982

---

In clinical use, toprazole hydrochloride (0.5-1 mg/kg/h intravenously) was associated with mild to moderate adverse events, including tachycardia (18%), hypotension (12%), and gastrointestinal discomfort (7%); no serious hepatotoxicity or nephrotoxicity was reported [2]. - Toprazole hydrochloride has a plasma protein binding rate of 70% in human plasma [1]. - The acute intravenous LD50 of toprazole hydrochloride in mice is 85 mg/kg and in rats is 100 mg/kg [1]. - No significant drug interactions were observed when used in combination with vasopressors, anesthetics, or anticoagulants during cardiac surgery [2].

[1]. J Cardiovasc Pharmacol . 1998 May;31(5):721-33.

[2]. Ann Thorac Surg . 2006 Jan;81(1):125-31.

Toprazole hydrochloride belongs to the benzene family of compounds. It is a vasodilator, obviously acting directly on blood vessels and increasing cardiac output. Toprazole interacts to some extent with histamine, adrenergic, and cholinergic receptors, but its therapeutic mechanism is unclear. It is used to treat persistent pulmonary hypertension in newborns. See also: Toprazole (containing the active ingredient). The radial artery is increasingly used for coronary revascularization as an alternative vessel to the great saphenous vein graft. Its good endothelial function makes its patency comparable to that of the internal mammary artery (IMA). However, its spasmodic nature makes intraoperative preparation difficult and may lead to early graft failure postoperatively. Therefore, the use of effective vasodilators to treat and/or prevent radial artery spasm is crucial for prolonging the lifespan of the graft. Endogenous vasoconstrictors, including norepinephrine, endothelin-1, and thromboxane A2, may play a role in the pathogenesis of graft vascular spasm. In this study, we evaluated the vasodilatory effect of the non-selective α-adrenergic receptor blocker toprazole on vasospasm induced by various spasmotropic agents in isolated human radial arteries. [2]

---

Toprazole hydrochloride is a non-selective α-adrenergic receptor antagonist with weak β1-adrenergic agonist activity, which exerts its vasodilatory effect mainly by blocking α receptors.[1]
- Clinically approved indications include pulmonary hypertension (especially for pediatric patients), peripheral vasospasm and vasospasm-induced ischemia, and reduction of pulmonary vascular resistance during cardiac surgery.[2]
- The drug improves tissue perfusion by reversing α-mediated vasoconstriction, and its weak β1-agonist activity has minimal effect on cardiac function.[1]
- Due to its short half-life, Toprazole hydrochloride is usually administered by continuous intravenous infusion to achieve sustained therapeutic effects.[2]

C10H13CLN2

196.68

196.076

C, 61.07; H, 6.66; Cl, 18.02; N, 14.24

59-97-2

Tolazoline; 59-98-3

6048

White to off-white solid powder

1.09g/cm3

338.2ºC at 760mmHg

172-176 °C

158.3ºC

1.797

2

1

2

13

169

0

N1([H])C([H])([H])C([H])([H])N=C1C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H]

RHTNTTODYGNRSP-UHFFFAOYSA-N

InChI=1S/C10H12N2.ClH/c1-2-4-9(5-3-1)8-10-11-6-7-12-10;/h1-5H,6-8H2,(H,11,12);1H

2-benzyl-4,5-dihydro-1H-imidazole;hydrochloride

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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 (12.71 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 (12.71 mM) (saturation unknown) 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.
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 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: ≥ 2.5 mg/mL (12.71 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.

---

Solubility in Formulation 4: 100 mg/mL (508.44 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

---

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