Use of carbazole derivatives y16 for the preparation of medicaments for the treatment of cardiovascular diseases

Abstract

The application provides application of a carbazole derivative Y16 in preparation of a drug for treating cardiovascular diseases, and belongs to the technical field of medicines.The vasodilatation activity of Y16 is determined by using a rat isolated thoracic aorta tension measurement, and the change of the vasodilatation effect of Y16 under the intervention of various channel inhibitors is observed, and the influence of Y16 on blood pressure is determined by using a rat femoral artery cannulation experiment.The results show that the carbazole derivative Y16 has a good dose-dependent vasodilatation effect, and Y16 also shows a blood pressure lowering effect, so that the carbazole derivative Y16 can effectively treat cardiovascular diseases is disclosed for the first time, the application provides a theoretical basis for obtaining a candidate compound of a drug for treating cardiovascular diseases, and also provides a new selection for a drug for treating cardiovascular diseases in clinic.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to the application of a carbazole derivative Y16 in the preparation of drugs for treating cardiovascular diseases. Background Technology

[0002] Cardiovascular diseases, including hypertension, atherosclerosis, and myocardial infarction, are among the most prevalent and deadly diseases, posing a significant burden on individuals and society. Endothelial dysfunction and inflammation are common risk factors for cardiovascular diseases, particularly hypertension and atherosclerosis, and warrant serious attention and further research.

[0003] Endothelial dysfunction manifests as an imbalance between vasoconstriction and vasodilation, with weakened vasodilation resulting in elevated blood pressure and inflammatory responses. This is caused by a decrease in the secretion of endothelial vasodilator factor (EDRF) and its reduced bioavailability. Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), plays a crucial role in vasodilation, inhibiting smooth muscle cell contraction, migration, and proliferation, as well as endothelin production, platelet aggregation, and leukocyte adhesion into the endothelium, thus preventing atherosclerosis. NO promotes smooth muscle relaxation and vasodilation through the PI3K / Akt / eNOS / NO / sGC / cGMP / PKG pathway. Furthermore, endothelial cells also secrete prostacyclin (PGI2), which relaxes smooth muscle through the COX / PGI2 / sAC / cAMP / PKA pathway. Endothelial cells play a significant role in regulating vasodilation, but the state of related channels (such as potassium and calcium channels) on smooth muscle and related receptors on the cell membrane can also directly regulate the state of smooth muscle, thereby causing vasoconstriction or vasodilation. This is known as the non-endothelial pathway of vasomotor regulation.

[0004] Research on carbazole compounds in the pharmaceutical field mainly focuses on their antibacterial, antitumor, and antioxidant effects. Its application in cardiovascular diseases is less frequent, with carvedilol being a notable exception. Carvedilol, a beta-blocker, lowers blood pressure and also possesses antioxidant and calcium antagonistic effects. Recent studies have also shown that carvedilol can promote eNOS expression, thus providing cardioprotection. Y16[6-(9-(3-chlorobenzyl)-9-hydro-carbazole-3-yl)-N 2 N 2 [-Dimethyl-3,6-dihydro-1,3,5-triazine-2,4-diamine] is a newly synthesized carbazole derivative that has shown some antibacterial activity in preliminary experiments, but its cardiovascular effects are still unclear. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide the application of carbazole derivative Y16 (hereinafter referred to as Y16) in the preparation of drugs for treating cardiovascular diseases, wherein Y16 has a significant effect of lowering blood pressure and vasodilation, thereby achieving the purpose of treating cardiovascular diseases.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides the application of carbazole derivative Y16 in the preparation of drugs for treating cardiovascular diseases.

[0008] Preferably, the cardiovascular disease includes one or both of endothelial dysfunction and hypertension.

[0009] Preferably, the carbazole derivative Y16 has a vasodilatory effect.

[0010] Preferably, the carbazole derivative Y16 exerts its effects through both endothelial-dependent and non-endothelial-dependent pathways.

[0011] Preferably, the endothelial-dependent pathway includes one or both of the PI3K / Akt / eNOS / NO / sGC / cGMP pathway and the PGI2 pathway.

[0012] Preferably, the non-endothelial-dependent pathway includes one or more of the following: non-selective calcium-activated potassium channels, ATP-sensitive potassium channels, inward rectifying potassium channels, voltage-sensitive potassium channels, L-type voltage-dependent calcium channels, calcium release from the sarcoplasmic reticulum, and β-adrenergic receptor pathways.

[0013] Preferably, the carbazole derivative Y16 has a blood pressure-lowering effect.

[0014] Preferably, the drug further includes pharmaceutically acceptable excipients.

[0015] Compared with the prior art, the present invention has the following beneficial effects:

[0016] This invention provides the application of carbazole derivative Y16 in the preparation of drugs for treating cardiovascular diseases. The invention measures the vasodilatory activity of Y16 by measuring the tension of isolated rat thoracic aorta and observing changes in the vasodilatory effect of Y16 under various channel inhibitor interventions. A rat femoral artery cannulation experiment was conducted to determine the effect of Y16 on blood pressure. The results show that carbazole derivative Y16 has a good dose-dependent vasodilatory effect, and Y16 also exhibits a blood pressure-lowering effect. Therefore, this invention discloses for the first time that carbazole derivative Y16 can effectively treat cardiovascular diseases. This invention provides a theoretical basis for obtaining a candidate compound for treating cardiovascular diseases and also provides a new option for clinical treatment of cardiovascular diseases. Attached Figure Description

[0017] Figure 1 The chemical structural formula of Y16;

[0018] Figure 2 The effect of Y16 on the thoracic aortic rings with and without endothelium is shown in Figure A. The effect of Y16 on the thoracic aortic rings with intact endothelium is shown in Figure B. E+ represents intact endothelium and Cont represents the control group. The effect of Y16 on the thoracic aortic rings with endothelium removal is shown in Figure B. E+ represents intact endothelium and E- represents endothelium removal.

[0019] Figure 3 In the middle section, A represents the effect of triamcinolone acetonide (Tri) on the vasodilatory effect of Y16; B represents the effect of wrassenin (WT) on the vasodilatory effect of Y16; C represents the effect of L-NAME on the vasodilatory effect of Y16; D represents the effect of ODQ on the vasodilatory effect of Y16; E represents the effect of KT5823 on the vasodilatory effect of Y16; and F represents the effect of indomethacin (Indo) on the vasodilatory effect of Y16.

[0020] Figure 4 The effect of potassium ion channels on the vasodilatory effect of Y16, where A represents potassium. ATP Effect of channel inhibitor Gli on the vasodilatory effect of Y16; B represents K Ca Effect of the channel inhibitor TEA on the vasodilatory effect of Y16; C is K V The effect of the channel inhibitor 4-AP on the vasodilatory effect of Y16; D represents the effect of the Kir channel inhibitor BaCl2 on the vasodilatory effect of Y16.

[0021] Figure 5 The effects of calcium ion channels on the vasodilatory effect of Y16 are shown in Figure A, where GdCl3 has an effect on the vasodilatory effect of Y16; Figure B shows the effect of Y16 on the calcium ion contraction curve in calcium-free high-potassium solution; and Figure C shows the effect of Y16 on the vasoconstriction intensity of PE in calcium-free solution.

[0022] Figure 6 In Figure A, the effect of muscarinic M receptors on the vasodilatory effect of Y16 receptors is shown; in Figure B, the effect of β-adrenergic receptors on the vasodilatory effect of Y16 receptors is shown.

[0023] Figure 7 The effects of Y16 on blood pressure are as follows: A represents the effect of different concentrations of Y16 on the rate of change of systolic blood pressure; B represents the effect of different concentrations of Y16 on the rate of change of diastolic blood pressure; C represents the effect of Y16 on systolic blood pressure at different time points; and D represents the effect of Y16 on diastolic blood pressure at different time points. Detailed Implementation

[0024] This invention provides the application of carbazole derivative Y16 in the preparation of drugs for treating cardiovascular diseases.

[0025] The chemical name of the carbazole derivative Y16 of this invention is 6-(9-(3-chlorobenzyl)-9-hydro-carbazole-3-yl)-N 2 N 2 -Dimethyl-3,6-dihydro-1,3,5-triazine-2,4-diamine, see the specific chemical structural formula. Figure 1 The present invention does not have any particular limitation on the source of the carbazole derivative Y16, which can be obtained by conventional preparation methods.

[0026] This invention measures the vasodilatory activity of Y16 by measuring the tension of isolated rat thoracic aorta and the effect of Y16 on blood pressure by rat femoral artery cannulation experiment, exploring the efficacy of carbazole derivative Y16 in treating cardiovascular diseases. The results show that carbazole derivative Y16 has a good dose-dependent vasodilatory effect, and Y16 also shows a significant blood pressure-lowering effect, which can effectively treat cardiovascular diseases, especially hypertension and / or vascular endothelial dysfunction.

[0027] In this invention, the cardiovascular disease preferably includes one or both of endothelial dysfunction and hypertension.

[0028] In this invention, to elucidate the molecular mechanism of Y16 vasodilation, changes in the vasodilatory effect of Y16 were observed under the intervention of various channel inhibitors. The results showed that the vasodilatory effect of Y16 significantly decreased after endothelial removal from the thoracic aorta. Simultaneously, interventions with L-NAME, ODQ, woumacridine (WT), and indomethacin (Indo) reduced the vasodilatory effect of Y16 to varying degrees. Potassium channel inhibitors TEA, 4-AP, and BaCl2 inhibited the vasodilatory effect of Y16, while glibenclamide (Gli) had no significant effect. Y16 inhibited calcium ion contraction in calcium-free, high-potassium solutions, and also significantly inhibited PE-induced intracellular calcium release-dependent contraction, with the inhibition increasing with increasing concentration. However, GdCl3 had no significant effect on the vasodilatory effect of Y16. The β-receptor inhibitor propranolol partially participated in the vasodilatory effect of Y16, while the M-receptor inhibitor atropine did not participate in the vasodilatory effect of Y16. Therefore, the carbazole derivative Y16 preferably exerts its effects through endothelium-dependent and non-endothelium-dependent pathways. The endothelium-dependent pathways include one or both of the PI3K / Akt / eNOS / NO / sGC / cGMP pathway and the PGI2 pathway. The non-endothelium-dependent pathways include one or more of the following: non-selective calcium-activated potassium channels, ATP-sensitive potassium channels, inward rectifying potassium channels, voltage-sensitive potassium channels, L-type voltage-dependent calcium channels, calcium release from the sarcoplasmic reticulum, and β-adrenergic receptor pathways.

[0029] In this invention, the drug further includes pharmaceutically acceptable excipients. The pharmaceutical composition comprises an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient includes the aforementioned carbazole derivative Y16. The active ingredient constitutes 20% to 80% of the drug by mass, and the pharmaceutical excipients include one or more of flavoring agents, excipients, binders, and diluents. In this invention, "pharmaceutically acceptable" excipients are substances suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), i.e., substances with a reasonable benefit / risk ratio. The dosage form of the drug may be granules, tablets, lyophilized powder, or capsules. The drug may be administered orally, intravenously, or intramuscularly.

[0030] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0031] In the following examples, data processing and graphing were performed using Prism Graphed 5.0 software. Data are presented in Mean ± SEM format, and t-tests or one-way ANOVA were used to compare multiple groups of data. A p-value < 0.05 was considered statistically significant.

[0032] Example 1

[0033] Materials and Experiments

[0034] 1.1 Reagents: Carbazole derivative Y16 (chemical name 6-(9-(3-chlorobenzyl)-9-hydro-carbazole-3-yl)-N 2 N 2 -Dimethyl-3,6-dihydro-1,3,5-triazine-2,4-diamine, synthesized and provided by Professor Zhang Tianyi of Jilin Pharmaceutical College. The chemical structural formula of Y16 is shown below. Figure 1), Phenylephrine (PE), Acetylcholine (Ach), Nω-nitro-L-arginine methylester (L-NAME), 1H-[1,2,4]oxadiazolo-[4,3-α]quinoxalin-1-one (ODQ), Wortmannin (WT), Triciribine (Tri), KT5823 (purchased from Sigma), Indomethacin (Indo), Glibenclamide (Gli), Tetraethylammonium (TEA), 4-Aminopyridine (4-AP), Barium chloride (barium) chloride (BaCl2), gadolinium chloride (GdCl3), 2-aminoethyl diphenylborinate (2-APB), nifedipine (Nif), atropine (Atro), and propranolol (Prop).

[0035] Krebs nutrient solution: 118mM NaCl, 4.7mM KCl, 1.1mM MgSO4, 1.2mM KH2PO4, 25mM NaHCO3, 10.0mM Glucose, 1.5mM CaCl2, adjust pH to 7.4.

[0036] Y16 was prepared by dissolving it in 25% dimethyl sulfoxide (DMSO) to obtain different concentrations of Y16.

[0037] 1.2 Healthy male SD rats (250–300 g) were provided by the Animal Center of Yanbian University. This invention complies with the review requirements of the Experimental Animal Management and Animal Welfare Ethics Committee of Yanbian University.

[0038] 1.3 Thoracic aortic tension test

[0039] 1.3.1 Preparation of isolated thoracic aortic rings

[0040] SD rats were euthanized by cervical dislocation. The thoracic aorta was quickly removed and placed in pre-cooled Krebs nutrient solution at 4°C. After removing fat and connective tissue, vascular rings of 3–5 mm in length were cut. The vascular rings were suspended by stainless steel rings in a water bath containing 37°C Krebs nutrient solution and 95% O2 and 5% CO2, which was connected to the circulatory system. The stainless steel rings were connected to a tension sensor, and the tension signals were recorded and stored digitized by software.

[0041] The initial tension was adjusted to 1g, and 1μM PE was added to stimulate vascular ring contraction. After reaching the plateau phase, 1μM Ach was added to induce vasodilation. The highest contraction value and the lowest vasodilation value were recorded, and the vasodilation rate was calculated. A vasodilation rate greater than 80% was considered to indicate intact endothelium. If the endothelium was to be removed, the inner wall of the thoracic aorta was gently scraped with a bamboo skewer before shearing. A vasodilation rate less than 10% during tension testing was considered to indicate complete removal of the vascular endothelium.

[0042] 1.3.2 The vasodilatory effect of Y16 on PE-preconstricted thoracic aortic vascular rings

[0043] Using thoracic aortic vascular rings with and without endothelium, after vasoconstriction to the plateau phase following stimulation with 1 μM PE, Y16 at concentrations of 1 μM, 3 μM, 10 μM, 30 μM, and 100 μM was added sequentially every three minutes. The blank control group was the corresponding volume of solvent. The changes in tension curves were observed and the tension at each concentration addition node was recorded. The diastolic rate was calculated, and the diastolic rate-concentration gradient curve was plotted.

[0044] To investigate whether Y16 has a vasodilatory effect and whether the presence or absence of endothelium affects the function of Y16, the experiment used thoracic aortic rings with intact endothelium and those without endothelium to detect the effect of Y16.

[0045] like Figure 2 As shown in Figure A, compared with the control group, Y16 significantly dilated the thoracic aortic ring (Emax = 76.83 ± 5.22%, P < 0.001, n = 6), and this dilation was significantly concentration-dependent. Figure 2 B showed that the vasodilatory effect of Y16 was weakened after endothelial removal (Emax = 33.28 ± 2.64%, P < 0.001, n = 6), indicating that the vasodilatory effect induced by Y16 is endothelial-dependent and non-endothelial-dependent.

[0046] 1.4 Effects of various channel inhibitors on the vasodilatory effect of Y16

[0047] 1.4.1 The inhibitors related to each channel and their concentrations are shown in Table 1. In short, endothelial intact thoracic aortic rings prepared in part 1.3 were used. Twenty minutes before the addition of PE to constrict blood vessels, inhibitors were added for pre-incubation, with the control group (E+ group) receiving no inhibitors. After PE contraction stabilized, Y16 was added sequentially at gradient concentrations of 1 μM, 3 μM, 10 μM, 30 μM, and 100 μM. Data were recorded and curves were plotted.

[0048] Table 1. Channel inhibitors and their concentrations used in the tension measurement experiment.

[0049]

[0050]

[0051] After confirming that the vasodilatory effect of Y16 is related to vascular endothelium, this experiment then used relevant inhibitors to clarify the endothelial-related pathways involved by Y16.

[0052] Figure 3 A, B, C, D, E, and F respectively show the vasodilatory curves of Y16 under the intervention of tricerebroside (Tri), wollamedin (WT), L-NAME, ODQ, KT5823, and indomethacin (Indo). Except for KT5823, which had no significant effect (Emax = 84.39 ± 6.92%, n = 5), the other inhibitors all had varying degrees of interference. Among them, wollamedin (WT, Emax = 57.64 ± 3.23%, P < 0.01, n = 5), L-NAME (Emax = -6.33 ± 3.90%, P < 0.001, n = 6), and ODQ (Emax = -12.76 ± 2.16%, P < 0.001, n = 6) significantly reduced the vasodilatory effect of Y16 at all concentrations. Tricirebin (Tri, Emax = 59.90 ± 4.41%, P < 0.01, n = 5) and indomethacin (Indo, Emax = 58.19 ± 6.02%, P < 0.01, n = 6) significantly inhibited the vasodilatory effect induced by higher concentrations of Y16. These results indicate that the vasodilatory effect induced by Y16 is related to the PI3K / Akt / eNOS / NO / sGC / cGMP signaling pathway and the PGI2 pathway.

[0053] To investigate the effect of potassium ion channels on Y16 vasodilation, this study explored whether four potassium ion channels were involved in Y16 vasodilation. The results are as follows: Figure 4 As shown.

[0054] K ATP Channel inhibitor Gli (see) Figure 4A) The vasodilatory effect on Y16 was slightly decreased but not significantly different (Emax = 66.28 ± 9.86%, n = 4). However, K... Ca Channel inhibitors TEA (see Figure 4 B), K V Channel inhibitor 4-AP (see Figure 4 C), K IR Channel inhibitor BaCl2 (see Figure 4 D) After pre-incubation, the vasodilatory effect of Y16 was significantly weakened (TEA: Emax = 32.49 ± 8.77%, P < 0.005, n = 4; 4-AP: Emax = 24.42 ± 5.51%, P < 0.001, n = 4; BaCl2: Emax = 42.43 ± 7.54%, P < 0.001, n = 5).

[0055] To investigate whether calcium-related channels affect the relaxation of Y16, GdCl3 was first added to an intact thoracic aortic ring for incubation, and then the release of calcium from L-type voltage-dependent calcium channels and sarcoplasmic reticulum was examined.

[0056] The results are as follows Figure 5 A indicates that GdCl3 had no significant effect on the vasodilatory effect of Y16 (Emax = 84.46 ± 4.01%, n = 5).

[0057] 1.4.2 Effect of Y16 on the calcium ion contraction curve in calcium-free high-potassium solution

[0058] After the initial tension of the endothelial-removed thoracic aortic vascular ring stabilized, vasoconstriction was stimulated with a high-potassium solution (KCl, 60 mM). Once equilibrated, the thoracic aortic vascular ring was rinsed with Krebs nutrient solution until a stable state was achieved. This process was repeated twice. The normal Krebs nutrient solution was then replaced with a calcium-free Krebs solution containing 50 μM EGTA. Y16 was added at concentrations of 3 μM, 30 μM, and 100 μM for pre-incubation for ten minutes, followed by stimulation with high-potassium solution. Subsequently, CaCl2 solutions with concentrations ranging from 0.01 to 10 mM were added sequentially, and the vascular ring contraction phenomenon was observed and data recorded. The blank control group (Cont group) used an equal volume of solvent instead of Y16, while the positive control group received 1 μM nifedipine (Nif).

[0059] Figure 5 The curves in Figure B show that as the concentration of Y16 increases (3 μM, 30 μM, 100 μM), the vasomotor tension induced by external calcium intrusion decreases accordingly. At higher calcium concentrations, different concentrations of Y16 showed varying degrees of inhibition of increased contraction. Compared to the blank control group (N = 1.30 ± 0.06 g), Y16 (100 μM) significantly reduced the increase in tension (N = 0.79 ± 0.05 g, P < 0.001, n = 5). Figure 5 The results showed that high concentrations of Y16 inhibited L-type voltage-dependent calcium channels.

[0060] 1.4.3 Effect of Y16 on the vasoconstrictive strength of PE in calcium-free solution

[0061] After the endothelial-removed vascular rings stabilized at an initial tension of 1.0 g, they were replaced with calcium-free Krebs nutrient solution for further stabilization. Then, 1 μM PE was added to induce contraction, which was caused by calcium release from the sarcoplasmic reticulum due to PE (Con1). The vascular rings were then kept in equilibrium in normal Krebs nutrient solution for at least 40 minutes, followed by 20 minutes in calcium-free solution. Y16 was added at concentrations of 1 μM, 3 μM, 10 μM, 30 μM, and 100 μM for 10 minutes each time, and then PE was added again (Con2). The PE-induced contraction before drug treatment was considered the normal group (Cont group). The ratio of PE-induced vascular ring contraction intensity before and after drug treatment (Con2 / Con1) was recorded and compared. 50 μM 2-APB was used as a positive control.

[0062] like Figure 5 As shown in Figure C, the higher the concentration of Y16, the more pronounced the inhibitory effect. At a Y16 concentration of 100 μM, the contraction ratio decreased to 45.92 ± 2.53% (P < 0.001, n = 4), which was significantly different from the blank control group (83.18 ± 0.94%). These results indicate that Y16 also significantly inhibits PE-induced internal calcium release-dependent contraction.

[0063] Further investigation is needed to determine whether M receptors and β receptors are involved in the vasodilatory effect of Y16.

[0064] Figure 6 A showed that atropine treatment did not significantly inhibit [the activity] (P>0.05). Figure 6 In group B, although high concentrations of Y16 achieved the vasodilatory effect without inhibitors, propranolol significantly affected the effects of low and medium concentrations of Y16. (Atropine: Emax = 91.81 ± 0.38%, n = 4; Propranolol: Emax = 82.9 ± 4.04%, n = 4). This indicates that M receptors do not participate in the vasodilatory effect induced by Y16, while some β-adrenergic receptors do participate in the vasodilatory effect induced by Y16.

[0065] 1.5 Femoral artery cannulation experiment to measure blood pressure

[0066] SD rats weighing 270–300 g were anesthetized with 1.2 mg / kg urethane and fixed to wooden boards. The femoral artery and vein were separated using surgical scissors and a glass needle. Blood pressure was measured by cannulation of the femoral artery and administration of the drug via cannulation of the femoral vein. Blood pressure changes before and after administration of different concentrations (1 mg / kg, 3 mg / kg, 6 mg / kg) of Y16 were observed. The blank control group (Cont group) received an equal volume of physiological saline.

[0067] The effect of Y16 on blood pressure was detected by administering medication via femoral vein catheterization and measuring blood pressure via femoral artery catheterization. Results are as follows: Figure 7 As shown.

[0068] Figure 7 A and Figure 7 B illustrates the effects of Y16 on the rate of change in systolic blood pressure (SBP) and diastolic blood pressure (DBP). Compared with the blank control group, the addition of Y16 significantly altered both SBP and DBP. This demonstrates that Y16 has a significant blood pressure-lowering effect. Figure 7 C and Figure 7 D represents the time-dependent changes in systolic and diastolic blood pressure after administration of Y16 (6 mg / kg). Half a minute after intravenous administration of Y16 (6 mg / kg), blood pressure showed a significant decrease (SBP = 85.32 ± 3.66 mmHg, P < 0.001, n = 7; DBP = 56.76 ± 2.12 mmHg, P < 0.001, n = 7), followed by a slow recovery. This demonstrates that Y16 can rapidly and significantly reduce blood pressure (* indicates a difference compared to the control group). # (This is compared to 3 mg / kg Y16).

[0069] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. The application of carbazole derivative Y16 in the preparation of drugs for treating hypertension, characterized in that, The chemical structural formula of Y16 is:

2. The application according to claim 1, characterized in that, The carbazole derivative Y16 has a vasodilatory effect.

3. The application according to claim 1, characterized in that, The carbazole derivative Y16 exerts its effects through both endothelium-dependent and non-endothelium-dependent pathways.

4. The application according to claim 3, characterized in that, The endothelial-dependent pathways include one or both of the PI3K / Akt / eNOS / NO / sGC / cGMP pathways and the PGI2 pathway.

5. The application according to claim 3, characterized in that, The non-endothelial-dependent pathways include one or more of the following: non-selective calcium-activated potassium channels, ATP-sensitive potassium channels, inward rectifying potassium channels, voltage-sensitive potassium channels, L-type voltage-dependent calcium channels, calcium release from the sarcoplasmic reticulum, and β-adrenergic receptor pathways.

6. The application according to claim 3, characterized in that, The carbazole derivative Y16 has the effect of lowering blood pressure.

7. The application according to any one of claims 1 to 6, characterized in that, The drug also includes pharmaceutically acceptable excipients.

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