CN1568998A - Blood pressure lowering medicine - Google Patents
Blood pressure lowering medicine Download PDFInfo
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- CN1568998A CN1568998A CN 200310110450 CN200310110450A CN1568998A CN 1568998 A CN1568998 A CN 1568998A CN 200310110450 CN200310110450 CN 200310110450 CN 200310110450 A CN200310110450 A CN 200310110450A CN 1568998 A CN1568998 A CN 1568998A
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- rut
- rutaecarpine
- blood pressure
- cgrp
- capsaicin
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Abstract
The invention relates to a blood pressure lowering medicine which comprises rutaecarpine and its pharmaceutically acceptable auxiliary agents. The medicament can keep long-period and stabilized blood pressure reducing action.
Description
Affiliated technical field
The medicine that the present invention relates to bring high blood pressure down.
Background technology
Fructus Evodiae is a kind of traditional Chinese medicine, and the beginning is stated from Shennong's Herbal, in the history in existing hundreds of years of clinical practice.In recent years, Chinese scholars is furtherd investigate its chemical constituent and pharmacological action.Wherein important biomolecule alkali composition be rutaecarpin (evodiamine, Evo) and rutaecarpine (rutaecarpine, Rut).Evo and Rut can strengthen the Isolated Atrium of Guinea Pigs contractility, improve its contraction frequency.This effect can be by competitive capsaicin receptor (VR
1) antagonist Capsazepine and noncompetitive VR
1Antagonist ammoniated ruthenium oxychloride and selectivity calcitonin-gene-related peptide (CGRP) receptor antagonist CGRP
8-37Cancel, and can produce quick cross tolerance between these two kinds of alkaloids and the capsaicin, prompting Evo and Rut to the excitation of Isolated Atrium of Guinea Pigs with activate VR
1It is relevant to promote that CGRP discharges
[1]
Rut can produce dependent blood pressure lowering of dosage (or concentration) and vasodilator effect, and its mechanism relates generally to endotheliocyte Ca
2+-NO-cGMP approach is also with minimizing VSMC Ca
2+Interior stream is relevant
[7-9]Its evidence has: 1. nitricoxide synthase (NOS) inhibitor N
ω-nitro-argine (L-NNA) can obviously suppress the hypotensive effect of Rut
[9]2. at the rat chest aorta and the superior mesenteric artery ring of phyenlephrinium preshrinking (contraction of tetanic property), remove endothelium or adding no inhibitor such as L-NAME, L-NNA, L-N
GRut Ca can be cancelled or weaken to-nitro-argine and hydroquinone (hydroquinone) and ACI methylene blue
2+Dependent vasodilator reaction, and Ca in the cell
2+Mobilize antagonist TMB-8 that its effect is not had obviously influence
[8,9]3. Rut can promote to cultivate endotheliocyte Ca
2+Dependent NO discharges, and increases the generation of thoracic aortic ring cGMP, and its short cGMP generation effect significantly weakens behind the removal endothelium
[9]4. add Rut in advance, Ca is arranged in the extracellular
2The time, can obviously suppress due to the phyenlephrinium thoracic aortic ring position and shrink no Ca mutually
2+Shi Zewu obviously influences, and TMB-8 can suppress the vasodilation reaction of Rut
[8]5. in the extracellular Ca is arranged
2+Or there is not a Ca
2+Situation under, but add in advance Rut all concentration dependent suppress due to the norepinephrine thoracic aortic ring position and shrink mutually, can significantly weaken its stretching reaction when removing endothelium
[7]6. in the extracellular Ca is arranged
2+The time, Rut can increase Ca in the endotheliocyte
2+Concentration ([Ca
2+]
i), and do not have Ca
2+The time Rut to endotheliocyte [Ca
2+]
iThere is not influence; Ca is being arranged
2+The time, Rut can suppress to cultivate VSMC[Ca due to the KCl
2+]
iIncrease; No Ca
2+The time also can reduce VSMC[Ca due to the norepinephrine
2+]
iIncrease
[7]7. the experiment of full cell patch pincers finds that Rut can open the non-voltage-dependent Ca of endotheliocyte
2+Passage can be opened L-voltage-dependent Ca at VSMC
2+Passage
[9]
The applicant finds that intravenous injection Rut produces pressure reduction effect, and the plasma C GRP concentration that can raise is simultaneously tested preceding 4 days subcutaneous injection capsaicin (50mg/kg) exhaustion sensory nerve mediators (comprising CGRP), can cancel its blood pressure lowering and short CGRP release action; Use Capsazepine and CGRP in advance
8-37Can obviously weaken the diastole effect of Rut, and can produce quick cross tolerance between Rut and the capsaicin thoracic aorta and superior mesenteric artery ring, the prompting blood pressure lowering of Rut and vasodilator effect may with activate VR
1It is relevant that receptor promotes that CGRP discharges
[10]
On the other hand, hypertensive control is the important subject in the cardiovascular field always.Calcitonin-gene-related peptide (CGRP) is sensorineural main mediator, be present the strongest known vasodilator material, it can not be oral for polypeptide, and the half-life short (about 10 minutes), use limited, old friends seeking always promote endogenous CGRP synthetic with the medicine that discharges.
But prior art only shows that to the research of Rut hypotensive effect Rut can promote the release of CGRP, and its effect hold time of short duration (only about 2min).Therefore according to prior art, those of ordinary skill does not know whether Rut can be used as the medicine of blood pressure lowering.
The method that many synthetic Rut are arranged in the prior art.
Summary of the invention
The present invention has overcome the deficiency on the prior art understanding, finds another critical nature of Rut, thereby can be with the medicine of Rut as blood pressure lowering.
Altace Ramipril provided by the invention contains rutaecarpine or and available adjuvant pharmaceutically.
The inventor finds after deliberation first: give rutaecarpine for a long time and produce the dose dependent blood pressure lowering, can reach stable blood pressure lowering in 6～8 days after the administration, reach CGRP content in the dorsal root ganglion in the blood that raises simultaneously.After using capsaicin to make the sensory nerve desensitization, its hypotensive effect and short CGRP are synthetic obviously to be suppressed with release action.Therefore the hypotensive effect of rutaecarpine is by capsaicin receptor on the sensory nerve that activates capsaicin sensitive, promotes the synthetic and release of CGRP.
Hypertension needs long-term prescription, and Rut is oral effectively; Rut not only can promote CGRP to discharge, and can promote it synthetic, so can bring into play hypotensive effect steady in a long-term.Rut is become a reality as medicine active ingredient blood pressure lowering.
Description of drawings:
Fig. 1 single vein gives the influence of rutaecarpine (RUT) to the Hypertensive Rats mean arterial pressure; Veh wherein: solvent; Cap: capsaicin; CAPZ:Capsazepine (selectivity capsaicin receptor blocker).Data are expressed as mean ± standard error, n=9-12.
**P＜0.01vs+Veh(RUT)；
++P＜0.01vs+RUT(300μg/kg)。
Fig. 2 single vein gives the influence of rutaecarpine (RUT) to Hypertensive Rats plasma C GRP concentration; Hypertension wherein: hypertension; Veh: solvent; Cap: capsaicin; CAPZ:Capsazepine (selectivity capsaicin receptor blocker).Data are expressed as mean ± standard error, n=9-12.
**P＜0.01vs?Hypertension；
++P＜0.01vs+RUT(300μg/kg)。
Fig. 3 gives the influence of rutaecarpine (RUT) to Hypertensive Rats arteria caudalis systolic pressure for a long time; Animal blood pressure raises and reaches stable back (about 15 days), and gastric infusion is 12 days continuously, administration every day 2 times, and blood pressure is institute's measured value before each administration among the figure.Wherein animal blood pressure raises and reaches stable back (about 15 days), and gastric infusion is 12 days continuously, administration every day 2 times, and blood pressure is institute's measured value before each administration among the figure.Control: normal control group; Hypertension: hypertension group; RUT (L): low dosage rutaecarpine group (1.5mg/kg/ time); RUT (H): high dose rutaecarpine group (3mg/kg/ time); Cap: capsaicin.Data are expressed as mean ± standard error, n=9-12.
Fig. 4 gives the influence of rutaecarpine (RUT) to Hypertensive Rats plasma C GRP concentration for a long time; Animal blood pressure raises to reach and stablizes back (about 15 days), and gastric infusion is 12 days continuously, administration every day 2 times, and CGRP concentration is for putting to death the preceding institute of animal measured value among the figure.Control wherein: normal control group; Hypertension: hypertension group; RUT (L): low dosage rutaecarpine group (1.5mg/kg/ time); RUT (H): high dose rutaecarpine group (3mg/kg/ time) Cap: capsaicin.Data are expressed as mean ± standard error, n=8-11.
**P＜0.01vs?Control；
++P＜0.01vs?Hypertension；；
##P＜0.01vs+RUT(H)。
Fig. 5 gives the influence of rutaecarpine (RUT) to Hypertensive Rats dorsal root ganglion CGRP content for a long time; Animal blood pressure raises to reach and stablizes back (about 15 days), and gastric infusion is 12 days continuously, administration every day 2 times, and CGRP content is for putting to death the preceding institute of animal measured value among the figure.Control wherein: normal control group; Hypertension: hypertension group; RUT (L): low dosage rutaecarpine group (1.5mg/kg/ time); RUT (H): high dose rutaecarpine group (3mg/kg/ time); Cap: capsaicin.Data are expressed as mean ± standard error, n=8-9.
**P＜0.01vs?Control；
++P＜0.01vsHypertension；；
##P＜0.01vs+RUT(H)。
Specific embodiments
First's single gives the hypotensive effect and the Mechanism Study thereof of rutaecarpine
SD rat 200-250g, left inferior pole of kidney inject 10% phenol, 50 μ l (being dissolved in normal saline) and induce renal hypertension.Animal blood pressure raises and reaches stable back (about 15 days), single intravenous injection various dose rutaecarpine, and the variation of record mean arterial pressure after the administration is treated to take a blood sample when blood pressure lowering reaches at utmost and is surveyed plasma C GRP.
Experiment is set up separately: (1) hypertension group; (2) various dose rutaecarpine group (30,100,300 μ g/kg, iv); (3) Capsazepine (1.5mg/kg, iv)+rutaecarpine (300 μ g/kg) group; (4) capsaicin (50mg/kg, sc)+rutaecarpine (300 μ g/kg) group; (5) rutaecarpine solvent (20% dimethyl sulfoxine+80% ethanol) group; (6) capsaicin solvent (10% ethanol+10% tween 80+80% normal saline)+rutaecarpine (300 μ g/kg) group.Capsazepine is a selectivity capsaicin receptor blocker, and capsaicin is exhausted CGRP.
The result shows: basic blood pressure difference does not have significance between each group of Hypertensive Rats.The single vein gives the pressure reduction effect that rutaecarpine can produce dose dependent, but while dose dependent ground rising plasma C GRP concentration.Capsaicin exhausts that sensory nerve mediator CGRP and selectivity capsaicin receptor blocker capsazepine all can obviously suppress the release (Fig. 1,2) of the hypotensive effect and the CGRP of rutaecarpine.
Second portion gives the hypotensive effect and the Mechanism Study thereof of rutaecarpine for a long time
Above-mentioned hypertension model, animal blood pressure raise to reach and stablize back (about 15 days), random packet then: (1) normal control group; (2) hypertension group; The rutaecarpine of (3) two dosage (3,6mg/kg/d is made into suspension with 0.5% sodium carboxymethyl cellulose, irritates stomach at twice) group; (4) capsaicin (50mg/kg, sc)+rutaecarpine (6mg/kg).Rutaecarpine is handled and to be given capsaicin the previous day and make the sensory nerve desensitization, and gastric infusion is 12 days then, administration every day before measurement arteria caudalis systolic pressure.Before the execution, the equal arterial pressure of lining, plasma C GRP concentration and Dorsal root ganglion CGRP content.
The result shows: give rutaecarpine for a long time and produce the dose dependent blood pressure lowering, can reach stable blood pressure lowering in 6～8 days after the administration, reach CGRP content in the dorsal root ganglion in the blood that raises simultaneously.After using capsaicin to make the sensory nerve desensitization, its hypotensive effect and short CGRP are synthetic obviously to be suppressed (Fig. 3,4,5) with release action.
List of references
1?Kobayashi?Y，Hoshikuma?K，Nakano?Y?et?al.?The?positive?inotropic?and?chronotropic?effects?ofevodiamine?and?rutaecarpine，indoloquinazoline?alkaloids?isolated?from?the?fruits?of?Evodiarutaecarpa，on?the?guinea-pig?isolated?right?atria：possible?involvement?of?vanilloid?receptors.PlantaMed，2001；67(3)：244-8。
2?Hu?CP，Xiao?L，Deng?HW，Li?YJ.The?cardioprotection?of?rutaecarpine?is?mediated?by?endogenouscalcitonin?related-gene?peptide?through?activation?of?vanilloid?receptors?in?guinea-pig?hearts.PlantaMed，2002；68(8)：705-9
3?Hu?CP，Li?NS，Xiao?L?et?al.Involvement?of?capsaicin-sensitive?sensory?nerves?in?cardioprotection?ofrutaecarpine?in?rats.Regul?Pept，2003；in?press
4?Rang?WQ，Du?YH，Hu?CP?et?al.Protective?effects?of?calcitonin?gene-related?peptide-mediatedevodiamine?on?guinea-pig?cardiac?anaphylaxis.Naunyn?Schmiedebergs?Arch?Pharmacol，2003；367(3)：306-11
5?Chiou?WF，Liao?JF，Chen?CF.Comparative?study?of?the?vasodilatory?effects?of?three?quinazolinealkaloids?isolated?from?Evodia?rutaecarpa.J?Nat?Prod，1996；59(4)：374-8
6?Chiou?WF，Chou?CJ，Shum?AY，Chen?CF.The?vasorelaxant?effect?of?evodiamine?in?rat?isolatedmesenteric?arteries：mode?of?action.Eur?J?Pharmacol，1992；215(2-3)：277-83
7?Wang?GJ，Shan?J，Pang?PK?et?al.The?vasorelaxing?action?of?rutaecarpine：direct?paradoxical?effects?onintracellular?calcium?concentration?of?vascular?smooth?muscle?and?endothelial?cells.J?Pharmacol?ExpTher，1996；276(3)：1016-21
8?Chiou?WF，Shum?AY，Liao?JF，Chen?CF.Studies?of?the?cellular?mechanisms?underlying?thevasorelaxant?effects?of?rutaecarpine，a?bioactive?component?extracted?from?an?herbal?drug.JCardiovasc?Pharmacol，1997；29(4)：490-8
9?Wang?GJ，Wu?XC，Chen?CF?et?al.Vasorelaxing?action?of?rutaecarpine：effects?of?rutaecarpine?oncalcium?channel?activities?in?vascular?endothelial?and?smooth?muscle?cells.J?Pharmacol?Exp?Ther，1999；289(3)：1237-44
10?Hu?CP，Xiao?L，Deng?HW，Li?YJ.The?depressor?and?vasodilator?effects?of?rutaecarpine?are?mediatedby?calcitonin?gene-related?peptide.Planta?Medica，2003；69(2)：125-9
Claims (2)
1, the purposes of rutaecarpine in the preparation Altace Ramipril.
2, the medicine of blood pressure lowering contains rutaecarpine or and available adjuvant pharmaceutically.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310110450 CN1568998A (en) | 2003-10-24 | 2003-10-24 | Blood pressure lowering medicine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310110450 CN1568998A (en) | 2003-10-24 | 2003-10-24 | Blood pressure lowering medicine |
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| Publication Number | Publication Date |
|---|---|
| CN1568998A true CN1568998A (en) | 2005-01-26 |
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|---|---|---|---|
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7655659B2 (en) | 2004-08-19 | 2010-02-02 | Applied Genetics Incorporated Dermatics | Biomimetic of Evodia rutaecarpa fruit extract for amelioration of inflammation |
-
2003
- 2003-10-24 CN CN 200310110450 patent/CN1568998A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7655659B2 (en) | 2004-08-19 | 2010-02-02 | Applied Genetics Incorporated Dermatics | Biomimetic of Evodia rutaecarpa fruit extract for amelioration of inflammation |
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