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Xi-Xian
Yao, Dong-Lai Cui, Yi-Feng Sui, Xiao-Tian Li, 1Department
of Internal Medicine, Second Affiliated Hospital, Hebei Medical
University, Shijiazhang 050000, Hebei Province, China
Dr. Xi-Xian Yao, male, born on 1931-06-01 in Hebei Province,
graduated from Hebei Medical College, having 100 papers published,
member of Standing Committee of Chinese Society of Digestion, CMA
& Hebei Branch, professor, Department of Internal Medicine,
Second Affiliated Hospital, Hebei Medical University, Shijiazhang
050000, Hebei Province, China
Correspondence to: Dr. Xi-Xian Yao, Department of Internal
Medicine, Second Affiliated Hospital, Hebei Medical University,
Shijiazhang 050000, Hebei Province, China
Telephone:
+86-311-7046901 ext 5003
Received: 1998-05-06
Subject
headings: hypertension, portal; liver
cirrhosis; hemodynamics; drugs, Chinese herbal; blood activating and stasis eliminating
Yao XX, Cui DL, Sui YF, Li XT.Clinical and experimental study of
effect of Raondix Salviae Militiorrhiza and other blood-activating
and stasis-eliminating Chinese herbs on hemodynamics of portal
hypertension.World J Gastroenterol, 1998;4(5):439-442
Abstract
AIM: To study the effects of Radix Salviae Militiorrhiza (RSM),
other blood-activating and stasis-eliminating Chinese herbs on
hemodynamics of portal hypertension.
METHODS: Portal pressure of cirrhotic dogs after chronic
common bile duct ligation was measured directly; portal blood flow
in patients with liver cirrhosis were detected by ultrasound
Doppler.
RESULTS: After administration of RSM and Radix Angelicae
Sinensis (RAS) by intravenous infusion in cirrhosis dogs, the portal
venous pressure (Ppv), wedge hepatic venous pressure (WHVP), hepatic
venous pressure gradient (HVPG), were significantly decreased (P＜0.05-0.01),
but the mean arterial pressure (MAP), and the heart rate (HR)
remained unchanged. When nifedipine was used, Ppv, WHVP, MAP and HR
were significantly decreased (P＜0.05),
and the MVPG unchanged (P＞0.05).
After administration of RSM, RSM+nifedipine and RSM+Hirudin+Nifedpin
for 10-12 weeks, the diameter of portal vein (Dpv), spleen vein (Dsv),
the portal venous flow (Qpv) and splenic venous flow (Qsv) in
patients with hepatic cirrhosis were significantly lowered (P＜0.05-0.01),
and the effect of RAS was weaker.
CONCLUSIONS: The efficacy of decreasing Ppv by Chinese
herbs—RSM, RAS, etc. as compared with nifedipine, demonstrated
that the Chinese herbs were slower in action than that of nifedipine,
but more long-lasting and without side effects. Hence, long-term
administration of Chinese herbs, would be more beneficial.
INTRODUCTION
There has been no long-lasting and side effects free drugs to lower
the portal hypertension in patients with liver cirrhosis so far. The
blood vessel constrictive drugs can reduce the volume of blood flow
and lower the portal pressure by contracting visceral blood vessels
but can not improve the prognosis of the patients obviously because
of their bad dynamic effects, whereas drugs dilating blood vessels
such as calcium antagonist—nifedipine can lead to hypotension at
large doses although it is effective for portal hemodymics［1］.
Yigan infusion which contains blood-activating and
stasis-eliminating herbs such as large doses of RSM and RAM has some
effects of shrinking the liver and spleen; and some of blood
activating and stasis eliminating herbs can prevent and cure hepatic
fibrosis［2-5］.
Therefore, the effects of RAM and RSM in portal and systemic
dynamics were investigated in the present study.
MATERIALS AND METHODS
Animal model
Sixteen healthy mixed bred dogs, female and male, weighing
12.5kg-20kg, were divided into two groups randomly: protal
hypertension model group (n=12) made by chronic bile duct ligation
method described by Boschj et al and control group (n=4).
Drugs and administration route
RSM injection (40%), nifedipine injection (50%) (the Ninth Shanghai
Pharmaceutical Factory (batch no 940712123, original drug 1.5g/mL).
The dosage for dogs is 20 times higher than for adult people. The
dosage by intravenous drip (1/3 of oral doses) of RSM 6g/kg body
weight, RAS 3mg/kg body weight, nifedipine 0.3mg/kg body weight in
10% glucose were infused through thigh vein in 10 minutes, according
to our earlier studies. The time was calculated after the infusion.
The dogs were paralyzed with pentobarbital intravenous anesthesia at
fast for 12h in 8-11 weeks after bile ductligation, and tubes were
inserted through vein for infusion, through femoral artery for
measuring the mean arterial pressure and heart rate, through
femoralvein to inferior vena cave for icvp, through mesentery vein
to portal vein for Ppv and from right external jugular vein to
hepatic vein for FHVP and HVPG. The tubes were washed by heparin to
prevent from grume. The indexes were recorded by physiological
recorder (RM-6200) synchronously before and 10, 30 and 60 minutes
after administration of drugs according to Latin rank principle, 3
times per day, each drug being used for 90min-120min. The results
were analyzed by F test and q test.
Clinical study
Patients Fifty-nine patients with hepatic cirrhosis
(hepatitis B, 58 cases; hepatitis C, 1; female 21, male 38, mean age
45.5 years mean course 106 years) were included in. All
patients were consonant with the following conditions: patients with
hard hepato-spleenomegly and esophagogastric varices; patients with
portal diameter ＞1.4cm
with slight or without ascites, no upper digestive tract bleeding
and hepatic encephalopathy. The patients who took vaso-active drugs
such as propanolol, nifedipine and diuretics recently were asked to
stop taking these medicines for a week before entering this study.
Grouping and course of treatment
All patients were divided into 4 groups. Group 1, RSM, 60g/day, 21
patients; group 2, RAS 30g, 15 patients; group 3, RSM 60g/day +nifedipine 30mg/day, 12 patients; and group 4, RSM
60g/day +nifedipine 30mg/day +bloosucker 3g/day , 11 patients. A whole day dose of RSM and RAS were
added with 200ml water and immersed for 20 minutes and then added 600ml
water, cooked with low intensity of fire for three times into 100ml
and taken orally bid. Leech was baked and ground to fine powder and
put in to capusules and taken orally, bid. Nifedipine 30mg, tid, was
administered for 10 to 12 weeks.
Experimental apparatus and methods
The patients were examined by color Doppler ultrasounography (dectector
head 3 .5MHz) at cliostatism position quietly at fast. The Dpv, Vpv,
Dsv and Vsv were measured before and 2.6 and 10 weeks after
treatment. Qpv and Qsv were calculated by the formula: Q=πR2·V·60.
Q: quantity of blood flow, R: half vein diameter (D/2) , V: mean
velocity of blood stream.
RESULTS
Animal model
Two of 12 dogs died at week 2 and 3 respectively due to infection
and 3 dogs died between week 7 to 8 due to hepatic failure. Seven of
12 dogs developed into liver cirrhosis with ascites and abdominal
varices, with body weight loss by 1/4 after bile duct ligation at
week 5. All dogs had liver cirrhosis with a large amount of ascites,
vein of greater omentum congested and abnormal liver function (Bil
83.5μmol/L±4.95μmol/L, ALT 211.67U±44.8U), there was a significant difference compared
with normal animal, P＜0.01.
The special characters of anatomy and histology were coincided to
these of billiary cirrhosis. The mean portal pressure (2.56kPa±0.30kPa)
with cirrhosis were increased significantly compared with normal
dogs (1.18+0.02, P＜0.001).
Effects of RSM and RAS on hemodynamics in health dogs
The portal and systemic circulation index in healthy dogs were not
affected by intravenous administration of RSM and RAS. The MAP of
dogs were lowered 5-10 minutes after RAS administration, but
returned normal 60 minutes later. The portal pressure and MAP were
decreased significantly 60 minutes after administration of nifedpine
compared with those before the drug administration (Ppv 1.50kPa±0.45kPa
vs 1.27kPa±0.61kPa,P＜0.05;
MAP 16.5kPa±0.71kPa vs 0.21kPa±0.19kPa, P＜0.05).
Effects of RSM and RAS on hemodynamics in dogs with liver
cirrhosis
The Ppv, WHVP and HVPG were decreased significantly in dogs with
liver cirrhosis 60 minutes after administration of RSM and RAS (P＜0.05-0.01).
The other indexes were not changed significantly, P＞0.05.
The Ppv, MAP and HR decreased significantly 60 minutes after
administration of nifedipine (P＜0.01),
but HVPG was not changed significantly (P＞0.05).
This result showed that RSM and RAS have selective effects on portal
system in dogs with cirrhosis but without effects on blood pressure
and HR, while nifedepine had effects on blood pressure, Ppv and HR.
Comparison in effects of RSM, RAS and nifedipine on Ppv and
HVPG
The Ppv in dogs with liver cirrhosis were decreased significantly 10
minutes after administration of RSM and nifedipine as compared with
that before (2.62kPa±0.27kPa vs 2.45kPa±0.28kPa,P＜0.05,
2.42kPa±0.05kPa vs 2.05kPa±0.24kPa,P＜0.05).
Although RSM could lower Ppv but not statistically (2.56kPa±0.30kPa
vs 2.43kPa±0.39kPa,P＞0.05).
RAS has a more powerful effect in Ppv and HVPG 30 minutes
after treatment than nifedipine (P＜0.05)
whereas there was no significant difference in effects for Ppv and
HVPG among RSM, RAS and nifedipine (P＞0.05).
It is worthy noticing that RSM and RAS were more effective for Ppv
60 minutes after administration than nifedipine (P＜0.05),
but there was no significant difference between RSM and RAS. The
result demonstrated that the action of nifedipine on portal and
blood pressure is quick and short whereas RSM and RAS last long in
action but without effects on MAP and HR.
Clinical study
Effects of RSM and RAS on portal hemodynamics in patients with
cirrhosis
The Qpv, Dsv, Qpv and Qsv in patients with cirrhosis were lowered
significantly after using RSM (P＜0.01-0.001),
while Dpv, Dsv and Qsv were decreased markedly after using RAS (P=0.05-0.01),
but no significant effects on Qpv (P＞0.05).
The Dpv, Dsv, Dpv and Qsv were all decreased significantly in the
groups of RSM+nifedipine and RSM+bloodsucker+nifedipine 10 weeks
after treatment (P＜0.05-0.01).
The velocity of blood flow of portal and spleen vein were not
changed significantly (P＞0.05).
Comparison of effects of RSM, RAS on Dpv
Dpv decreased significantly in 2 weeks after treatment in the group
RSM+nifedipine and group RSM+leech+nifedipine. The rank order in
effect from strong to week is RSM+leech+nifrdipimne＞RSM
and RSM+nifedipine＞RAS
(P＜0.05-0.01).
Side effects
There was no side effects in the group taking the medicinal herbs. A
few patients had headache, dizziness and so on in the group taking
herbs and nifedipine in combination, but all recovered after
termination of medicine.
DISCUSSION
Calcium antagonist—nifedipine is one of the most common drugs used
to lower portal hypertension, but it can also lower the blood
pressure at large oral doses and some patients had bad tolerance to
it. More and more attention has been paid to the better effect of
RSM and RAS in portal hymodynamics in patients with hepatic
cirrhosis. The present study showed that RSM and RAS used
intravenously could lower Ppv (kPa, 2.56±0.30, 1.82±0.33, 2.43±0.05,
1.38±0.32, P＜0.01),
WHVP (kPa, 2.17±0.36, 1.70±0.30; 2.33±0.09, 1.90±0.33), and HVPG
(kPa, 0.93±0.33, 0.60±0.43; 1.35±0.16, 0.97±0.30) in dogs with
experimental liver cirrhosis, but without any influence on MAP and
HR in normal dogs. Although nifedipine could reduce Ppv, WHVP and HR
in dogs with liver cirrhosis, RSM and RAS had more powerful effects
in lowering portal hypertension and without effect on systemic
pressure as compared with nifedipine. The combination of RSM, RAS,
RSM+niedipine, RSM+nifedipine+leech could reduce Dpv, Dsv, Qpv and
Qsv in patients with liver cirrhosis. RSM and RAS could also improve
the patients′
symptoms and liver funcition. Rapid and prolonged effects could be
obtained, when combined therapy of the herbal medicine and western
drugs was used. This should be further studied. The effects of
nifedipine in lowering portal hypertension is rapid, which appeared
10 minutes after intravenous and 2 weeks oral administration but
with the disadvantage of reducing the blood pressure and HR. The
effect of intravenous RAS in reducing Ppv in dogs with liver
cirrhosis became stronger than nifedipine with the prdayed time of
drug administration (P＜0.05),
but without changes of blood pressure and HR. Although the effect of
RSM in reducing portal hypertension appeared in 30 minutes
intravenously and 6 weeks orally it last longer and became stronger,
and peaking at 60 minutes intravenously (2.56kPa±0.30kPa,1.82kPa±0.33kPa,P＜0.01)
and 10 weeks orally (14.84kPa±1.03kPa, 13.06kPa±1.58kPa,P＜0.001).
The result showed a long course of treatment or intravenous
administration is necessary in RSM. The effect of combination of RSM,
leech and nifedipine in treatment of portal hypertension appeared
rapidly and more powerful, which is a drug logimen of choice for
patients with high Ppv.
The mechanism of
RSM and RAS in lowering portal hypertension has not been well
understood yet. RSM can prevent from liver fibrosis if it is used
for a long time. It was reported that RSM can inhibit fibroblast
cells. Large doses of RSM can activate collagenase and help blockage
the extracellular matrix［4］.
The value P-Ⅲ-P
and lamin were decreased in patients with liver disease after oral
treatment of RSM. The present study demonstrated that long-term oral
treatment of RSM for 10-12 weeks can reduce the portal vein and
spleen diameters and blood flow, but the velocity of blood flow did
not change. The effect become more and more powerful with time. The
present study suggested that combination of RSM, RAS, leech and
nifedipine is effective in lowering hypertension and without side
effects in treatment of liver cirrhosis.
REFERENCES
1 Hu Y,
Wang XL, Li DG, Lu HM, Gu HD, Shi PW et al . Experimental study on
the effects of ca2+ antagonists on rat model
of
cirrhosis with portal hypertension.Chin J Dig, 1995;15(2):89-91
2
Song JB, Li SB. Experimental study of injection angelica and
natrii angelicae on rat portal pressure.Chin J Hepatol,
1996;4(3):158-160
3 Huang ZP,
Go B, Liang KH. Effects of radix angelicae sinensis on systemic and
portal hemodynamics in cirrhotics with
portal
hypertension. Chin J Med, 1996;35(1):15-18
4 Li XT,
Bai WY, Wang HM, Yao XX. Study of effects of Radix salviae
miltiorrhizae on portal hypertension in experimental
cirrhotic
dogs. New J Dig Dis, 1997;5(7):421-422
5 Yao XX,
Li XT, Li YW, Zhang XY. Clinical and experimental study of radix
salviae miltiorrhiza and other Chinese herbs
of
blood-activating and stasis-eliminating effects on hemodynamics of
portal hypertension. Chin J Dig, 1998;18(1):24-27
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