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Ranitidine as an inhibitor of liver regeneration
Ranitidine as an Inhibitor of Liver Regeneration
Ryoichi Kanashlma, MD, Fukuoka, Japan Naofuml Nagasue, MD, Hiroshima, Japan Kazuhide Sakato, MD, Fukuoka, Japan
During the last 5 years, hepatic disorder associated with cimetidine therapy has been a matter of great concern in treating patients with peptic ulcer disease [ I - 4 ] . Our previous work both in animals and human subjects has also denmnstrated that the histamine H2-receptor antagonist cimetidine produces a deleterious effect on liver regeneration after hepatectomy, if administered postoperatively for prophylaxis of the life-threatening complication of stress ulcer syndrome [5,6]. Recently, a new histamine H2-receptor antagonist ranitidine has been introduced in clinical trials. It was hoped that this more potent Ho-blocking agent would prodtice fewer side effects, especially less hepatotoxicity [7,8]. Indeed, ranitidine-induced liver damage has not been proved as yet, except for one case that has been reported by Australian internists, but without scientific data [9]. In this study, we used a protocol previously described to assess the effect of the ranitidine on hepatic regeneration and to evaluate the mechanism of liver disorder related to the administration of this H2-receptor antagonist. Material and Methods Adult female albino rats (Sprague-Dawley) that weighed 192 to 277 g were used for investigation. Standard pilled food and water were not restricted either before or after operation. While the rats were under light ether anesthesia, partial hepatectomy was carried out according to the tei:hnique of Higgins and Anderson [I0]. Surgery was performed between 9i00 and 11:00 AMto prevent the influence of diurnal variations of the regenerative response. The whc!e operation took less than 10 minutes. The animals were divided into three groups and treated. Group I consisted of 46 rats that were subjected to two-thirds hepatectomy; Group II consisted of 71 rats that received an intramuscular injection of ra~2tidine (8 mg/kg body weight) through the right thigh immediately and 24 and 48 hours after the same hepatectomy procedure; and Group III was composed of 35 rats that had a sham operation and received 8 mg/kg body weight of ranitidine. Frc~mthe Department of Surgery. N~tlonal FukuokaEast Hospital. Fukuoka. and the Department of Surgery. Hiroshima Red Cross Hospital. Hiroshlrna. Japan. Requestsfor reprints shOuld be addressed to RyoichlKanashlma,MD, Department of Surgery. Level 9. Addenbrooke's Hospital. Hills Road. Cambridge (31322QQ. United Kingdc,n.
Volume149,Febmar/1085
Five to 10 rats in Groups I and II and 4 to 5 animals in Group ]II were killed 24 and 30 hours and 2, 3, 5, 7, and 14 days postoperatively. Immediately before death, blood samples were taken for chemical analysis from tile inferior vena cava with the rats under light ether anesthesia, and the remnant livers were removed for the investigation of liver restoration, histologic characteristics, and mitotic activities. For each animal, serum activities of asparate aminotransferase and alanine aminotransferase were determined by the ultraviolet spectrophotometry method. For the preoperative controls of these compounds, elght normal rats were exsanguinated. The regenerative rate in each experiment was obtained by dividing the moist weight of the remaining liver by the estimated preoperative weight of the whole liver and multiplying by 100, Each liver specimen was stained for histologic examinations with hematoxylin-eosin, and the mitotic index of hepatocytes was counted. The statistical comparison for significance was performed according to the Student's t test and the Cochran-Cox test. A p value of less than 0.05 was considered to be significant. Results The administration of' ranitidine after hepatectomy (Group II) resulted in a high mortaliW (45 percent). All deaths occurred within 48 hours, 20 being within 24 hours and 12 between 24 and 48 hours after hepatectomy. Conversely, no rat in Group I died during the investigation, and only 1 of 35 in Group III died postoperatively. Statistical differences in mortalities among the experimental groups were as follows: Group II versus Group I, p <0.001; Group II versus Group III, p <0.001; and Group III versus Group I, 0.4 < p <0.5. The m e a n weights of the hepatic remnants are shown in Figure I as the percentages of the calculated preoperative whole liver weight. The weights of the remaining remnant livers increased rapidly during the first 7 days in Group I. In the group treated with ranitidine (Group II), the weight gain was stabilized between 5 and 7 days postoperatively, although there was no significant difference between the groups. The serum activities of alanine aminotransferase and asparate aminotransferase are serially depicted in Figure 2. Ranitidine therapy after hepatectomy caused elevations of both transaminases during the first 48 hours after operation, compared with the 223
Kanashima et al
(Karmen Units)
Regenerat ive Rate (%
~so i
S-ALT
100
Q............ • \
I A../..--!_-"i i
Hopatectomy
o. . . . . . . . o Hepatect omy
~Yr
~.....
~ Sham op.
Ranitidine e
Ranitidlne
"
f 800
600
, 24
Time in hours
|
i
I
Time in days
Figure 1. Wet weights of the hepatic remnants as petcenEages of the calculaled preoperattve whole fiver wetght (mean 4- standard error of the mean).
Mitotic ! ndex ~0
'/ J
!
Time in hours
! I
~
I
I
-'Z___J
Time in days
Figure 2. Changes In serum activities of alanltm amlnotransterase ( S-AL T) and asparate arhtnotransferase (S.AST) after two-thirds hepateclomy with and without ranitidb~e, and after the sham opera#on with ranitldlne (mean :k standard error of the mean). Asterisk indicates a sta#sticaity significant difference beRween the hepatectomlzed groups ( p <0.05). ........
~ Ranitidine
10
Time in hours
Time in days
Figure 3. Mitotic Index of hepatocytes per 1,000 counts after two-thirds ltepetectomy with and without the administration of ranttid#m, and after the Mlam operation with ranitidIne ( mean 4standard error of the mean). Asterisks Indicate a statistically significant dl/ferences between the hepatecfomized groups (p
transaminase levels in those who did not receive the drug (Group I). Between the two groups, the statistical significance was observed in the aspartate aminotransferase values 30 hours after hepatectomy. In
224
the shmn operation and ranitidine group (Group III), only a slight increase in both enzyme levels was noted 24 hours after surgery. Figure 3 demonstrates serial changes in mitotic activities of the hepatocytes in the remnant livers after hepatectomy in Groups I and II. The maximum mitotic acitivity of the hepatocytes was found 30 hours after hepatectomy in Group I, whereas it was delayed to 48 hours in the hepatectomized group treated with ranitidine (Group II). In Group III, few parenehymal cells were in the mitotic phase. H/stologic challges of the representative livers are illustrated in Figure 4. In Group I, infiltration of fat droplets were ~emarkable in the hepatoeytes during the first 48 hours. Slight dilation of the sinusoids was seen within the first week. On the other hand, in Group II, profound steatosis of the parenchymal cells continued until the fifth postoperative day. The sinusoidal space remained significantly dilated between the 3rd and 14th postoperative days. In Group III, no prominent abnormalities were observed.
The American Jo~rna! of Sutgecy
|
I
.,~A
.b-l~
}sI
a~
r-
~p
Kanashima et al
Comments
We have previously shown that cimetidine suppresses liver regeneration after partial hepatectomy in experimental and clinical studies [5,6]. Two possibilities were considered to be the causative mechanisms: a direct hepatocytotoxic effect and an indirect effect resulting from lowered hepatic blood flow. As for the former possibility, we suggested that the chemical structure of cimetidine, including a central imidazole ring, could be responsible for inhibiting hepatocyte proliferation, since many imidazole compounds impair the oxidation process in the hepatic microsomes [11]. Ranitidine, a new histamine H2-receptor antagonist, differs from cimetidine in that the imidazole nucleus has been replaced by a furanyl nucleus and the side chain has been modified. Both drugs have a common attribute of histamine H2-receptor antagonism, although ranitidine is 4 to 10 times more potent or~a weight basis than cimetidine in reducing gastri~ acid secretion [8]. Consequently, it has becomes'~vident that ranitidine, unlike cimetidine, does not change the hepatic handling of drugs that require microsomal enzyme oxidase activity [12-14]. Therefore, it seems likely that the suppressive effect of cimetidine therapy on hepatocyte proliferation would not be seen with ranitidine administration if the imidazole structure were the causative factor. In our work, however, the administration of therapeutic doses of ranitidine for 3 days after two-thirds hepatectomy resulted in substantial delay of liver cell proliferation. Coincident with the retardation of hepatocyte renewal, the profound liver steatosis remained longer after hepatectomy in the rats treated with ranitidine (Group II) than in the nontreated animals (Group I). The significant elevation of serum aminotransferase activities in Group II confirmed a harmful effect of ranitidine on the regenerating fiver. Furthermore, the extremely high mortality rate of the hepatectomized group treated with ranitidine, in which almost half of the animals died during the experiment, poses a question about the safety of its clinical use after extensive liver resection. The present results and recent reports by us indicate that the imidazole structure probably has a negligible role in the inhibition of liver cell proliferation [5,6]. Other direct cytotoxic mechanisms should be defined through further studies. In our previous study, we suggested a reduction in liver blood flow as another possible cause of the inhibitory effect of clmet]dme " " ~ on hepatic regeneration. In that paper, we cited the original report by Feely et al [I5], which stated that the short-term administration of cimetidine reduces fasting hepatic blood flow in healtby human subjects by almost 25 percent, as measured by indocyanine green clearance. They further showed that ranitidine also decreases liver
226
blood flow using the same technique [16]. However, their conclusions have not been accepted by several investigators because of the method used [17-22]. These scientists claimed that the blood clearance of indocyanine green was not equivalent to liver blood flow. There are ample data in both animal and human subjects to indicate that the decrease of indocyanine green clearance caused by cimetidine does not reflect the reduction in hepatic blood flow," but rather the alterations in indocyanine green extraction in the liver. Indeed, Tyden et al [22] directly measured the flow volume entering the liver in human subjects with electromagnetic flow probes, but they did not find any reduction in total hepatic blood flow after administration of cimetidine. It is necessary to determine exactly whether or not ranitidine reduces hepatic blood flow, especially after extensive hepatectomy, by using a more direct method such as electromagnetic flowmetry. On the basis of the present and previous observations by us, we conclude that ranitidine, like cimetidine, inhibits liver regeneration after hepatectomy. The chemical property, the central imidazole nucleus, is probably not related to the suppression of liver cell proliferation. Other causes must be searched for in further investigations. Summary
The effects of ranitidine, a new H2-receptor antagonist, on liver regeneration were investigated using a protocol described previously. The animals in Group I had standard two-thirds hepatectomy. In Group II, the rats received an 8 mg/kg intramuscular dose of ranitidine immediately and 24 and 48 hours after two-thirds hepatectomy. In Group III, the rats had the same amounts of ranitidine after a sham operation. Mortality rate, liver weight restoration, mitotic activities of the residual livers, and serum levels of aminotransferases were examined from 24 hours to 14 days after operation. The mortality was very high in Group II (45 percent), whereas no rats died in Group I, and only 1 of 35 animals died in Group III. Administration of ranitidine after hepatectomy resulted in suppression not only of liver restoration, but also of the mitotic activities of hepatocytes. The serum aminotransferase levels in Group II had a tendency to increase after hepatectomy, compared with the levels in Group I. Using light microscopy, we detected that the hepatectomized group treated with ranitidine (Group II) underwent profound hver steatosis and marked dilatation of sinusoidal spaces. The present and previous observations by us indicate that ranitidine also inhibits, like cimetidine, liver regeneration after hepatectomy. The causes of the inhibitory effects of both cimetidine and ranitidine on hepatocyte cell division have also been discussed herein.
The American Journal of Surgery
Ranltldine and Liver Regeneration
References 1. Lilly JR, Hitch DC, Javltt NB. Cimettdlne cholestatic jaundice in children. J Surg Res 1978;24:384-7. 2. VIIleneuve JP, Warner HA. Clmetidine hepatitis. C-=astroenterology 1979;77:143-4. 3. Rulz del A rbol t., Moreira V, Moreno A, Herbndez Ranz F, Cano A, Garcla Pk~zaA. Brldg|ng hepatic necrosis associated with clmetldlne. Am J Gastroenterol 1980;74:267-9. 4. Lorenzlnl 1,Jezequel AM, Orlandt F. Cimettdlne~lnduced hepatitis. Electron microscopic observations and clinical pattern of liver Inlury. Dig Dis Sci 1981;26:275-80. 5. Kanashlma R, Nagasue N, Furusawa M, Inokuchl K. Inhibitory effect of clmetidlne on liver regeneration after two-thirds hepatectomy in rats. Am J Surg 1983;146:293-8. 6. Nagasue N, Yukays H, Ogawn Y, Sasaki Y, HIrose S. Prophylaxis of upper gastrointestinal bleeding with cimefldlne in patients undergoing partial bepatectomy.Ann Chlr Gynaecol (In press). 7. Peden NR, Saunders JHB, Wormsley KG. Inhibition of pentagastrln.sttmulated and nocturnal gastric secretion by ranltidlne. Lancet t979; 1:690-2. 8. Brogden RN, Carmine AA, Heel RC, Spelght TM, Avery GS. Ranttidine:a review of its pharmacology and therapeutic use in peptic ulcer disease and other allied diseases. Drugs 1982;24:267-303. 9. Barr GD, Piper DW. Possible ranlUdlne hepatitis. Mad J Aust 1981;2:421. 10. HIgglns GM, Anderson RM. Experimental pathology of the liver. Arch Pathoi 1931:12:186-202.
Voltmle 149, February 1985
11. Wilkinson CF, Hetnarskl K, Hicks LJ. Substituted tmk.lazoles as Inhlbitors of mlcrosomal oxidation and insecticide synergtats. Pestlc Blochem Physlo11974;4:299-312. 12. Henry DA, Macdonald IA, KItchingman G, Bell GD, Langman MJS. Clmetidlne and ranltidtne: comparison of effects on hepatic metabolism. Br Mad J 1980;281:775-7. 13. SerUn RG, SIbeon RG, Breckenrtdge AM. Lack of effect of ranltldlne on warfarin action. Br J Clln Pharmacol 1981; 12:791-4. 14. Heagerty AM, Castleden CM, Petal L. Failure of ranltidlne to interact with propanoloL Br Mad J 1982;284:1304. 15. Feet)' J, Wilkinson EFt, Wood AJJ. Reduction of liver blood flow and propranolol metabolism by ctmetldfne. N Engl J Mad 1981;304:692-5. 16. Feeley J, Guy E. RanltidineaLsoreduces liver blood flow. Lancet 1982;1:169. 17. Jackson JE. Reduction of ltve~rblood flow by cimetidtne. N Engl J Mad 1981;305:99-100. 18. Lebrec D, Goldtarb G, Benhamou JP. Reduction of liver blood flow by c,~metidine.N Engl J Mad 1981;305:100. 19. Grainger SL, Marigold JH, Keeling PWN. Ranltidine and liver blood flow. Lancet 1982; 1:398. 20. Burroughs AK, Walt R, Dunk A, et aJ. Effect of clmetldine on portal hypertension In cirrhotic patients. Br Mad J 1982; 284:1159-60. 21. Herz R, Bonzel E, Keller E, Rbssle M, Gerok W. Clmetldlne Increases liver blood flow In cirrhosis. Hepatology 1982;1: 515. 22. Tyrian G, Thulin L, Nyberg B, The effect of ctmettdine on liver blood flow In anesthetized man, Acts Chtr Scand 1983; 149:303-5.
227
Ryoichi Kanashlma, MD, Fukuoka, Japan Naofuml Nagasue, MD, Hiroshima, Japan Kazuhide Sakato, MD, Fukuoka, Japan
During the last 5 years, hepatic disorder associated with cimetidine therapy has been a matter of great concern in treating patients with peptic ulcer disease [ I - 4 ] . Our previous work both in animals and human subjects has also denmnstrated that the histamine H2-receptor antagonist cimetidine produces a deleterious effect on liver regeneration after hepatectomy, if administered postoperatively for prophylaxis of the life-threatening complication of stress ulcer syndrome [5,6]. Recently, a new histamine H2-receptor antagonist ranitidine has been introduced in clinical trials. It was hoped that this more potent Ho-blocking agent would prodtice fewer side effects, especially less hepatotoxicity [7,8]. Indeed, ranitidine-induced liver damage has not been proved as yet, except for one case that has been reported by Australian internists, but without scientific data [9]. In this study, we used a protocol previously described to assess the effect of the ranitidine on hepatic regeneration and to evaluate the mechanism of liver disorder related to the administration of this H2-receptor antagonist. Material and Methods Adult female albino rats (Sprague-Dawley) that weighed 192 to 277 g were used for investigation. Standard pilled food and water were not restricted either before or after operation. While the rats were under light ether anesthesia, partial hepatectomy was carried out according to the tei:hnique of Higgins and Anderson [I0]. Surgery was performed between 9i00 and 11:00 AMto prevent the influence of diurnal variations of the regenerative response. The whc!e operation took less than 10 minutes. The animals were divided into three groups and treated. Group I consisted of 46 rats that were subjected to two-thirds hepatectomy; Group II consisted of 71 rats that received an intramuscular injection of ra~2tidine (8 mg/kg body weight) through the right thigh immediately and 24 and 48 hours after the same hepatectomy procedure; and Group III was composed of 35 rats that had a sham operation and received 8 mg/kg body weight of ranitidine. Frc~mthe Department of Surgery. N~tlonal FukuokaEast Hospital. Fukuoka. and the Department of Surgery. Hiroshima Red Cross Hospital. Hiroshlrna. Japan. Requestsfor reprints shOuld be addressed to RyoichlKanashlma,MD, Department of Surgery. Level 9. Addenbrooke's Hospital. Hills Road. Cambridge (31322QQ. United Kingdc,n.
Volume149,Febmar/1085
Five to 10 rats in Groups I and II and 4 to 5 animals in Group ]II were killed 24 and 30 hours and 2, 3, 5, 7, and 14 days postoperatively. Immediately before death, blood samples were taken for chemical analysis from tile inferior vena cava with the rats under light ether anesthesia, and the remnant livers were removed for the investigation of liver restoration, histologic characteristics, and mitotic activities. For each animal, serum activities of asparate aminotransferase and alanine aminotransferase were determined by the ultraviolet spectrophotometry method. For the preoperative controls of these compounds, elght normal rats were exsanguinated. The regenerative rate in each experiment was obtained by dividing the moist weight of the remaining liver by the estimated preoperative weight of the whole liver and multiplying by 100, Each liver specimen was stained for histologic examinations with hematoxylin-eosin, and the mitotic index of hepatocytes was counted. The statistical comparison for significance was performed according to the Student's t test and the Cochran-Cox test. A p value of less than 0.05 was considered to be significant. Results The administration of' ranitidine after hepatectomy (Group II) resulted in a high mortaliW (45 percent). All deaths occurred within 48 hours, 20 being within 24 hours and 12 between 24 and 48 hours after hepatectomy. Conversely, no rat in Group I died during the investigation, and only 1 of 35 in Group III died postoperatively. Statistical differences in mortalities among the experimental groups were as follows: Group II versus Group I, p <0.001; Group II versus Group III, p <0.001; and Group III versus Group I, 0.4 < p <0.5. The m e a n weights of the hepatic remnants are shown in Figure I as the percentages of the calculated preoperative whole liver weight. The weights of the remaining remnant livers increased rapidly during the first 7 days in Group I. In the group treated with ranitidine (Group II), the weight gain was stabilized between 5 and 7 days postoperatively, although there was no significant difference between the groups. The serum activities of alanine aminotransferase and asparate aminotransferase are serially depicted in Figure 2. Ranitidine therapy after hepatectomy caused elevations of both transaminases during the first 48 hours after operation, compared with the 223
Kanashima et al
(Karmen Units)
Regenerat ive Rate (%
~so i
S-ALT
100
Q............ • \
I A../..--!_-"i i
Hopatectomy
o. . . . . . . . o Hepatect omy
~Yr
~.....
~ Sham op.
Ranitidine e
Ranitidlne
"
f 800
600
, 24
Time in hours
|
i
I
Time in days
Figure 1. Wet weights of the hepatic remnants as petcenEages of the calculaled preoperattve whole fiver wetght (mean 4- standard error of the mean).
Mitotic ! ndex ~0
'/ J
!
Time in hours
! I
~
I
I
-'Z___J
Time in days
Figure 2. Changes In serum activities of alanltm amlnotransterase ( S-AL T) and asparate arhtnotransferase (S.AST) after two-thirds hepateclomy with and without ranitidb~e, and after the sham opera#on with ranitldlne (mean :k standard error of the mean). Asterisk indicates a sta#sticaity significant difference beRween the hepatectomlzed groups ( p <0.05). ........
~ Ranitidine
10
Time in hours
Time in days
Figure 3. Mitotic Index of hepatocytes per 1,000 counts after two-thirds ltepetectomy with and without the administration of ranttid#m, and after the Mlam operation with ranitidIne ( mean 4standard error of the mean). Asterisks Indicate a statistically significant dl/ferences between the hepatecfomized groups (p
transaminase levels in those who did not receive the drug (Group I). Between the two groups, the statistical significance was observed in the aspartate aminotransferase values 30 hours after hepatectomy. In
224
the shmn operation and ranitidine group (Group III), only a slight increase in both enzyme levels was noted 24 hours after surgery. Figure 3 demonstrates serial changes in mitotic activities of the hepatocytes in the remnant livers after hepatectomy in Groups I and II. The maximum mitotic acitivity of the hepatocytes was found 30 hours after hepatectomy in Group I, whereas it was delayed to 48 hours in the hepatectomized group treated with ranitidine (Group II). In Group III, few parenehymal cells were in the mitotic phase. H/stologic challges of the representative livers are illustrated in Figure 4. In Group I, infiltration of fat droplets were ~emarkable in the hepatoeytes during the first 48 hours. Slight dilation of the sinusoids was seen within the first week. On the other hand, in Group II, profound steatosis of the parenchymal cells continued until the fifth postoperative day. The sinusoidal space remained significantly dilated between the 3rd and 14th postoperative days. In Group III, no prominent abnormalities were observed.
The American Jo~rna! of Sutgecy
|
I
.,~A
.b-l~
}sI
a~
r-
~p
Kanashima et al
Comments
We have previously shown that cimetidine suppresses liver regeneration after partial hepatectomy in experimental and clinical studies [5,6]. Two possibilities were considered to be the causative mechanisms: a direct hepatocytotoxic effect and an indirect effect resulting from lowered hepatic blood flow. As for the former possibility, we suggested that the chemical structure of cimetidine, including a central imidazole ring, could be responsible for inhibiting hepatocyte proliferation, since many imidazole compounds impair the oxidation process in the hepatic microsomes [11]. Ranitidine, a new histamine H2-receptor antagonist, differs from cimetidine in that the imidazole nucleus has been replaced by a furanyl nucleus and the side chain has been modified. Both drugs have a common attribute of histamine H2-receptor antagonism, although ranitidine is 4 to 10 times more potent or~a weight basis than cimetidine in reducing gastri~ acid secretion [8]. Consequently, it has becomes'~vident that ranitidine, unlike cimetidine, does not change the hepatic handling of drugs that require microsomal enzyme oxidase activity [12-14]. Therefore, it seems likely that the suppressive effect of cimetidine therapy on hepatocyte proliferation would not be seen with ranitidine administration if the imidazole structure were the causative factor. In our work, however, the administration of therapeutic doses of ranitidine for 3 days after two-thirds hepatectomy resulted in substantial delay of liver cell proliferation. Coincident with the retardation of hepatocyte renewal, the profound liver steatosis remained longer after hepatectomy in the rats treated with ranitidine (Group II) than in the nontreated animals (Group I). The significant elevation of serum aminotransferase activities in Group II confirmed a harmful effect of ranitidine on the regenerating fiver. Furthermore, the extremely high mortality rate of the hepatectomized group treated with ranitidine, in which almost half of the animals died during the experiment, poses a question about the safety of its clinical use after extensive liver resection. The present results and recent reports by us indicate that the imidazole structure probably has a negligible role in the inhibition of liver cell proliferation [5,6]. Other direct cytotoxic mechanisms should be defined through further studies. In our previous study, we suggested a reduction in liver blood flow as another possible cause of the inhibitory effect of clmet]dme " " ~ on hepatic regeneration. In that paper, we cited the original report by Feely et al [I5], which stated that the short-term administration of cimetidine reduces fasting hepatic blood flow in healtby human subjects by almost 25 percent, as measured by indocyanine green clearance. They further showed that ranitidine also decreases liver
226
blood flow using the same technique [16]. However, their conclusions have not been accepted by several investigators because of the method used [17-22]. These scientists claimed that the blood clearance of indocyanine green was not equivalent to liver blood flow. There are ample data in both animal and human subjects to indicate that the decrease of indocyanine green clearance caused by cimetidine does not reflect the reduction in hepatic blood flow," but rather the alterations in indocyanine green extraction in the liver. Indeed, Tyden et al [22] directly measured the flow volume entering the liver in human subjects with electromagnetic flow probes, but they did not find any reduction in total hepatic blood flow after administration of cimetidine. It is necessary to determine exactly whether or not ranitidine reduces hepatic blood flow, especially after extensive hepatectomy, by using a more direct method such as electromagnetic flowmetry. On the basis of the present and previous observations by us, we conclude that ranitidine, like cimetidine, inhibits liver regeneration after hepatectomy. The chemical property, the central imidazole nucleus, is probably not related to the suppression of liver cell proliferation. Other causes must be searched for in further investigations. Summary
The effects of ranitidine, a new H2-receptor antagonist, on liver regeneration were investigated using a protocol described previously. The animals in Group I had standard two-thirds hepatectomy. In Group II, the rats received an 8 mg/kg intramuscular dose of ranitidine immediately and 24 and 48 hours after two-thirds hepatectomy. In Group III, the rats had the same amounts of ranitidine after a sham operation. Mortality rate, liver weight restoration, mitotic activities of the residual livers, and serum levels of aminotransferases were examined from 24 hours to 14 days after operation. The mortality was very high in Group II (45 percent), whereas no rats died in Group I, and only 1 of 35 animals died in Group III. Administration of ranitidine after hepatectomy resulted in suppression not only of liver restoration, but also of the mitotic activities of hepatocytes. The serum aminotransferase levels in Group II had a tendency to increase after hepatectomy, compared with the levels in Group I. Using light microscopy, we detected that the hepatectomized group treated with ranitidine (Group II) underwent profound hver steatosis and marked dilatation of sinusoidal spaces. The present and previous observations by us indicate that ranitidine also inhibits, like cimetidine, liver regeneration after hepatectomy. The causes of the inhibitory effects of both cimetidine and ranitidine on hepatocyte cell division have also been discussed herein.
The American Journal of Surgery
Ranltldine and Liver Regeneration
References 1. Lilly JR, Hitch DC, Javltt NB. Cimettdlne cholestatic jaundice in children. J Surg Res 1978;24:384-7. 2. VIIleneuve JP, Warner HA. Clmetidine hepatitis. C-=astroenterology 1979;77:143-4. 3. Rulz del A rbol t., Moreira V, Moreno A, Herbndez Ranz F, Cano A, Garcla Pk~zaA. Brldg|ng hepatic necrosis associated with clmetldlne. Am J Gastroenterol 1980;74:267-9. 4. Lorenzlnl 1,Jezequel AM, Orlandt F. Cimettdlne~lnduced hepatitis. Electron microscopic observations and clinical pattern of liver Inlury. Dig Dis Sci 1981;26:275-80. 5. Kanashlma R, Nagasue N, Furusawa M, Inokuchl K. Inhibitory effect of clmetidlne on liver regeneration after two-thirds hepatectomy in rats. Am J Surg 1983;146:293-8. 6. Nagasue N, Yukays H, Ogawn Y, Sasaki Y, HIrose S. Prophylaxis of upper gastrointestinal bleeding with cimefldlne in patients undergoing partial bepatectomy.Ann Chlr Gynaecol (In press). 7. Peden NR, Saunders JHB, Wormsley KG. Inhibition of pentagastrln.sttmulated and nocturnal gastric secretion by ranltidlne. Lancet t979; 1:690-2. 8. Brogden RN, Carmine AA, Heel RC, Spelght TM, Avery GS. Ranttidine:a review of its pharmacology and therapeutic use in peptic ulcer disease and other allied diseases. Drugs 1982;24:267-303. 9. Barr GD, Piper DW. Possible ranlUdlne hepatitis. Mad J Aust 1981;2:421. 10. HIgglns GM, Anderson RM. Experimental pathology of the liver. Arch Pathoi 1931:12:186-202.
Voltmle 149, February 1985
11. Wilkinson CF, Hetnarskl K, Hicks LJ. Substituted tmk.lazoles as Inhlbitors of mlcrosomal oxidation and insecticide synergtats. Pestlc Blochem Physlo11974;4:299-312. 12. Henry DA, Macdonald IA, KItchingman G, Bell GD, Langman MJS. Clmetidlne and ranltidtne: comparison of effects on hepatic metabolism. Br Mad J 1980;281:775-7. 13. SerUn RG, SIbeon RG, Breckenrtdge AM. Lack of effect of ranltldlne on warfarin action. Br J Clln Pharmacol 1981; 12:791-4. 14. Heagerty AM, Castleden CM, Petal L. Failure of ranltidlne to interact with propanoloL Br Mad J 1982;284:1304. 15. Feet)' J, Wilkinson EFt, Wood AJJ. Reduction of liver blood flow and propranolol metabolism by ctmetldfne. N Engl J Mad 1981;304:692-5. 16. Feeley J, Guy E. RanltidineaLsoreduces liver blood flow. Lancet 1982;1:169. 17. Jackson JE. Reduction of ltve~rblood flow by cimetidtne. N Engl J Mad 1981;305:99-100. 18. Lebrec D, Goldtarb G, Benhamou JP. Reduction of liver blood flow by c,~metidine.N Engl J Mad 1981;305:100. 19. Grainger SL, Marigold JH, Keeling PWN. Ranltidine and liver blood flow. Lancet 1982; 1:398. 20. Burroughs AK, Walt R, Dunk A, et aJ. Effect of clmetldine on portal hypertension In cirrhotic patients. Br Mad J 1982; 284:1159-60. 21. Herz R, Bonzel E, Keller E, Rbssle M, Gerok W. Clmetldlne Increases liver blood flow In cirrhosis. Hepatology 1982;1: 515. 22. Tyrian G, Thulin L, Nyberg B, The effect of ctmettdine on liver blood flow In anesthetized man, Acts Chtr Scand 1983; 149:303-5.
227