Protective Effect of Diltiazem Hydrochloride on the Occurrence of Alloxan- or Streptozotocin-Induced Diabetes in Rats
Summary This study demonstrated that 20mg/kg of the Ca 2+ channel blocker, diltiazem hydrochloride, administered by intraperitoneal injection 15 min before 200mg/kg of alloxan given by the same route to induce diabetes, served to suppress disease onset completely in rats. Even though 48-h fasting promoted the onset of alloxan diabetes, 40 mg/ kg of diltiazem hydrochloride completely prevented the occurrence of diabetes induced by intraperitoneal injection of 200mg/kg of alloxan. Forty mg/kg of the same agent, however, failed to prevent the onset of diabetes induced by the intravenous injection of streptozotocin (50mg/kg). From the fact that Ca 2+ channel blockers such as nicardipine, verapamil and bepridil have a similar suppressive effect on the occurrence of alloxan diabetes, one may readily infer that this action is characteristic of Ca 2+ channel blockers. Moreover, the results suggest the close connection of Ca 2+ in the occurrence of alloxan diabetes in rats. Key words Diabetes - Alloxan - Streptozotocin - Ca 2+ Channel Blocker - Diltiazem Hydrochloride
Introduction It is reported that there is an increased production of superoxide (Hermgren and Lyckeberg 1980) and H2O2 in the B cell of the rat pancreeas (Takasu, Asawa, Komiya, Nagasawa and Yamada 1991) in the initial stage of alloxan diabetes, and that the occurrence of alloxan diabetes can be prevented by suppressing the superoxide production in rat (Uchigata, Yamamoto and Okamoto 1982). It is also reported that H2O2 generation or an increase of superoxide at B cell of pancreas in rats induced by alloxan has a key role in the DNA strand break, an important step in the occurrence of alloxan diabetes as well as streptozotocin diabetes (Yamamoto, Uchigata and Okamoto 1981), although Lenzen and Panten believe that the step of the inhibition of glucokinase is important for the occurrence of alloxan diabetes (Lenzen and Panten 1988). Re-
Horm. metab. Res. 24 (1992) 508-510 © Georg Thieme Verlag Stuttgart • New York
cently, it is reported that superoxide anion increases intracellular free calcium in human myometrial cells (Matsumoto, Tasaka, Miyake and Tanizawa 1990) and also in human endothelial cells (Franceshi, Graham, Sarasua and Zollinger 1990). Inversely, a Ca 2+ increase has been found to result in a superoxide increase in rat liver (Nakashima, Seto, Nakajima, Shima, Sakamoto, Sano and Cho 1990), or in cultured rat ventricular myocytes (Burton, Morris, Massey Buja and Hagler 1990). Thus, there is some possibility that alloxan and streptozotocin diabetes could be prevented by inhibiting the Ca 2+ increase with a Ca 2+ blocker. In fact, the present investigators earlier reported that verapamil (Katsumata and Katsumata 1988b) and nicardipine (Katsumata and Katsumata 1988a) prevented the occurrence of alloxan diabetes in rats. In the present study, we sought to determine whether this same suppression is common to the Ca 2+ channel blockers, whether this same result could be effected with diltiazem hydrochloride, and at the same time attempted to ascertain if it would have the same effect on streptozotocin diabetes in rats. In addition, we wished to determine whether a Ca 2+ channel blocker has an action to suppress the onset of alloxan diabetes in the sustained fasting condition, in which the occurrence of alloxan diabetes is reportedly promoted in rats (Kass and Waisbren 1945). Materials and Method Male Wistar rats weighing approximately 150 g were individually housed in metabolic cages in a temperature-controlled animal room (23±2°C) and fed a commercial diet with free access to water. After overnight fast, the rats were given an intraperitoneal injection of 13 or 20 mg/kg of diltiazem hydrochloride (Herpesser, Tanabe Co. Tokyo) and injected 15 minutes later with different concentrations of alloxan (Wako Pure Chemical Inc. Osaka) which were dissolved in normal saline just before use. In control rats, instead of diltiazem hydrochloride physiological saline was intraperitoneally injected. In the sustained fasting experiment, following a 48-h fast, the rats were given an intraperitoneal injection of various concentrations of diltiazem hydrochloride and injected 15 min later with different concentrations of alloxan. Another group was fasted overnight and diltiazem hydrochloride at a dose of 20 mg/kg or 40 mg/kg was intraperitoneally injected and 15 min later injected in the tail vein with various levels of streptozotocin (Sigma Chemical Co. USA) dissolved in 50 mM citrate buffer (pH 4.5) instead of alloxan. Controls were injected with physiological saline instead of 40 mg/kg of diltiazem hydrochloride. After alloxan or streptozotocin administration, the animals were given food and water ad lib for two days. Then, they were fasted overnight, and their blood was sampled through the tail vein for the measurements of Received: 29 Oct. 1991
Accepted: 28 Feb. 1992
Downloaded by: East Carolina University. Copyrighted material.
K. Katsumata1, K. Katsumata, Jr.2 and Y. Katsumata3 1 Katsumata Hospital, Nagoya 2 Chukyo Hospital, Nagoya 3 Department of Legal Medicine, Nagoya University School of Medicine, Nagoya, Japan
Diltiazem Hydrochloride and Alloxan Diabetes
Horm. metab. Res. 24 (1992) Table 2 Effect of diltiazem hydrochloride on the occurrence of alloxan diabetes in 48-h fasted rats.
Blood glucose level (mg/dl) Alloxan (mg/kg)
Control fed
Diltiazem hydrochloride 13 mg/kg 20 mg/kg
100
97 + 4 (0)
120
96±16* (0)**
150
297 ±15* (5)**
237 ±25* (5)**
180
325 ±46 (5)
200
385 ±54 (5)
Blood glucose level (mg/dl) Alloxan (mg/kg)
Control fed
Diltiazem hydrochloride 20 mg/kg 40 mg/kg
80
87 ±10* (0)**
100
219±18* (5)**
101 ± 7 (0)
83± 7 (0)
90±7 (0)
120
323 ±43 (5)
98±11 (0)
97 ±13 (0)
309 ±20 (5)
99±4 (0)
150
391 ±11 (5)
109± 9 (0)
89 ± 8 (0)
424 ±32 (5)
103±9 (0)
180
569 ±19 (5)
496±17 (5)**
115±25 (0)
200
629 ±34 (5)
611 ±25 (5)
155±29 (0)
Number of rats developing diabetes out of five rats are given in parentheses. Rats showing more than 200 mg/dl of blood glucose at overnight fasting were diagnosed as diabetic. * P < 0.001 Student's t-test ** P < 0.01 Fisher's exact test.
blood glucose by the glucose oxidase method. Diabetes was considered to have occurred at a high blood glucose level of over 200 mg/dl at fasting. Alloxan dosages weere 100, 120, 150, 180 and 200mg/kg, while those of strepotzotocin were 30, 40 and 50mg/kg. Five rats on each dose formed a single group in the experiment. The rate of diabetes occurrence was statistically handled by Fisher's exact test and blood glucose by Student's t-test. Results As shown in Table 1, diabetes was induced in all controls at more than 150mg/kg alloxan, while 20mg/kg of diltiazem hydrochloride suppressed the diabetes induced in all rats by 150, 180 or 200 mg/kg of alloxan. There was no suppression, however, at 13 mg/kg of diltiazem hydrochloride. From Table 2, it is clear that alloxan-induced diabetes was markedly promoted by 48-h fasting of the controls, but 40 mg/ kg of diltiazem hydrochloride could completely suppress the onset of the diabetes induced by 200 mg/kg of alloxan. Diabetes induced by 180 or 200 mg/kg of alloxan was not suppressed, however, in 48-h fasted rats given only 20 mg/kg of diltiazem hydrochloride. Diltiazem hydrochloride failed to show a demonstrable effect on streptozotocin diabetes (Table 3). Discussion The present results indicated that 20 mg/kg of diltiazem hydrochloride given by intraperitoneal injection, just as with the other Ca 2+ blockers, verapamil and nicardipine, could completely suppress the diabetes induced in overnightfasted rats by intraperitoneal injection of alloxan at a dose of 200 mg/kg. Although the onset of alloxan diabetes is reportedly enhanced by fasting (Kass and Waisbren 1945), diltiazem hydrochloride at 40 mg/kg managed to suppress diabetes induced through intraperitoneal injection of 200 mg/kg of alloxan, something it did not do for streptozotocin diabetes.
Number of rats developing diabetes out of five rats are given in parentheses. * P < 0.001 Student's t-test ** P < 0.01 Fisher's exact test.
Table 3 Effect of diltiazem hydrochloride on the occurrence of streptozotocin diabetes in rats. Blood gl ucose level (mg/dl) Streptozotocin (mg/dl)
Control fed
Diltiazem hydrochloride 20 mg/kg 40 mg/kg
30
154 ± 13 (0)
159±16 (0)
154±23 (0)
40
463 ±35 (5)
459±35 (5)
472 ±43 (5)
50
579 ±65 (5)
585 ±86 (5)
587 ±72 (5)
Recently, the Ca 2+ channel blocker, Bepridil, was found to prevent the onset of alloxan diabetes in the mouse (Constantine, Bromont, Tickat and Massingham 1990), a result well corroborated by the present authors. Constantine et al. (1990) speculated that the Ca 2+ blocker contributed to this suppression by serving to diminish the increase in superoxide induced by alloxan in the pancreatic islets. But the onset of streptozotocin diabetes was not prevented by Ca 2+ channel blockers (nicardipine, verapamil and diltiazem hydrochloride) in our study {Katsumata and Katsumata 1988a, b). It is reported that in streptozotocin-diabetic rats not superoxide generation, but alkylation on B cell of pancreas has a key role in the DNA strand break, an important step in the occurrence of experimental diabetes (Bennitt and Pegg 1981). This report may explain the different results obtained using Ca 2+ channel blocker on alloxan or streptozotocin diabetes.
Downloaded by: East Carolina University. Copyrighted material.
Table 1 Effects of diltiazem hydrochloride on the occurrence of alloxan diabetes in rats.
509
Horm. metab. Res. 24 (1992) Now, it is clear that a total of four Ca 2+ channel blockers (i.e., three reported by the present authors and one by Constantine et al. 1990) suppressed the occurrence of alloxan diabetes. This inhibiting action may be considered common to the Ca 2+ channel blockers. It is also known that a Ca 2+ channel blocker can inhibit Ca 2+ flow into the pancreatic islets (Malaisse and Sener 1981), which confirms the important role in triggering alloxan diabetes played by Ca 2+ in the pancreatic islets. This point deserves further investigation.
K. Katsumata, K. Katsumata Jr. and Y. Katsumata Requests for reprints should be addressed to: K. Katsumata, M.D. Katsumata Hospital 1-32-22 Shinsakae, Naka-ku Nagoya 460 Japan
Bennitt, R. A., A. E. Pegg: Alkylation of DNA in rat tissues following administration of streptozotocin. Cancer Res. 41: 2786-2790 (1981) Burton, K. P., A. C. Morris, K. D. Massey, L. M. Buja, H. K. Hagler: Free radicals alter ionic calcium levels and membrane phospholipids in cultured rat ventricullar myocytes. J. Moll. Cell Cardial. 22 (9): 1035-1047(1990) Constantine, M., C. Bromont, R. Tickat, R. Massingham: Studies on the activity of bepridil as a scavenger of free radical. Biochem. Pharmacol. 40 (7): 1615-1622 (1990) Franceshi, D., D. Graham, M. Sarava, D. M. Zollinger Jr.: Mechanism of oxygen free radical-induced calcium overload in endothelial cells. Surgery 108 (2): 292-297 (1990) Hermgren, A., C. Lyckeberg: Generation of superoxide by alloxan. Proc. Natl. Acad. Sci (USA) 77: 49-51 (1980) Kass, E. H., B. A. Waisbren: Fasting and alloxan diabetes. Proc. Soc. Exp. Biol. Med. 60: 303-306 (1945) Katsumata, K., Y. Katsumata: Nicardipine induces protection against alloxan but not streptozotocin diabetes in rats. Horm. Metabol. Res. 20: 309-310 (1988a) Katsumata, K, Y. Katsumata: Verapamil induces protection of alloxan but not streptozotocin-induced diabetes in rats. Horm. Metabol. Res. 20: 65 (1988b) Lenzen, S., U. Panten: Alloxan history and mechanism of action. Diabetologa31: 337-342(1988) Malaisse, W. J, A. Sener: Calcium-antagonist and islet function. Biochem. Pharmacol. 30: 1039-1041 (1981) Matsumoto, K, K. Tasaka, A. Miyake, O. Tanizawa: Superoxide anion increase intracellular free calcium in human myometrial cells. J. Biol. Chem. 265 (36): 2253-2256 (1990) Nakashima, T., Y. Seto, T. Nakajima, T. Shima, Y Sakamoto, A. Sano, H. Cho: Calcium-associated cytoprotective effect of taurine when the calcium and oxygen paradoxes in isolated hepatocytes. Liver 19 (3): 167-172 (1990) Takasu, N., T. Asawa, I. Komiya, Y. Nagasawa, T. Yamada: Alloxan induced DNA strand breaks in pancreatic islets. J. Biol. Chem. 266:2112-2114(1991) Uchigata, Y., H. Yamamoto, H. Okamoto: Protection by superoxide dismutase catalase and polysynthetase inhibitors against alloxan and streptozotocin-induced islet DNH strand break and against the inhibition of protein synthesis. J. Biol. Chem. 251: 6084-6088 (1982) Yamamoto, H., Y. Uchigata, H. Okamoto: Streptozotocin and alloxan induce DNA strand break and polysynthetase in pancreatic islets. Nature 294: 284-286 (1981)
Downloaded by: East Carolina University. Copyrighted material.
References
Summary This study demonstrated that 20mg/kg of the Ca 2+ channel blocker, diltiazem hydrochloride, administered by intraperitoneal injection 15 min before 200mg/kg of alloxan given by the same route to induce diabetes, served to suppress disease onset completely in rats. Even though 48-h fasting promoted the onset of alloxan diabetes, 40 mg/ kg of diltiazem hydrochloride completely prevented the occurrence of diabetes induced by intraperitoneal injection of 200mg/kg of alloxan. Forty mg/kg of the same agent, however, failed to prevent the onset of diabetes induced by the intravenous injection of streptozotocin (50mg/kg). From the fact that Ca 2+ channel blockers such as nicardipine, verapamil and bepridil have a similar suppressive effect on the occurrence of alloxan diabetes, one may readily infer that this action is characteristic of Ca 2+ channel blockers. Moreover, the results suggest the close connection of Ca 2+ in the occurrence of alloxan diabetes in rats. Key words Diabetes - Alloxan - Streptozotocin - Ca 2+ Channel Blocker - Diltiazem Hydrochloride
Introduction It is reported that there is an increased production of superoxide (Hermgren and Lyckeberg 1980) and H2O2 in the B cell of the rat pancreeas (Takasu, Asawa, Komiya, Nagasawa and Yamada 1991) in the initial stage of alloxan diabetes, and that the occurrence of alloxan diabetes can be prevented by suppressing the superoxide production in rat (Uchigata, Yamamoto and Okamoto 1982). It is also reported that H2O2 generation or an increase of superoxide at B cell of pancreas in rats induced by alloxan has a key role in the DNA strand break, an important step in the occurrence of alloxan diabetes as well as streptozotocin diabetes (Yamamoto, Uchigata and Okamoto 1981), although Lenzen and Panten believe that the step of the inhibition of glucokinase is important for the occurrence of alloxan diabetes (Lenzen and Panten 1988). Re-
Horm. metab. Res. 24 (1992) 508-510 © Georg Thieme Verlag Stuttgart • New York
cently, it is reported that superoxide anion increases intracellular free calcium in human myometrial cells (Matsumoto, Tasaka, Miyake and Tanizawa 1990) and also in human endothelial cells (Franceshi, Graham, Sarasua and Zollinger 1990). Inversely, a Ca 2+ increase has been found to result in a superoxide increase in rat liver (Nakashima, Seto, Nakajima, Shima, Sakamoto, Sano and Cho 1990), or in cultured rat ventricular myocytes (Burton, Morris, Massey Buja and Hagler 1990). Thus, there is some possibility that alloxan and streptozotocin diabetes could be prevented by inhibiting the Ca 2+ increase with a Ca 2+ blocker. In fact, the present investigators earlier reported that verapamil (Katsumata and Katsumata 1988b) and nicardipine (Katsumata and Katsumata 1988a) prevented the occurrence of alloxan diabetes in rats. In the present study, we sought to determine whether this same suppression is common to the Ca 2+ channel blockers, whether this same result could be effected with diltiazem hydrochloride, and at the same time attempted to ascertain if it would have the same effect on streptozotocin diabetes in rats. In addition, we wished to determine whether a Ca 2+ channel blocker has an action to suppress the onset of alloxan diabetes in the sustained fasting condition, in which the occurrence of alloxan diabetes is reportedly promoted in rats (Kass and Waisbren 1945). Materials and Method Male Wistar rats weighing approximately 150 g were individually housed in metabolic cages in a temperature-controlled animal room (23±2°C) and fed a commercial diet with free access to water. After overnight fast, the rats were given an intraperitoneal injection of 13 or 20 mg/kg of diltiazem hydrochloride (Herpesser, Tanabe Co. Tokyo) and injected 15 minutes later with different concentrations of alloxan (Wako Pure Chemical Inc. Osaka) which were dissolved in normal saline just before use. In control rats, instead of diltiazem hydrochloride physiological saline was intraperitoneally injected. In the sustained fasting experiment, following a 48-h fast, the rats were given an intraperitoneal injection of various concentrations of diltiazem hydrochloride and injected 15 min later with different concentrations of alloxan. Another group was fasted overnight and diltiazem hydrochloride at a dose of 20 mg/kg or 40 mg/kg was intraperitoneally injected and 15 min later injected in the tail vein with various levels of streptozotocin (Sigma Chemical Co. USA) dissolved in 50 mM citrate buffer (pH 4.5) instead of alloxan. Controls were injected with physiological saline instead of 40 mg/kg of diltiazem hydrochloride. After alloxan or streptozotocin administration, the animals were given food and water ad lib for two days. Then, they were fasted overnight, and their blood was sampled through the tail vein for the measurements of Received: 29 Oct. 1991
Accepted: 28 Feb. 1992
Downloaded by: East Carolina University. Copyrighted material.
K. Katsumata1, K. Katsumata, Jr.2 and Y. Katsumata3 1 Katsumata Hospital, Nagoya 2 Chukyo Hospital, Nagoya 3 Department of Legal Medicine, Nagoya University School of Medicine, Nagoya, Japan
Diltiazem Hydrochloride and Alloxan Diabetes
Horm. metab. Res. 24 (1992) Table 2 Effect of diltiazem hydrochloride on the occurrence of alloxan diabetes in 48-h fasted rats.
Blood glucose level (mg/dl) Alloxan (mg/kg)
Control fed
Diltiazem hydrochloride 13 mg/kg 20 mg/kg
100
97 + 4 (0)
120
96±16* (0)**
150
297 ±15* (5)**
237 ±25* (5)**
180
325 ±46 (5)
200
385 ±54 (5)
Blood glucose level (mg/dl) Alloxan (mg/kg)
Control fed
Diltiazem hydrochloride 20 mg/kg 40 mg/kg
80
87 ±10* (0)**
100
219±18* (5)**
101 ± 7 (0)
83± 7 (0)
90±7 (0)
120
323 ±43 (5)
98±11 (0)
97 ±13 (0)
309 ±20 (5)
99±4 (0)
150
391 ±11 (5)
109± 9 (0)
89 ± 8 (0)
424 ±32 (5)
103±9 (0)
180
569 ±19 (5)
496±17 (5)**
115±25 (0)
200
629 ±34 (5)
611 ±25 (5)
155±29 (0)
Number of rats developing diabetes out of five rats are given in parentheses. Rats showing more than 200 mg/dl of blood glucose at overnight fasting were diagnosed as diabetic. * P < 0.001 Student's t-test ** P < 0.01 Fisher's exact test.
blood glucose by the glucose oxidase method. Diabetes was considered to have occurred at a high blood glucose level of over 200 mg/dl at fasting. Alloxan dosages weere 100, 120, 150, 180 and 200mg/kg, while those of strepotzotocin were 30, 40 and 50mg/kg. Five rats on each dose formed a single group in the experiment. The rate of diabetes occurrence was statistically handled by Fisher's exact test and blood glucose by Student's t-test. Results As shown in Table 1, diabetes was induced in all controls at more than 150mg/kg alloxan, while 20mg/kg of diltiazem hydrochloride suppressed the diabetes induced in all rats by 150, 180 or 200 mg/kg of alloxan. There was no suppression, however, at 13 mg/kg of diltiazem hydrochloride. From Table 2, it is clear that alloxan-induced diabetes was markedly promoted by 48-h fasting of the controls, but 40 mg/ kg of diltiazem hydrochloride could completely suppress the onset of the diabetes induced by 200 mg/kg of alloxan. Diabetes induced by 180 or 200 mg/kg of alloxan was not suppressed, however, in 48-h fasted rats given only 20 mg/kg of diltiazem hydrochloride. Diltiazem hydrochloride failed to show a demonstrable effect on streptozotocin diabetes (Table 3). Discussion The present results indicated that 20 mg/kg of diltiazem hydrochloride given by intraperitoneal injection, just as with the other Ca 2+ blockers, verapamil and nicardipine, could completely suppress the diabetes induced in overnightfasted rats by intraperitoneal injection of alloxan at a dose of 200 mg/kg. Although the onset of alloxan diabetes is reportedly enhanced by fasting (Kass and Waisbren 1945), diltiazem hydrochloride at 40 mg/kg managed to suppress diabetes induced through intraperitoneal injection of 200 mg/kg of alloxan, something it did not do for streptozotocin diabetes.
Number of rats developing diabetes out of five rats are given in parentheses. * P < 0.001 Student's t-test ** P < 0.01 Fisher's exact test.
Table 3 Effect of diltiazem hydrochloride on the occurrence of streptozotocin diabetes in rats. Blood gl ucose level (mg/dl) Streptozotocin (mg/dl)
Control fed
Diltiazem hydrochloride 20 mg/kg 40 mg/kg
30
154 ± 13 (0)
159±16 (0)
154±23 (0)
40
463 ±35 (5)
459±35 (5)
472 ±43 (5)
50
579 ±65 (5)
585 ±86 (5)
587 ±72 (5)
Recently, the Ca 2+ channel blocker, Bepridil, was found to prevent the onset of alloxan diabetes in the mouse (Constantine, Bromont, Tickat and Massingham 1990), a result well corroborated by the present authors. Constantine et al. (1990) speculated that the Ca 2+ blocker contributed to this suppression by serving to diminish the increase in superoxide induced by alloxan in the pancreatic islets. But the onset of streptozotocin diabetes was not prevented by Ca 2+ channel blockers (nicardipine, verapamil and diltiazem hydrochloride) in our study {Katsumata and Katsumata 1988a, b). It is reported that in streptozotocin-diabetic rats not superoxide generation, but alkylation on B cell of pancreas has a key role in the DNA strand break, an important step in the occurrence of experimental diabetes (Bennitt and Pegg 1981). This report may explain the different results obtained using Ca 2+ channel blocker on alloxan or streptozotocin diabetes.
Downloaded by: East Carolina University. Copyrighted material.
Table 1 Effects of diltiazem hydrochloride on the occurrence of alloxan diabetes in rats.
509
Horm. metab. Res. 24 (1992) Now, it is clear that a total of four Ca 2+ channel blockers (i.e., three reported by the present authors and one by Constantine et al. 1990) suppressed the occurrence of alloxan diabetes. This inhibiting action may be considered common to the Ca 2+ channel blockers. It is also known that a Ca 2+ channel blocker can inhibit Ca 2+ flow into the pancreatic islets (Malaisse and Sener 1981), which confirms the important role in triggering alloxan diabetes played by Ca 2+ in the pancreatic islets. This point deserves further investigation.
K. Katsumata, K. Katsumata Jr. and Y. Katsumata Requests for reprints should be addressed to: K. Katsumata, M.D. Katsumata Hospital 1-32-22 Shinsakae, Naka-ku Nagoya 460 Japan
Bennitt, R. A., A. E. Pegg: Alkylation of DNA in rat tissues following administration of streptozotocin. Cancer Res. 41: 2786-2790 (1981) Burton, K. P., A. C. Morris, K. D. Massey, L. M. Buja, H. K. Hagler: Free radicals alter ionic calcium levels and membrane phospholipids in cultured rat ventricullar myocytes. J. Moll. Cell Cardial. 22 (9): 1035-1047(1990) Constantine, M., C. Bromont, R. Tickat, R. Massingham: Studies on the activity of bepridil as a scavenger of free radical. Biochem. Pharmacol. 40 (7): 1615-1622 (1990) Franceshi, D., D. Graham, M. Sarava, D. M. Zollinger Jr.: Mechanism of oxygen free radical-induced calcium overload in endothelial cells. Surgery 108 (2): 292-297 (1990) Hermgren, A., C. Lyckeberg: Generation of superoxide by alloxan. Proc. Natl. Acad. Sci (USA) 77: 49-51 (1980) Kass, E. H., B. A. Waisbren: Fasting and alloxan diabetes. Proc. Soc. Exp. Biol. Med. 60: 303-306 (1945) Katsumata, K., Y. Katsumata: Nicardipine induces protection against alloxan but not streptozotocin diabetes in rats. Horm. Metabol. Res. 20: 309-310 (1988a) Katsumata, K, Y. Katsumata: Verapamil induces protection of alloxan but not streptozotocin-induced diabetes in rats. Horm. Metabol. Res. 20: 65 (1988b) Lenzen, S., U. Panten: Alloxan history and mechanism of action. Diabetologa31: 337-342(1988) Malaisse, W. J, A. Sener: Calcium-antagonist and islet function. Biochem. Pharmacol. 30: 1039-1041 (1981) Matsumoto, K, K. Tasaka, A. Miyake, O. Tanizawa: Superoxide anion increase intracellular free calcium in human myometrial cells. J. Biol. Chem. 265 (36): 2253-2256 (1990) Nakashima, T., Y. Seto, T. Nakajima, T. Shima, Y Sakamoto, A. Sano, H. Cho: Calcium-associated cytoprotective effect of taurine when the calcium and oxygen paradoxes in isolated hepatocytes. Liver 19 (3): 167-172 (1990) Takasu, N., T. Asawa, I. Komiya, Y. Nagasawa, T. Yamada: Alloxan induced DNA strand breaks in pancreatic islets. J. Biol. Chem. 266:2112-2114(1991) Uchigata, Y., H. Yamamoto, H. Okamoto: Protection by superoxide dismutase catalase and polysynthetase inhibitors against alloxan and streptozotocin-induced islet DNH strand break and against the inhibition of protein synthesis. J. Biol. Chem. 251: 6084-6088 (1982) Yamamoto, H., Y. Uchigata, H. Okamoto: Streptozotocin and alloxan induce DNA strand break and polysynthetase in pancreatic islets. Nature 294: 284-286 (1981)
Downloaded by: East Carolina University. Copyrighted material.
References
