Species dependent pancreatic islet toxicity produced by cyproheptadine: Alterations in beta cell structure and function

Wold, J. S.; Longnecker, Daniel S.; Fischer, Lawrence J.

doi:10.1016/0041-008x(71)90106-2

Cited by 32 publications

(21 citation statements)

References 24 publications

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“…Electron micrographs (not shown) of pancreatic B cells from 10-and 50-day-old rats treated with 14 daily doses of CPH demonstrated characteristic morphological changes: a loss of insulin-con taining granules, vésiculation of endoplas mic reticulum and formation of cytoplasmic vacuoles. The ultrastructural changes were identical to those previously observed in adult rats given similar long-term treatment [3][4][5], Similar changes were also observed after two daily insulin-depleting doses of the drug to young animals in all age groups except that large cytoplasmic vacuoles were not seen after this shorter period of treat ment. No morphologic changes in the gluca gon-containing A cells or somatostatin-con taining D cells were observed after CPH treatment.…”

Section: Age-related Differences In the Susceptiblity Of Endocrine Pasupporting

confidence: 73%

“…Fifty-dayold animals were used for comparison because forma tion of cytoplasmic vacuoles has been shown pre viously in B cells of adult rats (including 50-day-old rats) following the same dosage regimen [3], The ani mals were killed 24 h after the last dose. Pancreatic tissue was obtained for insulin and glucagon determi nation and electron microscopy [15], Glucagon was measured because previous results from adult animals indicated that the effects of CPH were specific for insu…”

Section: Effects Of Cph In the Pancreas Of Rats At Various Agesmentioning

confidence: 99%

“…Pre vious studies from this laboratory using adult rats showed that the antihistaminic, antiserotonin drug, cyproheptadine (CPH), causes pancreatic beta cell (B cell) lesions after repeated oral doses [3,4], The morpho logic alterations are characterized initially by a loss of insulin secretion granules and subsequently by vacuolization of the rough endoplasmic reticulum. These changes were observed in conjunction with hyperglycemia and glucose intolerance caused by a reduc tion in serum and pancreatic insulin due to a drug-related inhibition of insulin synthesis and secretion [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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Postnatal Changes in the Insulin-Depleting Action and Disposition of Cyproheptadine in Rats

Chow¹,

Fischer²

1991

Dev Pharmacol Ther

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The relationship between age-related differences in cyproheptadine (CPH)- induced alteration of endocrine pancreas function and the disposition of the drug was examined in this study. Various doses of CPH (5, 11, 22.5 or 45 mg/kg) were given orally once daily for 2 days to 10-, 15-, 25- and 50-day-old rats. Pancreatic and serum insulin measured 24 h after the second dose showed a drug-dependent decline, and the extent of this effect was dependent on the dose administered and the age of the animal. In 50-day-old rats, a significant reduction in pancreatic and serum insulin was detected only after high doses (22.5 and 45 mg/kg) of the drug. However, in 10- and 15-day-old rats, the effects were observed after the lowest dose (5 mg/kg). In separate experiments, the concentrations of CPH and its active metabolites, desmethylcyproheptadine (DMCPH), desmethylcyproheptadine-10,11-epoxide (DMCPH-epoxide) and cyproheptadine-10,11-epoxide (CPH-epoxide), were measured in the pancreas, liver and lung of neonatal and young rats at various times after the second dose of CPH (11 mg/kg). In the younger age groups (10- and 15-day-olds), there were significantly higher tissue levels of unchanged drug at all times examined. Certain of the drug metabolites known to be inhibitors of insulin synthesis had higher and/or more prolonged tissue concentrations in younger animals. For example, the metabolite CPH-epoxide was found only in tissues from younger age groups. Twenty-four hours after the second dose of CPH, no drugderived product was present in tissues of 25- and 50-day-old rats, whereas significant amounts of DMCPH-epoxide, a potent CPH metabolite inhibiting insulin synthesis, was detected in the tissues of 10- and 15-day-old rats. The data show that there are age-related differences in the susceptibility of pancreatic B cells to the actions of CPH, and that these differences are associated with age-related changes in the disposition of the drug.

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Section: Age-related Differences In the Susceptiblity Of Endocrine Pasupporting

confidence: 73%

Section: Effects Of Cph In the Pancreas Of Rats At Various Agesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Postnatal Changes in the Insulin-Depleting Action and Disposition of Cyproheptadine in Rats

Chow¹,

Fischer²

1991

Dev Pharmacol Ther

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“…The inhibitory effect of cyproheptadine on insulin release in vivo after prolonged treatment [2,3] or single injections [5], and in vitro [5,6,7,8] has been well established. Our results confirm that cyproheptadine is a very potent inhibitor of glucose-induced insulin release, since the low concentration of 1 ~M was still effective.…”

Section: Discussionmentioning

confidence: 99%

“…The antihistaminic-antiserotonin compound cyproheptadine [1] has been reported to produce selective B-cell abnormalities, glucose intolerance, and depletion of pancreatic insulin in rats [2,3,4] when chronically administered. Acute hyperglycemia after single injections of cyproheptadine, accompanied by a decrease of plasma insulin, was observed in the rat [5] and in the Syrian hamster [6].…”

mentioning

confidence: 99%

Inhibition of insulin and glucagon release from the perfused rat pancreas by cyproheptadine (Periactinol�, Nuran�)

et al. 1976

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Summary. The tricyclic compound cyproheptadine (Feriactinol | Nuran | inhibited glucose-induced insulin release from the peffused rat pancreas. Tolbutamide-stimulated insulin release was significantly reduced in the presence and completely suppressed in the absence of a substimulatory glucose concentration (5 mM). Arginine produced a slow rise of insulin release, which was completely abolished by cyproheptadine. Furthermore the biphasic glucagon release due to the stimulus was inhibited. Oxidation of ~4C-glucose in isolated islets was unaltered in the presence of cyproheptadine, and pyruvate added to the perfusion medium failed to reverse the inhibitory effect on glucose induced insulin release, indicating that impaired glucose metabolism is not responsible for the inhibition. In addition, the inhibition remained unchanged when phentolamine was present, suggesting that the effect is not mediated by inhibitory adrenergic alpha receptors. Theophylline, in contrast, partly overcame the inhibition. When the calcium concentration of the medium was enhanced, the inhibitory effect of cyproheptadine was still visible, although the relative inhibition had become smaller. The results suggest that cyproheptadine blocks insulin release by affecting a fundamental step of the stimulus-secretion coupling common to peptide hormones. A participation of a calcium-antagonizing effect in the inhibition is discussed.Key words: Insulin release, glucagon release, cyproheptadine, tolbutamide, arginine, theophylline, calcium, peffused rat pancreas. The antihistaminic-antiserotonin compound cyproheptadine [1] has been reported to produce selective B-cell abnormalities, glucose intolerance, and depletion of pancreatic insulin in rats [2, 3, 4] when chronically administered. Acute hyperglycemia after single injections of cyproheptadine, accompanied by a decrease of plasma insulin, was observed in the rat [5] and in the Syrian hamster [6]. In addition, in vitro experiments using the perfused rat pancreas [5], isolated islets [7,8], and pieces of Syrian hamster pancreas [6] revealed the inhibitory effect of cyproheptadine on insulin release.To gain further insight into this inhibition we investigated the effects of cyproheptadine on insulin release as caused by various stimulators and effectors.Cyproheptadine has also been reported to inhibit growth hormone (HGH) secretion [9,10] and cortisol release [11], suggesting that cyproheptadine has a general inhibitory effect on hormone release. Thus we studied the effects of cyproheptadine on the arginineinduced glucagon release by the perfused rat pancreas. Materials and Methods ChemicalsCyproheptadine-hydrochloride (Sharp and Dohme, Miinchen), Trasylol | (Farbwerke Bayer AG, Wuppertal-Elberfeld), tolbutamide (Hoechst AG, Frankfurt) and dextran (Knoll AG, Ludwigshafen) were obtained as gifts. Bovine albumin, pentobarbital and arginine were purchased from Serva, Heidelberg, Phentolamine (Regitin | ampoules) from Ciba AG, 1-125 labelled insulin and glucagon (50-60% immunoreactive glucagon) from Farb...

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Morphological and immunocytochemical study of rat pancreatic beta cell changes induced by cyclizine

Hanai

1984

J of Applied Toxicology

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Wistar rats were treated daily with cyclizine (50-75 mg kg-1) and autopsied every week until the eighth week of the treatment. Although no evident change could be detected by either serum analysis or by light microscopy from the first week to the fourth week, electron microscopy revealed that beta cells showed depletion of secretory granules and cystic dilation of the rough endoplasmic reticulum from the first week. A significantly higher level of plasma glucose and a lower level of plasma insulin than those of untreated rats were recognized from the fifth week. A diabetic pattern was also observed in the glucose tolerance test which was conducted at the seventh week. From the sixth week, large cytoplasmic vacuoles were observed light microscopically in islet cells. Electron microscopic examination revealed that the vacuoles originated from the rough endoplasmic reticulum in beta cells, while no prominent change was found on the Golgi apparatus. In addition to the above findings, immunocytochemical study with anti-insulin serum demonstrated that the staining intensity of the beta cell cytoplasm became weaker (as judged by light microscopy) from the fifth week, but large cytoplasmic vacuoles were stained positively under both the light microscope (PAP method) and the electron microscope (enzyme-labelled antibody method). These findings suggested that the depletion of secretory granules and accumulation of insulin or its precursor in the rough endoplasmic reticulum occurred in beta cells. The diabetogenic effect of cyclizine on rats is discussed with reference to the immunocytochemical findings.

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Species dependent pancreatic islet toxicity produced by cyproheptadine: Alterations in beta cell structure and function

Cited by 32 publications

References 24 publications

Postnatal Changes in the Insulin-Depleting Action and Disposition of Cyproheptadine in Rats

Postnatal Changes in the Insulin-Depleting Action and Disposition of Cyproheptadine in Rats

Inhibition of insulin and glucagon release from the perfused rat pancreas by cyproheptadine (Periactinol�, Nuran�)

Morphological and immunocytochemical study of rat pancreatic beta cell changes induced by cyclizine

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