Monoamine oxidase inhibition: Possible mechanism for cyproheptadine-induced alterations in insulin secretion

Feldman, Jerome M.; Chapman, Barbara; Plonk, James W.

doi:10.1016/s0024-3205(74)80009-3

Cited by 13 publications

(10 citation statements)

References 15 publications

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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%

“…Feldman et al [6] observed that the enzyme monoamine oxidase was inhibited by cyproheptadine and attributed the inhibition of insulin release to this effect. In view of our experiments it is unlikely that direct or indirect effects of cyproheptadine on adrenergic alpha receptors at the B-cell cause the inhibition of insulin release.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 98%

“…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.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

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

et al. 1976

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“…The histamine and 5-hydroxytryptamine (5-HT) antagonist, cyproheptadine (CPH), inhibits glucosemediated insulin release both in vivo and in vitro (Joost, Poser & Panten, 1974;Feldman, Chapman & Plonk, 1974;Rickert & Fischer, 1974). Recent studies on isolated islets of Langerhans from the rat have shown that this results from an immediate and direct action of CPH on the insulin secreting pancreatic fl-cell (Richardson, McDaniel & Lacy, 1975).…”

Section: Introductionmentioning

confidence: 99%

Mechanism by Which Cyproheptadine Inhibits Insulin Secretion

Donatsch¹,

Lowe²,

Richardson³

et al. 1980

British J Pharmacology

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Isolated islets of Langerhans from the rat have been used in studies designed to elucidate the mechanism by which cyproheptadine inhibits insulin secretion. d‐Glucose and tolbutamide, both of which require extracellular Ca2+ to produce insulin release, failed to evoke a secretory response from islets pretreated with cyproheptadine. Conversely veratridine, the calcium ionophore A23187 and theophylline, all of which are capable of mobilizing sufficient intracellular Ca2+ to evoke insulin secretion in the absence of extracellular Ca2+, produced similar responses from cyproheptadine pretreated and control islets. Cyproheptadine completely inhibited Ca2+ uptake induced by d‐glucose and high K+o, two agents which depolarize the islet β‐cell membrane, whilst Ca2+ uptake elicited by removal of extracellular Na+ (i.e. Na+‐Ca2+ counter transport) was only slightly reduced. A significant increase in Na+ uptake produced by veratridine was sensitive to tetrodoxin but only partially reduced by cyproheptadine. These results suggest that cyproheptadine inhibits depolarization‐dependent calcium entry into pancreatic β‐cells.

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Therapeutic Doses of Cyproheptadine Do Not Inhibit Monoamine Oxidase in Man

Feldman

Plonk

1976

The Journal of Clinical Pharma

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Cypro, a serotonin and histamine antagonist, has been shown to be a moderately potent reversible inhibitor of tissue monoamine oxidase (MAO) obtained from hamsters and rabbits. In the present study, Cypro inhibits MAO obtained from human platelets with the same potency as harmine (Ki = 5 x 10(-5) M). However, when ten normal volunteers received conventional therapeutic doses of Cypro (16 mg/day) for two days, there was no alteration in their urinary excretion of tryptamine, 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxymandelic acid, epinephrine, or norepinephrine. We conclude that, when used in conventional clinical doses, Cypro does not inhibit MAO in man.

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Monoamine oxidase inhibition: Possible mechanism for cyproheptadine-induced alterations in insulin secretion

Cited by 13 publications

References 15 publications

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

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

Mechanism by Which Cyproheptadine Inhibits Insulin Secretion

Therapeutic Doses of Cyproheptadine Do Not Inhibit Monoamine Oxidase in Man

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