Calmodulin Inhibitors Decrease the CRF- and AVP-Induced ACTH Release in vitro: Interaction of Calcium-Calmodulin and the Cyclic AMP System

Murakami, Kazuharu; Hashimoto, Kozo; Ota, Zensuke

doi:10.1159/000124146

Cited by 22 publications

(6 citation statements)

References 23 publications

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“…Loperamide had no effect on membrane adenylate cyclase activity but significantly decreased CRH-and BuocAMP-induced ACTH secretion in rat anterior pitu itary cell culture. In contrast, in NG 108-15 cells, opiates have been shown to regulate the adenylate cyclase activity and to lower cAMP levels [24] by acting through a G pro tein and stimulation of a membrane-bound GTPase [25], But in rat corticotrophs, calmodulin inhibitors like tri fluoperazine and W-7 were shown to decrease CRH-induced ACTH release but not alter cAMP levels [26]. Won et al [27] have recently reported that penfluridol, another calmodulin inhibitor, inhibited CRH-and 8-Br-cAMPstimulated ACTH release.…”

Section: Discussionmentioning

confidence: 92%

“…These results indicate that the AVPstimulated phospholipase C activity and generation of IPs [31-33] is not decreased by loperamide. Also, direct stim ulation of protein kinase C with PMA [33,34] was not sup pressed by loperamide, suggesting no direct inhibitory ef fect of loperamide on protein kinase C. Murakami et al [26] have reported a decrease of AVP-induced ACTH re lease by calmodulin inhibitors like trifluoperazine and W-7. Therefore, loperamide acting at a level distal to IPi generation again appears to decrease the AVP-induced ACTH secretion by inhibition of the Ca2 + /CaM system ( fig.…”

Section: Discussionmentioning

confidence: 99%

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Loperamide Inhibits Corticotrophic Cell Function by a Naloxone-lnsensitive Mechanism in the Rat in vitro

Auernhammer

Renner

Müller³

et al. 1993

Neuroendocrinology

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The effect of the antidiarrheal drug loperamide, a µ-opiate agonist, on ACTH secretion and biosynthesis, cAMP generation and phosphoinositide turnover was studied in rat anterior pituitary cell cultures. The cAMP-dependent protein kinase A pathway was stimulated with both corticotropin-releasing hormone (CRH; 2–5 nM) and the membrane-permeable Bu(2)cAMP (0.5–2.5 mM). The protein kinase C pathway was stimulated with 1 µM arginine vaso-pressin (AVP) and 1-10 nM phorbol 12-myristate 13-acetate (PMA). After 3.5 h, loperamide (10 µM) had no effect on basal ACTH levels but significantly suppressed CRH-induced ACTH release, in a dose-dependent manner, to 60 ± 4% of control (100%) (p < 0.0001). After 24 h, basal proopiomela-nocortin mRNA was significantly decreased to 50% of control by loperamide (p < 0.05). The suppressive effect of loperamide on CRH-induced ACTH secretion was not reversible by naloxone (0.1-1,000 µM). Morphine (0.01-10 µM) had no effect on basal and CRH-induced ACTH secretion. Loperamide did not influence basal and CRH-induced adenylate cyclase activity in anterior pituitary cell membrane preparations, but it significantly blunted Bu₍₂₎cAMP-induced ACTH secretion in cell culture from 100 ± 4 to 77 ± 4% (p < 0.05). In Ca²⁺-depleted medium (Ca²⁺ < 0.1 mM), loperamide had no suppressive effect on CRH-induced ACTH secretion. AVP-induced ACTH secretion was significantly suppressed by loperamide from 100 ± 5 to 74 ± 3% (p < 0.0001), while basal and AVP-induced inositol 1-phosphate generation and PMA-induced ACTH secretion were not affected by loperamide. In comparison with the known effects of the calmodulin-inhibitors trifluoperazine, W-7 and penfluridol, loperamide mimicked all their effects on ACTH secretion. We conclude: (1) the effects of loperamide on corticotrophic cell function in vitro are naloxone-insensitive and not mediated by µ-opiate receptors; and (2) our data provide a strong argument for loperamide working as a calmodulin inhibitor in the rat anterior pituitary in vitro.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Loperamide Inhibits Corticotrophic Cell Function by a Naloxone-lnsensitive Mechanism in the Rat in vitro

Auernhammer

Renner

Müller³

et al. 1993

Neuroendocrinology

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“…The rate of stopping secretion when the secretagogue is removed from the perifusion medium is more rapid with AVP, and AVP plus CRF, than with CRF alone, and may be explained by differences in dissociation of the hormones from their respective receptors for these secretagogues , 1985Wynn et al 1983; Leroux & Pelletier, 1984;Spinedi & Negro-Vilar, 1984). However, differences in the intracellular systems controlling ACTH release may also be involved, since AVP appears to exert its action through phosphoinositide hydrolysis (Raymond, Leung, Veilleux & Labrie, 1985) and the calciumcalmodulin systems (Murakami, Hashimoto & Ota, 1985) while CRF stimulates release through the calcium-calmodulin and cyclic AMP systems (Murakami et al 1985). When both secretagogues are given together, AVP enhances the CRF-induced cyclic AMP formation in rat cells (Labrie et al 1984) or pituitary quarters (Knepel et al 1984).…”

Section: Discussionmentioning

confidence: 99%

Characteristics of the ACTH response to repeated pulses of corticotrophin-releasing factor and arginine vasopressin in vitro

Evans

Brett²,

McIntosh³

et al. 1988

Journal of Endocrinology

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A multi-column perifusion system was used to investigate the dynamics of the dose-response relationships of ACTH release by ovine pituitary cells when stimulated by both corticotrophin-releasing hormone (CRF) and arginine vasopressin (AVP) given alone and in combination. A dose-response relationship was obtained when 10-min pulses were given at 60-min intervals over the range of 0.002-2000 nmol CRF/1 and 1-2000 nmol AVP/1, with a minimum effective concentration of 0.02 nmol CRF/1 or 1 nmol AVP/1. When AVP was given together with CRF, the expected potentiation of the ACTH response occurred when compared with the summed response of these secretagogues given separately. At the higher concentrations of CRF and AVP used, the ACTH responses to repeated pulses decreased with time during the experiment. The rate of this loss of responsiveness was significantly correlated to the size of the response to the first pulse (for CRF: r = 0.89, P less than 0.01; for AVP: r = 0.95, P less than 0.01), being greatest when the response was potentiated by adding the secretagogues together (for CRF plus AVP: r = 0.95, P less than 0.01). Reduced availability of receptors or changes in intracellular transduction processes may contribute to this desensitization. Reduced levels of secretable ACTH do not appear to be implicated because desensitization to pulses of one secretagogue did not cause equivalent desensitization to the other. In addition, cells stimulated continuously with submaximal levels of either secretagogue showed desensitization while more ACTH was still available for release to higher levels of stimulant.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Loperamide seems able to inhibit calmodulin ac tivity [15], independently from the adenylate cyclase sys tem, through which other opiates usually act. CRH and vasopressin act through diverse ACTH-secreting intracellu lar mechanisms, the former activating both cyclic AMP and calcium-calmodulin system, the latter mainly through the calcium-calmodulin system [17]. The different involvement of these intracellular secretory mechanisms might explain the different interactions between loperamide and vaso pressin or CRH.…”

Section: Discussionmentioning

confidence: 99%

Loperamide, an Opiate Analog, Differently Modifies the Adrenocorticotropin Responses to Corticotropin-Releasing Hormone and Lysine Vasopressin in Patients with Addison’s Disease

1988

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Loperamide is a peripheral opiate agonist able to inhibit ACTH secretion. In this work, the interactions between loperamide and two ACTH secretagogues, lysine vasopressin (LVP) and corticotropin-releasing hormone (CRH), were investigated in patients with Addison’s disease. After loperamide (16 mg orally) or placebo administration, 5 patients received LVP (0.06 IU/kg i.v. over 1 h) and 6 patients received oCRH (1 µg/kg i.v. as bolus). In all patients loperamide induced a significant fall in plasma ACTH levels. LVP increased ACTH levels after both loperamide (from 48 ± 17.3 to a peak of 95 + 21 pmol/l) and placebo (from 231 ± 59.5 to 365 ± 86.6 pmol/l): the interaction between treatments and time was not significant. CRH caused a rise in plasma ACTH after both loperamide (from 30 ± 16.6 to a peak of 108 ± 31 pmol/l) and placebo (from 98.5 ± 47 to 211 ± 61.7 pmol/l): the interaction between treatments and time was significant, and the first phase of CRH-induced ACTH secretion was significantly lower after loperamide. These data demonstrate that loperamide differently modifies the stimulatory action of LVP and CRH on ACTH secretion: namely, LVP and loperamide act in an additive manner, while CRH and loperamide interact in a non additive way. Although these findings might be explained by the involvement of different intracellular ACTH-secreting mechanisms, an influence of loperamide on some suprapituitary factors modulating the ACTH response is suggested.

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Calmodulin Inhibitors Decrease the CRF- and AVP-Induced ACTH Release in vitro: Interaction of Calcium-Calmodulin and the Cyclic AMP System

Cited by 22 publications

References 23 publications

Loperamide Inhibits Corticotrophic Cell Function by a Naloxone-lnsensitive Mechanism in the Rat in vitro

Loperamide Inhibits Corticotrophic Cell Function by a Naloxone-lnsensitive Mechanism in the Rat in vitro

Characteristics of the ACTH response to repeated pulses of corticotrophin-releasing factor and arginine vasopressin in vitro

Loperamide, an Opiate Analog, Differently Modifies the Adrenocorticotropin Responses to Corticotropin-Releasing Hormone and Lysine Vasopressin in Patients with Addison’s Disease

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