Broad-spectrum antiemetic efficacy of the l-type calcium channel blocker amlodipine in the least shrew (Cryptotis parva)

Zhong, Weixia; Chebolu, Seetha; Darmani, Nissar A.

doi:10.1016/j.pbb.2014.03.005

Cited by 19 publications

(29 citation statements)

References 33 publications

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“…An administration of FPL64176 at 10 mg/kg (i.p.) has previously been shown to evoke vomiting with a maximal frequency in 100% of tested shrews (Darmani et al, 2014; Zhong et al, 2014a). Thus, this dose was used for subsequent antagonist and biochemical studies.…”

Section: Methodsmentioning

confidence: 91%

“…Direct support comes from the identification of a novel emetogen FPL64176 (a selective L-type Ca 2+ channel (LTCC) agonist), which causes vomiting in least shrews ( Cryptotis parva ) (Darmani et al, 2014). Moreover, LTCC blockers nifedipine and amlodipine are broad-spectrum antiemetics against diverse emetogens including FPL64176 (Darmani et al, 2014; Zhong et al, 2014a). …”

Section: Introductionmentioning

confidence: 99%

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Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva)

Zhong

Chebolu

Darmani

2018

European Journal of Pharmacology

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Ca2+ plays a major role in maintaining cellular homeostasis and regulates processes including apoptotic cell death and side-effects of cancer chemotherapy including vomiting. Currently we explored the emetic mechanisms of FPL64176, an L-type Ca2+ channel (LTCC) agonist with maximal emetogenic effect at its 10 mg/kg dose. FPL64176 evoked c-Fos immunoreactivity in shrew brainstem sections containing the vomit-associated nuclei, nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus. FPL64176 also increased phosphorylation of proteins ERK1/2, PKCα/βII and Akt in the brainstem. Moreover, their corresponding inhibitors (PD98059, GF 109203X and LY294002, respectively) reduced FPL64176-evoked vomiting. A 30 min subcutaneous (s.c.) pretreatment with the LTCC antagonist nifedipine (10 mg/kg) abolished FPL64176-elicited vomiting, c-Fos expression, and emetic effector phosphorylation. Ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP3Rs) mediate intracellular Ca2+ release from the sarcoplasmic/endoplasmic reticulum. The RyR antagonist dantrolene (i.p.), or a combination of low doses of nifedipine and dantrolene, but not the IP3R antagonist 2-APB, significantly attenuated FPL64176-induced vomiting. The serotonin type 3 receptor (5-HT3R) antagonist palonosetron (s.c.), the neurokinin 1 receptor (NK1R) antagonist netupitant (i.p.) or a combination of non-effective doses of netupitant and palonosetron showed antiemetic potential against FPL64176-evoked vomiting. Serotonin (5-HT) and substance P immunostaining revealed FPL64176-induced emesis was accompanied by an increase in 5-HT but not SP-immunoreactivity in the dorsomedial subdivision of the NTS. These findings demonstrate that Ca2+ mobilization through LTCCs and RyRs, and subsequent emetic effector phosphorylation and 5-HT release play important roles in FPL64176-induced emesis which can be prevented by 5-HT3R and NK1R antagonists.

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Section: Methodsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva)

Zhong

Chebolu

Darmani

2018

European Journal of Pharmacology

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“…In another study we also utilized a combination of non-effective doses of amlodipine (0.5 mg/kg or 1 mg/kg) with a non-or semi-effective dose of the 5-HT 3 R antagonist palonosetron (0.05 or 0.5 mg/kg). 33 The combined antiemetic doses produced a similar additive efficacy against vomiting induced by either FPL 64176 or cisplatin. In fact relative to each antagonist alone, the combination was at least 4 times more potent in reducing the vomit frequency and provided more protection against FPL 64176-induced vomiting.…”

Section: Cross-talk Between Ltccs and 5ht 3 Rsmentioning

confidence: 91%

“…with respective ID 50 values 2-12 times larger than that of nifedipine. 28,33 Thus, comparatively nifedipine appears to be more potent than amlodipine in suppression of emetic behaviors evoked by 2-Me-5-HT.…”

Section: Antiemetic Potential Of Ltcc Blockersmentioning

confidence: 99%

“…requires more exposure time (30-45 min) to begin to induce emesis in the least shrew since only its metabolites are emetogenic. 39 Lack of antiemetic action of nifedipine versus the efficacy of amlodipine in reducing the frequency of cisplatin-induced vomiting by 80% 28,33 could be explained in terms of amlodipine having more exposure time not only to reach its sites of action, but also to compensate for its slower receptor binding kinetics. Another potential contributing factor for the efficacy of amlodipine against cisplatin-induced vomiting is its ability to bind an additional Ca 2+ site.…”

Section: Antiemetic Potential Of Ltcc Blockersmentioning

confidence: 99%

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Role of Calcium in Vomiting: Revelations from the Least Shrew Model of Emesis

Darmani

Zhong²

2015

Gastro Open J

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Citation-ATPase inhibitor) cause vomiting in the least shrew, whereas blockade of LTCC by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic activity against diverse emetogens including agonists of 5-HT 3 (e.g. 5-HT or 2-Me-5-HT)-, NK 1 (GR73632)-, D 2 (apomorphine or quinpirole)-, and M 1 (McN-A343)-receptors, but can also potentiate the antiemetic efficacy of well-established antiemetic palonosetron against the non-specific emetogen, cisplatin. The transmission of emesis signals in the gastrointestinal tract and brainstem is crucially dependent on Ca 2+ channels in neurons. In this review, we will examine the current knowledge on the role of Ca 2+ channels and Ca 2+-dependent signaling pathways in the perception and modulation of emesis.

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A re-consideration of neural/receptor mechanisms in chemotherapy-induced nausea and vomiting: current scenario and future perspective

Ullah

Ayaz

2023

Pharmacol. Rep

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Broad-spectrum antiemetic efficacy of the l-type calcium channel blocker amlodipine in the least shrew (Cryptotis parva)

Cited by 19 publications

References 33 publications

Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva)

Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva)

Role of Calcium in Vomiting: Revelations from the Least Shrew Model of Emesis

A re-consideration of neural/receptor mechanisms in chemotherapy-induced nausea and vomiting: current scenario and future perspective

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