The
dihydropyridine l-type
calcium (Ca(2+)) channel blockers
nifedipine and
amlodipine reduce extracellular Ca(2+) entry into cells. They are widely used for the treatment of hypertensive disorders. We have recently demonstrated that extracellular Ca(2+) entry via l-type Ca(2+) channels is involved in
emesis and that
nifedipine has broad-spectrum
antiemetic activity. The aim of this study was to evaluate the
antiemetic efficacy of the longer-acting l-type Ca(2+) channel blocker,
amlodipine. Fully effective
emetic doses of diverse emetogens such as the l-type Ca(2+) channel agonist (
FPL 64176) as well as selective and/or nonselective agonists of serotonergic 5-HT3 (e.g. 5-HT or 2-Me-5-HT)-,
dopamine D2 (e.g.
apomorphine or
quinpirole)-,
cholinergic M1 (e.g.
pilocarpine or
McN-A343)- and tachykininergic NK1 (e.g. GR73632)-receptors, were administered intraperitoneally (i.p.) in the least shrew to induce
vomiting. The broad-spectrum
antiemetic potential of
amlodipine was evaluated against these emetogens. Subcutaneous (s.c.) administration of
amlodipine (0.5-10mg/kg) attenuated in a dose-dependent and potent manner both the frequency and percentage of shrews
vomiting in response to intraperitoneal (i.p.) administration of
FPL 64176 (10mg/kg),
5-HT (5mg/kg), 2-Me-5-HT (5mg/kg),
apomorphine (2mg/kg),
quinpirole (2mg/kg),
pilocarpine (2mg/kg),
McN-A343 (2mg/kg), or
GR73632 (5mg/kg). A combination of non-effective doses of
amlodipine (0.5mg/kg, s.c.) and the
5-HT3 receptor antagonist
palonosetron (0.05 mg/kg, s.c.) was more effective against FPL 64176-induced
vomiting than their corresponding doses tested alone.
Amlodipine by itself suppressed the frequency of acute
cisplatin (10mg/kg, i.p)-induced
vomiting in a dose-dependent manner. Moreover, a combination of a non-effective dose of
amlodipine (1mg/kg) potentiated the
antiemetic efficacy of a semi-effective dose of
palonosetron (0.5mg/kg, s.c.) against acute
vomiting caused by
cisplatin. We confirm that influx of extracellular Ca(2±) ion underlies
vomiting due to diverse causes and demonstrate that l-type Ca(2+) channel blockers are a new class of broad-spectrum
antiemetics.