Cisplatin-like chemotherapeutics cause
vomiting via release of multiple
neurotransmitters (
dopamine,
serotonin (5-HT), or
substance P (SP)) from the gastrointestinal enterochromaffin cells and/or the brainstem via a
calcium dependent process. Diverse channels in the plasma membrane allow extracellular Ca(2+) entry into cells for the transmitter release process. Agonists of 5-HT3 receptors increase
calcium influx through both 5-HT3 receptors and L-type Ca(2+) channels. We envisaged that L-type
calcium agonists such as
FPL 64176 should cause
vomiting and corresponding antagonists such as
nifedipine would behave as broad-spectrum
antiemetics. Administration of
FPL 64176 did cause
vomiting in the least shrew in a dose-dependent fashion.
Nifedipine and the
5-HT3 receptor antagonist
palonosetron, potently suppressed FPL 64176-induced
vomiting, while a combination of ineffective doses of these antagonists was more efficacious. Subsequently, we investigated the broad-spectrum
antiemetic potential of
nifedipine against diverse emetogens including agonists of serotonergic 5-HT3- (e.g. 5-HT or 2-Me-5-HT), SP
tachykinin NK1- (
GR73632),
dopamine D2- (
apomorphine or
quinpirole), and
cholinergic M1- (McN-A-343) receptors, as well as the non-specific emetogen,
cisplatin.
Nifedipine by itself suppressed
vomiting in a potent and dose-dependent manner caused by the above emetogens except
cisplatin. Moreover, low doses of
nifedipine potentiated the
antiemetic efficacy of non-effective or semi-effective doses of
palonosetron against
vomiting caused by either 2-Me-5-HT or
cisplatin. Thus, our findings demonstrate that activation of
L-type calcium channels causes
vomiting, whereas blockade of these
ion channels by
nifedipine-like antagonists not only provides broad-spectrum
antiemetic activity but can also potentiate the
antiemetic efficacy of well-established
antiemetics such as
palonosetron.
L-type calcium channel antagonists should also provide
antiemetic activity against
drug-induced
vomiting as well as other emetogens including bacterial and
viral proteins.