Comparative studies of AJG049, a novel Ca2+ channel antagonist, on voltage-dependent L-type Ca2+ currents in intestinal and vascular smooth muscle.
OBJECTIVE
Antagonists of Ca2+ channels reduce contraction of intestinal smooth muscle but also affect vascular smooth muscle. We have therefore examined the effects of AJG049, a newly synthesized antagonist for regulation of gut motility, on voltage-dependent L-type Ca2+ channels, in vascular and intestinal smooth muscle, comparing AJG049 with two other Ca2+ channel antagonists, verapamil and diltiazem.


METHODS
Affinities of AJG049 for various types of voltage-dependent Ca2+ channels were examined by binding studies. Effects of AJG049 on voltage-dependent inward Ca2+ (or Ba2+) currents (ICa or IBa) in dispersed smooth muscle cells from guinea-pig ileum, colon and mesenteric artery were measured using conventional whole-cell configurations.


RESULTS
In binding studies, AJG049 showed a high affinity for the diltiazem-binding site of L-type Ca2+ channels. In whole-cell configuration, AJG049 suppressed ICa in ileal myocytes, with concentration-, voltage-and use-dependencies. AJG049 shifted the steady-state inactivation curve of ICa to the left. The order of potency to inhibit ICa in ileal myocytes was AJG049>verapamil>diltiazem. AJG049 also suppressed IBa in guinea-pig mesenteric arterial myocytes, showing concentration- and voltage-dependencies and the potency order for this action was also AJG049>verapamil>diltiazem. For the relative ratio of Ki values between ileal and mesenteric arterial myocytes, the order was AJG049>diltiazem>>verapamil.


CONCLUSIONS
These results show that AJG049 inhibits L-type Ca2+ channels mainly through the diltiazem-binding site(s). From our results, AJG049 showed a little selectivity for these Ca2+ channels in intestinal smooth muscle.
Hashimoto
M
M
Pharmaceutical Research Laboratories, Ajinomoto Co Inc, Kawasaki, Japan.
Teramoto
N
N
Zhu
H-L
HL
Takahashi
K
K
Ito
Y
Y
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects; D006168:Guinea Pigs; D007422:Intestines / Q000187:drug effects; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D010077:Oxazepines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C515916:5,11-dihydro-5-(1-(4-methoxyphenethyl)-2-pyrrolidinylmethyl)dibenzo(b,e)(1,4)oxazepine hydrochloride; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D010077:Oxazepines; D011759:Pyrrolidines