title: Dual action of AJG049, a novel gut selective Ca2+ channel antagonist, on Ba2+ currents and contractions in guinea-pig antrum myocytes.
abstract: Ca(2+) channel antagonists are useful to reduce the abnormal motility in patients with irritable bowel syndrome. We have therefore examined the effects of a newly synthesized antagonist AJG049, on voltage-dependent L-type Ca(2+) channels in gastric antrum. Intracellular recordings were made from sheets of the circular muscle layer of guinea-pig gastric antrum, with simultaneous measurement of spontaneous contraction activity, and the effects of AJG049 were studied. The effects of AJG049 on voltage-dependent Ba(2+) currents (I(Ba)) and the basal membrane currents at -70 mV in dispersed smooth muscle cells were also investigated by the use of conventional whole-cell patch-clamp techniques. Although AJG049 (100 nM) enhanced the peak amplitude of spontaneous contractions, high concentrations (>or=10 microM) had inhibitory effects. In whole-cell configuration, AJG049 (10 nM) reversibly enhanced the peak amplitude of I(Ba) in a voltage-dependent manner whilst high concentrations (>or=100 nM) suppressed the peak amplitude in a concentration- and voltage-dependent manner. AJG049 (300 nM) caused little shift in the activation curve at a holding potential of -70 mV although the voltage dependence of the steady-state inactivation was shifted to more negative potentials by 5 mV in its presence. AJG049 caused a delay of the recovery from the inactivated state of I(Ba). Furthermore, AJG049 reduced the amplitude of the basal membrane currents at -70 mV in a concentration-dependent manner. These results suggest that AJG049 possesses a dual action on voltage-dependent Ca(2+) channels in circular layer of guinea-pig antrum.
authors.affiliation: Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Higashi Ward, Fukuoka, Japan.
authors.forename: Hai-Lei
authors.initials: HL
authors.lastname: Zhu
authors.forename: Masaki
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Teramoto
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010077:Oxazepines / Q000008:administration & dosage / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011706:Pyloric Antrum / Q000187:drug effects / Q000378:metabolism; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: 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