Dual action of AJG049, a novel gut selective Ca2+ channel antagonist, on Ba2+ currents and contractions in guinea-pig antrum myocytes

Abstract: Ca2+ 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 Ca2+ 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 Ba2+ 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 (≥10 µM) 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 (≥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 Ca2+ channels in circular layer of guinea-pig antrum. [Copyright &y& Elsevier]