Prevention by nimodipine, a calcium entry blocker, of the effect of alpha 2-adrenoceptor blocking agents on noradrenaline release: differential effects of nimodipine, on [3H]noradrenaline and [14C]acetylcholine release measured concomitantly from the guinea-pig ileum
The calcium channel blocker, nimodipine (Bay e 9736), inhibited the evoked (1 Hz, 1 msec, 180 pulses) release of [14C]acetylcholine ([14C]ACh) while it enhanced the release of [3H]noradrenaline ([3H]NA) measured concomitantly from the same longitudinal muscle strip of guinea-pig ileum loaded with [14C]choline and [3H]noradrenaline. These effects of nimodipine were concentration-dependent: in 0.1 microM concentration yielding maximal inhibition of [14C]ACh release and in 0.5 microM concentration yielding half maximal stimulation of [3H]NA-release. Enhancement of [3H]NA-release by nimodipine was strongly dependent on stimulation frequency while the inhibitory effect of nimodipine on release of [14C]ACh did not depend on stimulation frequency in the 0.5-10 Hz range. In addition, in the presence of nimodipine when the release of [3H]NA was enhanced, i.e. when a significant negative feedback operation could have been expected, alpha 2-adrenoceptor blocking agents (yohimbine and idazoxane) failed to enhance [3H]NA-release. It is proposed that nimodipine somehow exerts a presynaptic alpha 2-adrenoceptor blocking property at noradrenergic axon terminals through an effect on calcium entry, which may be an essential step in events linking alpha 2-adrenoceptor activation and inhibition of noradrenaline release.