Ca 2+ antagonist inhibition of intestinal motor activity

Abstract

Different Ca2 + channel subtypes seem to be present in excitable cells, which are believed to contribute to the variety in sensitivity to organic Cal' antagonists exhibited by muscular and nervous structures [1, 2] . Although evidence is accumulating that dihydropyridine (DHP) binding sites in the enteric neuromuscular structures are associated with functional Cal+ channels [3], attention has only recently been focused on the functional role of drug sensitive Cal+ channels at the level of enteric interneuronal and neuromuscular synapses . In fact, to what extent smooth muscle inhibition or impairment of neurotransmission in the enteric plexuses could contribute to the end effect of Cal' antagonists on intestinal motor function is far from being elucidated . Both muscular and nerve mediated effects of the Ca21 channel activator Bay K8644 and of the Cal+ antagonists nifedipine, verapamil and diltiazem have been studied in guinea-pig isolated colon . The efficiency of the peristaltic reflex, circular muscle tone and contraction and response to carbachol, resting and electrically stimulated acetylcholine (ACh) output and the longitudinal muscle non-adrenergic non-cholinergic (NANC) relaxation were measured as described in Frigo et al. [4] . The efficiencies of the peristaltic reflex, resting ACh output and the amplitude of NANC relaxation were highly dependent on Ca2 + I their maximal values being reached at the concentrations of 1 . 5-1 . 8 mM ICa21 1 0 . Bay K8644 at a concentration as low as 3 x 10 -9M was capable of increasing the maximal velocity of propulsion and NANC relaxation, while concentrations at least 60 times higher were required to increase ACh output and circular muscle tone and contractility. Nifedipine, verapamil and diltiazem were found to inhibit in a concentration dependent way both muscular and nervemediated responses, nifedipine always exhibiting the highest potency . However, a very different behaviour for each Ca 2 + antagonist appeared when the potencies exhibited in producing muscular and nerve-mediated effects were compared (Table I). Moreover, efficacies of different drugs were very different in producing muscular or nerve-mediated effects, as the Emax values for nifedipine, verapamil and diltiazem were 49 94 . 4 and 65 . 8 in inhibiting resting ACh output, and 81 40 . 6 and 56 . 6 in relaxing circular muscle. Both the circular muscle sensitivity to verapamil and the ACh output sensitivity to nifedipine proved to depend on the degree of excitation. Indeed, both potency and efficacy of verapamil were significantly 119