Ca2+ antagonist inhibition of intestinal motor activity

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Ca2' ANTAGONIST INHIBITION OF INTESTINAL MOTOR ACTIVITY M. MARCOLI, S . LECCHINI, G . M . FRIGO and A . CREMA Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, Piazza Botta 10, 27100 Pavia, Italy KEY

wows : ACh output, Bay K8644, Cal+ antagonists, myenteric plexus, propulsion .

Different Ca 2 + 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 Ca 21 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 I Ca2 + I " their maximal values being reached at the concentrations of 1 . 5-1 . 8 mM ICa21 10 . 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 0031-6989/89/010119-03/$03 .00/0

© 1989 The Italian Pharmacological Society



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Pharmacological Research, Vol. 21, No. 1, 1989

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Pharmacological Research, Vol 21, No . 1, 1989

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enhanced in carbachol-excited muscle, while the potency and the efficacy of nifedipine increased against ACh output elicited by field stimulation and Bay K8644, respectively. It is concluded that an important contribution of cholinergic neurotransmission inhibition to the impairment of propulsion can be suggested in the case of verapamil, while for nifedipine such a contribution seems to be negligible. Resting ACh output from the enteric neurons seems to be only partially dependent on DHP sensitive Cal+ channels . However, DHP sensitive channels regulating neurotransmitter release seem to be present on the enteric neurons, which can be acted upon by both the agonist and the antagonist . As deduced from the effect of Bay K8644, a different sensitivity to pharmacological manipulation seems to be exhibited by Call channel on different neuron types . In any case, enteric neurons add to the number of neuronal cells in which organic Cat + antagonists can produce functionally relevant changes [5] . If the degree of sensitivity to different Cal' antagonists is to be considered linked to the presence of different Call channel subtypes, a different relative importance of Call channel type and/or of channels in a functional state leading to selective verapamil or nifedipine sensitivity seem to be present on enteric nervous and muscular structures .

REFERENCES 1. Reuter H . Nature 1983 ; 301 : 569 . 2 . Nowycky MC, Fox AP, Tsien RW. Nature 1985 ; 316 : 440 . 3 . Godfraind T, Wibo M . BrJPharmacol 1985 ; 85: 335 . 4 . Frigo GM, Lecchini S, Marcoli M, Tonini M, d'Angelo Schmiedeberg's Arch Pharmac 1984 ; 325 : 145 . 5 . Miller RJ. Science 1987 ; 235 : 46 .

L, Crema A .

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