The Ca²⁺ antagonists, Mn²⁺, Co²⁺, D 600 (α-isopropyl-α-[(N-methyl-N-homoveratryl)-γ-aminopropyl]-3,4,5-trimethoxyphenylacetonitrile), and BAY-1040 (2,6-dimethyl-3,5-dicarbo-methoxy-4-(2-nitro)phenyl-1,4-dihydropyridine) inhibited the response of guinea pig ileal longitudinal muscle to the muscarinic agonist CD (cis-2-methyl-4-dimethylaniinomethyl-1,3-dioxolane methiodide). With the exception of Tm³⁺ these agents were more effective against the tonic component of response.BAY-1040 was equally effective against phasic components of CD and K⁺ responses and, although more potent against tonic responses, also failed to discriminate between the tonic components of response to CD and K⁺. D 600, although less potent than BAY-1040, behaved similarly to BAY-1040 in failing to discriminate between CD and K⁺ responses. These data suggest that CD and K⁺ utilize identical, or at least very similar, sources of Ca²⁺ to sustain excitation-contraction coupling. The tonic component of the CD response showed an apparently cooperative dependence on Ca²⁺ concentration but D 600 and BAY-1040 behaved as powerful competitive antagonists against Ca²⁺ in both components of the response to CD (D 600, K_I, 1.2 × 10⁻⁷ M (phasic), 9.8 × 10⁻⁹ M (tonic); BAY-1040, K_I,1.8 × 10⁻⁸ M (phasic), 4.8 × 10⁻⁹ M (tonic)) with potencies similar to those found in other tissues where these agents inhibit membrane Ca²⁺ currents. The complete additivity of antagonism produced by combination of equieffective concentrations of Tm³⁺ and D 600 or BAY-1040 indicated that Tm³⁺ acts at a site distinct from that occupied by D 600 or BAY-1040. In contrast, D 600 and BAY-1040 appear to interact at a common site. No increase in total ⁴⁵Ca uptake in the presence of 5 × 10⁻⁷ M CD could be detected at 0.5 min (phasic component) or 10 min (tonic component) but a significant decrease was found at 5 min and significant increases were found at later times (30 min, 60 min). However, an increase in the ⁴⁵Ca cellular content, measured after washing in La³⁺ to remove superficial Ca²⁺ and to retain cellular Ca²⁺, could be detected at 0.5 and 10 min in the presence of 5 × 10⁻⁷ M CD, in tissues preequilibrated in ⁴⁶Ca²⁺ for 60 min. This increase in cellular ⁴⁶Ca was blocked by atropine, D 600, BAY-1040, and Tm³⁺ at concentrations that blocked mechanical response. It is concluded that the mechanical responses of guinea pig ileal longitudinal smooth muscle produced by muscarinic agonists or by KCl use Ca²⁺ that enters through Ca²⁺ channels similar to those described in other excitable tissues.

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