Effects of 2,3-butanedione monoxime on whole-cell Ca2+ channel currents in single cells of the guinea-pig taenia caeci.

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1. The inhibitory actions of cadmium (Cd2+), nifedipine and 2,3-butanedione monoxime (BDM) on whole-cell Ca2+ channel currents in single cells of the guinea-pig taenia caeci were investigated using a single-electrode whole-cell voltage-clamp technique. 2. Calcium channel currents were isolated using pipette solutions containing Cs+, tetraethylammonium and ATP (3 mM). Ca2+ or Ba2+ (7.5 mM) in the bathing solution acted as the charge carrier during inward current flow. Ca2+ channel currents in 7.5 mM-Ba2+ (IBa) were recorded at potentials positive to -40 mV, were maximal near 0 mV and reversed near +60 mV. Ca2+ channel activation showed a sigmoidal relationship with potential, which was half-maximal at -13 mV. 3. Both the inward and outward flow of current was depressed and eventually blocked by 0.3-100 microM-Cd2+, 0.1-10 microM-nifedipine and 2-20 mM-BDM. Half-maximal blockade of IBa at 0 mV was achieved with approximately 3 microM-Cd2+, 1 microM-nifedipine and 10 microM-BDM. Steady-state activation curves were not affected by Cd2+ or BDM, but were shifted in the hyperpolarizing direction by nifedipine at concentrations > 1 microM. 4. Calcium channel currents in single cells and K+ contractures in intact strips were both blocked in a voltage-dependent manner. Steady-state inactivation curves (f infinity (V)) for IBa were shifted 20 mV in the hyperpolarizing direction by 0.3 microM-nifedipine and 4 mV by 10 mM-BDM. From these shifts a dissociation binding constant to inactivated Ca2+ channels for nifedipine was estimated as 78 nM, and for BDM, 5 mM. 5. At 10 microM Cd2+ produced a 43 +/- 6% (n = 3) block of the inward current at 0 mV when Ca2+ (7.5 mM) was the charge carrier (ICa), compared with the 36 +/- 3% block of IBa induced by 1 microM-Cd2+, consistent with the suggestion that Ca2+, Ba2+ and Cd2+ compete for the same binding site. In contrast, nifedipine (1 microM) and BDM (10 mM) blocked ICa more effectively than IBa. 6. Bay K 8644 (1.0 microM) increased Ca2+ channel currents two- to fourfold at all potentials due to a shift, of approximately 10 mV in the negative direction, of their activation curve and an equal shift in the positive direction of their inactivation curve. BDM (5-10 mM) could antagonize the action of Bay K 8644, shifting both curves back towards their control.(ABSTRACT TRUNCATED AT 400 WORDS)

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