Differential antagonism of the negative inotropic effect of gentamicin by calcium ions, Bay K 8644 and isoprenaline in canine ventricular muscle: Comparison with cobalt ions

1. Gentamicin (10^-4-10^-2 M) and Co²⁺ (10^-4-10^-2 M) produced a decrease in developed tension of canine isolated ventricular muscles leading to near abolition at 10^-2 M. Their negative inotropic effects developed rapidly and wore off shortly after wash-out. 2. The concentration-negative inotropic effect curves for gentamicin were shifted to the right in a parallel manner by increasing external Ca²⁺, or by the presence of Bay K 8644 (10^-7-10^-5 M) or isoprenaline (10^-7-10^-5 M). IC₅₀ values for gentamicin increased about 3-fold with about a 6 fold increase in external Ca²⁺. The Schild plot yielded a pA₂ of 2.29 for Ca²⁺ and its slope was -1.17 (r = -0.79). 3. The concentration-negative inotropic effect curves for Co²⁺ were shifted to the right in a parallel manner by increasing external Ca²⁺, or by the presence of isoprenaline (10^-7-10^-5 M). IC₅₀ values for Co²⁺ increased about 5-fold with about a 6-fold increase in external Ca²⁺. The Schild plot gave a pA₂ value of 2.60 for Ca²⁺ and its slope was -1.11 (r = -0.86). 4. The concentration-positive inotropic effect curves for Ca²⁺, which were computer-fitted to a logistic equation, gave 2.88 x 10^-3 M for EC₅₀. This value was very close to the K(Ca) calculated from pA₂ values for Ca²⁺ based on antagonism between gentamicin or Co²⁺ and Ca²⁺ (5.13 x 10^-3 and 2.51 x 10^-3 M). 5. It is concluded that like Co²⁺, gentamicin molecules compete with Ca²⁺ for the same binding sites presumably located at the outer orifice of Ca-channels in the cardiac sarcolemma.