A quantitative analysis of the Na⁺-dependence of$\dot V_{max}$ of the fast action potential in mammalian ventricular myocardium

Abstract

In microelectrode experiments on papillary muscles of guinea pigs, the quantitative dependence of$\dot V_{{\text{max}}}$ of the fast action potential, taken as a measure of I_Na, on external Na⁺ concentration has been analyzed under different experimental conditions including the presence of antiarrhythmic drugs such as lidocaine, procaine and propafenone.

• 1. External Na⁺ concentration changes between 225 mmol/l and 45 mmol/l led to a non-linear response of$\dot V_{{\text{max}}}$ in that the$\dot V_{{\text{max}}}$ changes obtained experimentally were significantly smaller than predicted theoretically from a linear dependence of$\dot V_{{\text{max}}}$ on [Na⁺] _o .

• 2. Each individual$\dot V_{{\text{max}}}$ relationship exhibited saturation characteristics. In Lineweaver-Burk plots,$\dot V_{{\text{max}}}$ correlated extremely well to 1/[Na⁺] _o with correlation coefficients between 0.995 and 0.999. In 16 experiments, the apparentK _m for Na⁺ varied within a range from 170 to 455 mmol/l. Values of 450 V/s–900 V/s were calculated for the saturated$\dot V_{{\text{max}}}$ (at an infinitely large [Na⁺] _o ).

• 3. The apparentK _m for Na⁺ rose from 232.0±24.7 mmol/l to 544.0±50.2 mmol/l when the K⁺ concentration of the medium was increased from 5.4 to 10 mmol/l and, thus, resting potential declined from −90.5±2.5 mV to −76.1±1.8 mV.

• 4. Alkalization (pH 9.0) of the medium lowered the apparentK _m for Na⁺ and, simultaneously, reduced the saturated$\dot V_{{\text{max}}}$. This typical shift of the straight relating$\dot V_{{\text{max}}}$ to 1/[Na⁺] _o in the Lineweaver-Burk plot excludes a competitive interaction between Na⁺ and H⁺ ions.

• 5. Lidocaine (5×10⁻⁵–2×10⁻⁴ mol/l), procaine (2×10⁻⁴ mol/l) and propafenone (0.5–3×10⁻⁵ mol/l) depressed$\dot V_{{\text{max}}}$ the stronger the lower [Na⁺] _o was. The changes of the$\dot V_{{\text{max}}}$ relationship induced by these drugs indicated neither a competitive nor a non-competitive interaction of these compounds with Na⁺.

• 6. As tested with propafenone, external Na⁺ changes modulated the tonic and the phasic block of$\dot V_{{\text{max}}}$. The Na⁺ sensitivity of both types of block differed considerably. In a Na⁺-poor (50 mmol/l) medium, the apparentK _m for the tonic block declined from 5×10⁻⁵ to 1.4×10⁻⁵ mol/l and the apparentK _m for the phasic block from 3.8×10⁻⁵ to 2.3×10⁻⁵ mol/l.

• 7. Na⁺ is not the sole cation that determines the strength of a drug-induced blockade of$\dot V_{{\text{max}}}$ as it can be substituted by the permeant Li⁺.

• 8. In the presence of drugs like propafenone which are capable of shifting the steady state inactivation (h _∞) of I_Na to more negative potentials, the voltage-dependence ofh _∞ can be modified by external Na⁺ variations. Na⁺ withdrawal led to a considerable shift in the hyperpolarizing direction.