In microelectrode experiments on ventricular myocardium of guinea pigs, the dependence of verapamil-induced cardiac slow inward current (Isi) block on pH and temperature and the modulation of block after chemical channel modification by formaldehyde was studied taking Vmax of Isi-mediated action potentials as an estimate for Isi. Higher verapamil concentrations (1 X 10(-6) M) evoked in addition to phasic Vmax inhibition a second type of block, tonic Vmax blockade. With increasing stimulation frequencies, phasic Vmax block became stronger and developed faster. Alkalization (pH 9.0) failed to enhance the verapamil action, but cooling accentuated the drug effect. Thus, the apparent Km for tonic blockade declined from 1.72 X 10(-5) M at 35 degrees C to 1.22 X 10(-5) M at 30 degrees C. The decrease of the dissociation constant for the phasic block from 8.6 to 4.4 X 10(-7) M (interstimulus interval, 5 s) was more markedly pronounced. Chemical channel modification produced by short applications of formaldehyde (10 mM) sensitized the Isi system of the cardiac membrane and facilitated verapamil binding preferentially under resting state conditions. Block intensification persisted after withdrawal of the chemical for at least 30 min. Block potentiation by formaldehyde is not specifically related to the drug applied to inhibit Vmax of Isi-mediated action potentials. Thus, nifedipine-induced Vmax block rises significantly in response to an intervention with formaldehyde. The increase of apparent Km for nifedipine-induced blockade from 1.4 X 10(-6) to 2.7 X 10(-7) M suggests an increase in receptor affinity.