Direct quantification of apparent binding indices from quinidine-induced in vivo conduction delay in canine myocardium.

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Abstract

To characterize quantitatively the quinidine (QUIN)-induced conduction delay (CD) in vivo, canine ventricular activation times were examined with an epicardial mapping technique. A high-resolution index of normalized (N) QUIN CD, derived from all 56 recording sites, was used to quantify QUIN effect. Repetitive stimulation elicited monoexponential increases in CD(N), the rates of which were a linear function of interpulse recovery interval, tr. Steady-state CD(N) was also linearly related to an exponential function of tr and drug uptake rates. The frequency-dependent properties of QUIN in 14 dogs were characterized by apparent binding and unbinding rates of ka = 7.1 +/- 3.5 x 10(6) M-1 s-1, la = 81 +/- 51 s-1 for activated, and kr = 12.6 +/- 11.3 x 10(3) M-1 s-1, lr = 0.51 +/- 0.26 s-1 for resting states. ka and la were similar to values previously derived in canine Purkinje fibers. Drug unbinding at resting potentials was faster in vivo than previously observed in vitro. The time constant of recovery from QUIN block extracted from the interpulse recovery rate was also identical to that determined from post-mature stimulus diastolic scanning. As predicted by the two-state model, similar binding rates were also derived from declining CD(N) elicited by step decreases in heart rate. These findings represent a complete quantitative description of use-dependent QUIN CD in vivo and provide a firm foundation for characterizing antiarrhythmic drug action under physiologic and pathologic conditions.

Authors

F N Haugland, S B Johnson, D L Packer