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1. The effects of 14 lignocaine homologues on the maximum upstroke velocity (Vmax) of the action potentials (AP) were studied in guinea-pig papillary muscles. These drugs possess one, two or three methyl groups in different positions: an ortho-chloro, -carbomethoxy or -ethyl group instead of an ortho-methyl group; or an N-butyl group instead of an N-diethyl group in lignocaine molecules. 2. At 50-100 mumol/L, six drugs possessing two ortho substituents (but not the other eight) reduced Vmax more prominently at 2-4 Hz than at 1 Hz, and slowed the time courses of recovery of the premature responses. None of the drugs affected resting potential. 3. Besides the two-state piecewise exponential model (models I and II) frequently used, a time-dependent and time-independent, two-state model (model III) was formulated and applied to these experimental data. The above two groups were effectively distinguished by the difference of the estimated association and dissociation rate constants (model II) and equilibrium constants for phasic state (model III) and for resting (model II) or tonic (model III) states. 4. The equilibrium constants for resting or tonic state correlated well with log P (where P = the n-octanol: water partition coefficients), but correlated better with an indicator variable that denotes the existence of two ortho substituents, suggesting the importance of the contribution of steric factors to the activity.

Effects of 18.5 mumol/l lidocaine on the Vmax in the absence and presence of 10 mmol/l tetraethylammonium chloride (TEA), which specifically prolongs the action potential duration with little effects on Vmax, were studied in guinea-pig papillary muscles in a 10 mmol/l K+ Tyrode solution. The frequency-dependent reduction of Vmax was significantly increased at high frequencies (3 and 4 Hz) in the presence of lidocaine plus TEA. A simulation study was performed under the assumption that lidocaine interacts with open, inactivated and resting sodium channels and that TEA specifically prolongs the inactivated state, and a reasonable fit to the experimental Vmax changes was obtained. There were no significant differences between the effects of lidocaine alone and lidocaine plus TEA on the tonic blocks, time constants and zero-time intercepts of reactivation process of Vmax. The F-test shows that these reactivation processes in all preparations examined are described sufficiently well by monoexponential functions, that is, under the assumption of the linear relationship between available sodium conductance and Vmax. The finding that a nonlinear model does not significantly improve the fit indicates the possibility that the nonlinearity may not be prominent under the present experimental conditions.

Exercise tests with sublingual nitroglycerin were performed on 7 patients with true positive and 8 patients with false positive exercise test results. Four of 7 patients with true positive changes and 8 patients with false positive changes underwent exercise cardiac scintigraphy. Scintigrams showed perfusion defects in 4 patients with true positive outcomes, and no perfusion defect in 8 patients with false positive outcomes. Exercise tests with sublingual nitroglycerin were performed with the same load as that without nitroglycerin. In all 7 patients with true positive exercise test results, ST segment depression observed in the control exercise test was not observed in the nitroglycerin exercise test. In the false positive patients, ST segment depression observed in the control exercise test remained unchanged in 7 of 8 patients receiving nitroglycerin. Exercise tests with sublingual nitroglycerin as well as exercise cardiac scintigraphy are valuable tods in differentiating false positive from true positive patients. Furthermore, these data suggest that ST segment depression in the false positive patients may not be related to myocardial ischemia.