The effect of tedisamil 10 |J.M on total outward current was use-dependent. After 2 mins of rest at -80 mV, reduction of peak current developed more quickly when clamp steps to +60 mV (duration 300 ms) were applied with a frequency of 1 Hz than one of 0.2 Hz; Ton values were 0.7 s and 3.7 s, respectively (Figure 7A). After a steady state of block had been obtained with a train of 10 pulses to +60 mV (duration 300 ms) at 1 Hz, recovery from block was tested with the same clamp step after intervals of 0.5 to 60 s duration at -80 mV. Total outward current recovered completely from tedisamil block after 30 s at a potential of -80 mV (Figure 7B); on average, the recovery time constant was 7.9±1.6 s (n=3).
Figure 6 Kinetic analysis oftedisamil-induced block of sustained outward current (Iso) in human atrial myocytes. A Development of fractional block ([control – drug] / control) during the first 100 ms of a steady state test step to +50 mV for 1, 2, 5 and 10 fiM of tedisamil. The time constants, ron, were 53.5±18.6 ms (n=4)for 1 juM, 30.7 ms (n=2)for 2 juM, 10.6±1.1 ms (n=3) for 5 juM and 10.9±3.6 ms (n=5)for 10juM of tedisamil. B Calculation of rate constants from the linear regression (B) of the plot of1/Ton versus the concentration of tedisamil in micromoles according to the formula (1/ton = kj x [tedisamil] + k2), where kj and k2 are association and dissociation rate constants, respectively. From the regression line k1 was 8.4×106/M/s, and k2 was 22.1/s. The apparent dissociation constant, Kd, was calculated to be 2.6juM, which agrees with the experimentally measured concentration of half maximum block
Figure 7 Onset oftedisamil-induced block on peak outward current (M) and recovery from block in human atrial myocytes (tedisamil 10 uM). A After 2 mins’ rest at-80 mV, clamp steps to +60 mV were applied at a frequency of 0.2 Hz (circles) or 1 Hz(squares). Open symbols, control; filled symbols, in the presence of tedisamil 10 uM. B Recovery of total outward current from tedisamil block. т Time constant Most advantageous shopping with best pharmacy you can choose in just a second: buy ortho tri-cyclen online best price and find out exactly how little it could cost you to be getting your medications quick and easy.