MECHANICAL AND ELECTROPHYSIOLOGICAL EFFECTS OF 8-OXOBERBERINE (JKL1073A) ON ATRIAL TISSUE

1 The effects of 8-oxoberberine (JKL1073A) on contractions and electro physiological characteristics of atrial tissues were examined. 2 In dr iven left atria of the rat JKL1073A (10-100 mu M) increased twitch ten sion dose-dependently. In spontaneously beating right atria, JKL1073A increased twitch tension but decreased beating rate slightly. 3 The po sitive inotropic and the negative chronotropic effect of 30 mu M JKL10 73A was not affected by prazosin (1 mu M), propranolol (1 mu M) and 3- isobutyl-1-methyl-xanthine (10 mu M) but significantly suppressed by 4 -aminopyridine (2 mM 4-AP). 4 Current-clamp study revealed that JKL107 3A prolonged rat atrial action potential duration (APD). This prolonga tion of APD by JKL1073A was decreased by pretreating the cells with 2 mM 4-AP. Voltage-clamp study showed that JKL1073A inhibited the integr al of the transient outward current (I-to) dose-dependently with a K-D value of 3.66+/-0.93 mu M in rat atrial myocytes. The equilibrium dis sociation constant (K-d) for JKL1073A bindings to open state I-to was 0.50+/-0.08 mu M. The suppression of I-to by 3 mu M JKL1073A was accom panied by shortening of its inactivation time constant from 52.5+/-0.9 ms to 16.8+/-0.7 ms. V-0.5 for the steady-state inactivation curve of I-to was shifted from -25.7+/-3.3 mV to -34.8+/-3.2 mV. 5 In human at rial cells, similar inhibition of I-to and prolongation of APD by JKL1 073A was found. The K-D value of JKL1073A for inhibition of the integr al of I-to in human atrial cells is 4.03+/-0.02 mu M. The K-d for bind ings to open state I-to is 0.5 mu M. 6 Currents through K-1 channels o f rat and human atrial myocytes were not inhibited by JKL1073A at conc entrations up to 10 mu M. 7 These results indicate that JKL1073A exert s a positive inotropic effect by inhibition of I-to. JKL1073A inhibit I-to by binding to open state channels or shifting of the steady-state inactivation curve of I-to.