Ls. Song et al., Electrophysiological effects of protopine in cardiac myocytes: inhibition of multiple cation channel currents, BR J PHARM, 129(5), 2000, pp. 893-900
1 Protopine (Pro) from Corydalis tubers has been shown to have multiple act
ions on cardiovascular system, including anti-arrhythmic, anti-hypertensive
and negative inotropic effects. Although it was thought that Pro exerts it
s actions through blocking Ca2+ currents, the electrophysiological profile
of Pro is unclear. The aim of this study is to elucidate the ionic mechanis
ms of Pro effects in the heart.
2 In single isolated Ventricular myocytes from guinea-pig, extracellular ap
plication of Pro markedly and reversibly abbreviates action potential durat
ion, and decreases the rate of upstroke (dV/dt)(max), amplitude and oversho
ot of action potential in a dose-dependent manner. Additionally, it produce
s a slight, but significant hyperpolarization of the resting membrane poten
tial.
3 Pro at 25, 50 and 100 mu M reduces L-type Ca2+ current (I-Ca,I-L) amplitu
de to 89.1, 61.9 and 45.8% of control, respectively, and significantly slow
s the decay kinetics of ICa,L at higher concentration. The steady state ina
ctivation of I-Ca,I-L is Shifted negatively by 5.9-7.0 mV (at 50-100 mu M P
ro), whereas the voltage-dependent activation of I-Ca,I-L remains unchanged
. In contrast, Pro at 100 mu M has no evident effects on T-type Ca2+ curren
t (I-Ca,I-T).
4 In the presence of Pro, both the inward rectifier (I-Kl) and delayed rect
ifier (I-K) potassium currents are variably inhibited, depending on Pro con
centrations.
5 Sodium current (I-Na), recorded in low [Na+](o) (40 mM) solution, is more
potently suppressed by Pro. At 25 mu M, Pro significantly attenuated I-Na
at most of the test voltages (-60- + 40 mV, with a 53% reduction at -30 mV.
6 Thus, Pro is not a selective Ca2+ channel antagonist. Rather, it acts as
a promiscuous inhibitor of cation channel currents including I-Ca,I-L, I-K,
I-Kl as well as I-Na. These findings may provide some mechanistic explanat
ions for the therapeutic actions of Pro in the heart.