DIFFERENTIAL INHIBITION OF POTASSIUM CURRENTS IN RAT VENTRICULAR MYOCYTES BY CAPSAICIN

Objective: Capsaicin is a pungent irritant present in peppers of the Capsicum family. Its major target of action is believed to be sensory neurones. Capsaicin has also been shown to prolong cardiac action potential in atrial muscle, perhaps by local release of calcitonin gene related peptide which in tum enhances inward calcium currents. However, capsaicin has been shown to inhibit K+ currents in neurones. Since such an action could contribute to action potential prolonging activity of capsaicin in heart, the aim of the study was to examine the effects of capsaicin on cardiac K+ currents. Methods: Ionic currents and action potentials were examined in isolated adult rat ventricular myocytes using the whole cell variant of the patch clamp technique at 25-degrees-C. Results: Capsaicin (10 muM) increased the action potential duration (APD50) from 45 ms to 166 ms. This effect was associated with an inhibition of three distinct K+ currents. The decreasing rank order of potency was: transient outward K+ current (I(TO), IC50=6.4 muM), a voltage dependent non-inactivating outward current (I(K), IC50=11.5 muM), and the inward rectifier K+ current (I(K1), IC50=46.9 muM). Capsaicin induced block of I(TO) was characterised by a decrease in the peak current amplitude and an increase in the rate of inactivation. The inactivation of I(TO) in the absence of capsaicin was well described by a single exponential [tau=77 (SEM 2) ms at +40 mV, n=10]. However, in the presence of 10 mum capsaicin inactivation was best described by the sum of two exponentials [tau(FAST)=4.4(0.5) ms, tau(SLOW)=92.4(3.0) ms, n=10] with the fast component contributing 46(2)% of the total decay. A small but consistent hyperpolarising shift (approximately 3 mV) in the steady state voltage dependence of inactivation of I(TO) was induced by 10 muM capsaicin. Capsaicin had no effect on the rate of I(TO) recovery from inactivation (tau=49 ms and 48 ms for control and drug respectively). The capsaicin analogue, resiniferatoxin, which as an irritant is up to 10(4)-fold more potent than capsaicin, had no effect on any of the K+ currents when present at concentrations of up to 10 muM. In contrast another capsaicin analogue, zingerone (30 muM) blocked I(TO) by 52(12)% and I(K) by 35%. Conclusions: Capsaicin produces a prolongation of the rat ventricular action potential, an effect which is associated with inhibition of potassium currents.