Relation between veratridine reaction dynamics and macroscopic Na current in single cardiac cells.

Abstract

Veratridine modification of Na current was examined in single dissociated ventricular myocytes from late-fetal rats. Extracellularly applied veratridine reduced peak Na current and induced a noninactivating current during the depolarizing pulse and an inward tail current that decayed exponentially (~ = 226 ms) after repolarization. The effect was quantitated as tail current amplitude, /tail (measured 10 ms after repolarization), relative to the maximum amplitude induced by a combination of 100 IzM veratridine and 1 ~M BDF 9145 (which removes inactivation) in the same cell. Saturation curves for Itail were predicted on the assumption of reversible veratridine binding to open Na channels during the pulse with reaction rate constants determined previously in the same type of cell at single Na channels comodified with BDF 9145. Experimental relationships between veratridine concentration and Itau confirmed those predicted by showing (a) haftmaximum effect near 60 ~M veratridine and no saturation up to 300 ~M in cells with normally inactivating Na channels, and (b) haft-maximum effect near 3.5 p,M and saturation at 30 ~M in cells treated with BDF 9145. Due to its known suppressive effect on single channel conductance, veratridine induced a progressive, but partial reduction of noninactivating Na current during the 50-ms depolarizations in the presence of BDF 9145, the kinetics of which were consistent with veratridine association kinetics in showing a decrease in time constant from 57 to 22 and 11 ms, when veratridine concentration was raised from 3 to 10 and 30 I.LM, respectively. As predicted for a dissociation process, the tail current time constant was insensitive to veratridine concentration in the range from 1 to 300 o,M. In conclusion, we have shown that macroscopic Na current of a veratridine-treated cardiomyocyte can be quantitatively predicted on the assumption of a direct relationship between veratridine binding dynamics and Na current and as such can be successfully used to analyze molecular properties of the veratridine receptor site at the cardiac Na channel.

Pathophysiology of the cardiac late Na current and its potential as a drug target

“…There are various compounds that can increase late I Na including veratridine [114], peptide toxins (e.g. ATX-II, AP-A, AP-Q, β-pompilidotoxin) [115], pyrethroids [116-118], and small molecules (BDF9148, DPI201106) [6, 83, 84, 117].…”

Effects of veratridine on sodium currents and fluxes

“…5.6). In cardiac cells the inactivation inhibitor BDF 9145 also increases the veratridine effect (Wang et al 1990;Zong et al 1992).…”

“…This has also been reported for snail neurones (Leicht et al 1971a,b). Obviously it must be postulated that the dissociation is, directly or indirectly, potential dependent (see also Zong et al 1992). Biphasic relaxation, mentioned above for the O*-I* transition in muscle, is also observed in neuroblastoma cells, where tails following long (but not short) trains of impulses show a biexponential decay (Barnes and Hille 1988), thus requiring an extended kinetic model.…”

“…Diffusion through the membrane and intracellular accumulation is also thought to account for the onset of veratridine action on cardiomyocytes, with a time constant of about i min (20°C; Zong et al 1992). In crayfish giant axons most veratridine effects persist, but the maintained current at the holding potential between pulses during a train vanishes on washout (Warashina 1985).…”

HOE 694 affords protection versus veratrine contractures in rat atria by Na+ channel blockade

“…Since other Na+-H+ exchange inhibitors possess properties unrelated to Na+-H+ exchange such as inhibition of ionic currents, we investigated the effects Table 11. Veratridine-induced low conductance state is characterized by a predominant open state alternating with brief closures in cardiomyocytes and is thus better described as a "burst" of Na+ current (Leibowitz et al, 1986;Zong et al, 1992). of HOE 694 on Na+ channel function.…”