Electrophysiological properties of HBI-3000: a new antiarrhythmic agent with multiple-channel blocking properties in human ventricular myocytes.

HBI-3000 (sulcardine sulfate) has been shown to suppress various ventricular arrhythmias in animal models. The electrophysiological properties of HBI-3000 were investigated using standard microelectrode and patch-clamp techniques in single human ventricular myocytes. HBI-3000 led to concentration-dependent suppression of dofetilide-induced early afterdepolarizations in single nonfailing human ventricular myocytes and early afterdepolarizations seen in failing ventricular myocytes. The concentration-dependent prolongation of action potential duration (APD) by HBI-3000 was bell shaped with maximum response occurring around 10 µM. Interestingly, HBI-3000 at the concentration of 10 µM modestly prolonged the APD at all 3 basic cycle lengths. The slope of APD-cycle length curve of HBI-3000 was only slightly steeper than that of control (88.8 ± 7.7 ms/s vs. 78.9 ± 5.2 ms/s in control, n = 8, P > 0.05). HBI-3000 only showed a minimal use-dependent prolongation of the APD in human ventricular myocytes. HBI-3000 inhibited fast sodium current (INa-F), late sodium channel (INa-L), L-type calcium current (ICa-L), and rapidly activating delayed rectifier K current (IKr) in single human ventricular myocytes. The estimated half-maximal inhibitory concentration values of INa-F, INa-L, ICa-L, and IKr were 48.3 ± 3.8, 16.5 ± 1.4, 32.2 ± 2.9, and 22.7 ± 2.5 µM, respectively. The ion channel profile and electrophysiological properties of HBI-3000 are similar to those of ranolazine and chronic amiodarone (reduced INa-F, INa-L, ICa-L, and IKr). HBI-3000 may be a promising antiarrhythmic agent with low proarrhythmic risk.

The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens.

Neurosteroids are a subclass of steroids that can be synthesized in the central nervous system independently from peripheral sources. Clinical studies in humans have associated these hormones with depression and postpartum mood disorders. In rodents, allopregnanolone (AlloP) has been shown to have anxiolytic and rewarding properties. These observations suggest that neurosteroids could interact with mood and motivation. However, the possible neural substrates of these effects remain unknown. In this report, we have studied the action of AlloP on the activity of the mesencephalic dopaminergic (DA) projection to the nucleus accumbens, which is considered one of the biological substrates of motivation and reward. This study was conducted by measuring extracellular concentrations of dopamine (DA) in the nucleus accumbens by means of microdialysis in freely moving rats. We studied both the direct effect of AlloP and the influence of this hormone on the DA response to an injection of morphine. AlloP dose-dependently increased the release of DA in the nucleus accumbens. Furthermore, this hormone doubled the DA response to morphine. These effects were observed for AlloP doses of 50 and 100 pmol injected intracerebroventricularly. These results suggest that the stimulatory effect of AlloP on DA could mediate some of the behavioural effects of neurosteroids and, in particular, the interaction of these hormones with mood and motivation.