Sodium channel modulators: potential for treatment of heart failure
thesisposted on 06.12.2017, 00:00 by AJ Hoey
Explores the sodium channel modulating drugs DPI 201-106 and BDF 9148 to investigate in detail their potential for the treatment of heart failure.. Heart failure is a significant cause of morbidity and mortality in our society. Many current therapeutic compounds exhibit reduced efficacy in diseased myocardium, or produce toxic side effects. A drug that remains effective in the failing heart and possesses no side effects is still required. The sodium channel modulating drugs DPI 201-106 and BDF 9148 have been examined in detail to investigate their potential for the treatment of heart failure. First the effects of these compounds were investigated. In atrial tissues from guinea-pigs, rats and humans, these compounds induced positive inotropic responses, and in healthy guinea-pig and rat ventricular preparations both compounds produced significant increases in force of contraction and action potential duration (APD). Similar effects of BDF 9148 were also seen in healthy and diseased human ventricular tissues. The positive inotropic effects were maintained in ventricular preparations from hyperthyroid, hypothyroid, dwarf, diabetic, Wistar-Kyoto and spontaneously hypertensive rats. In contrast, BDF 9148 produced a negative inotropic effect in atria from hyperthyroid rats, but retained its positive inotropic effective-ness in atria from rats with other disease states. Next the mechanisms of action of these compounds were elucidated. These compounds inhibit the inactivation of the Na+ channel, thus allowing enhanced influx of Na+ into the cell. This increases the intracellullar Na+ concentration, thereby modifying the activity of the Na/Ca exchanger to inhibit Ca²+ efflux and/or promote Ca²+ influx. The prolongation of the APD also promotes Ca²+ influx by a longer duration of; (i) the calcium current and; (ii) the Na/Ca exchanger promoting Ca²+ accumulation. The accumulated intracellular Ca²+ is taken up into the sarcoplasmic reticulum released subsequent beats to produce a positive inotropic effect. Differences in APD prolongation between DPI 201-106 and BDF 9148 were evident in the guinea-pig ventricular tissues only. This difference was not due to differing effects on Na+ or Ca²+ currents, but was due to DPI 201-106 producing greater inhibition of the delayed and inward rectifier K+ currents than BDF 9148. Experiments in vivo have shown DPI 201-106 may promote arrhythmogenesis by excessively prolonging the APD, and via neural mechanisms. BDF 9148 also prolongs the human APD, but its effect on neural mechanisms are unclear. Clinical trials with BDF 9148 will determine its final usefulness. The work described above has shown sodium channel modulating drugs are effective positive inotropic compounds that maintain full efficacy, even in severely diseased myocardium. Their mechanisms of action have now been elucidated, and together with beneficial effects of positive inotropy, vasodilation (calcium channel antagonism) and Class III anti-arrhythmic protection (APD prolongation), the present results suggest that this group of drugs has potential for the treatment of heart failure.