BDF-9198

In the first part of this study, we characterized 24-month-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs), their heart weights, and the responses of the isolated left ventricles to electrical stimulation. In the main part of the study, we tested whether the positive inotropic effects of BDF 9198, which prevents the closure of the cardiac sodium channel, were present in senescence and heart failure. Thus, we studied the effects of BDF 9198 on the left ventricle strips of 24-month-old WKY rats (senescence) and SHRs using contractility methods. In comparison with WKY rats, the left ventricles of 24-month-old SHRs were hypertrophied and had prolonged times to peak contraction. BDF 9198 (10−8 to 10−6m) was a positive inotrope on the left ventricles of WKY rats, with a maximum augmenting effect of 122% with BDF 9198 at 10−7m. The magnitude of the augmenting effects of BDF 9198 were reduced in SHR heart failure, with a maximum augmenting effect of 26% at 10−7m. BDF 9198 at 10−6 m attenuated the responses of the SHR left ventricle to electrical stimulation. In conclusion, the potential of drugs that prevent closure of the sodium channel as positive inotropes in the treatment of heart failure should be further considered.

The Na+ channel agonists DPI 201-106, BDF 9148 and BDF 9198 are a new group of positive inotropic agents which increase cardiac contractility in a cAMP independent manner. The most likely mechanism by which positive inotropy is mediated is an enhancement of Na+/Ca2+ exchange activity in response to a Na+ channel agonist induced increase in the cardiac myocyte intracellular Na+ concentration. While the positive inotropic effect of drugs which exert their effects in a cAMP dependent manner is blunted in failing compared to nonfailing myocardium, the efficacy and potency of Na+ channel agonists is not only maintained, but enhanced in failing myocardium. This finding makes these substances interesting for the treatment of patients with heart failure. The positive inotropic effects of the Na+ channel agonists, however, are accompanied by a potential increase in the incidence of cardiac arrhythmias. These side effects might limit the clinical use of Na+ channel agonists and demand future development of Na+ channel modulators without significant arrhythmogenic effects.