Effects of BDF 9148 on the Action Potentials and Contractions of Left Ventricles From Normo‐ and Hypertensive Rats

Abstract

1. The aim of the present study was to test the hypothesis that responses to BDF 9148, which prolongs the opening of sodium channels, are reduced in the spontaneously hypertensive rat (SHR) left ventricle in the presence of hypertrophy and failure. 2. We studied the effects of BDF 9148 on the action potentials and contractions of left ventricles from 5-week-old prehypertensive, 14-week-old hypertensive, 6- and 12-month-old hypertension-associated hypertrophy and 18-month-old hypertension-induced heart failure SHR and age-matched Wistar-Kyoto normotensive (WKY) rats. 3. Action potentials and left ventricular contractions did not alter in the early stages of hypertension (14-week-old SHR). The diastolic membrane potential did not change with hypertension-associated hypertrophy, but there was a reduction in amplitude and a prolongation of action potentials in the left ventricles of 6-18-month-old SHR. Cardiac stimulation responses and maximum contractions to 10(-6) mol/L isoprenaline were reduced at 6 months, whereas the maximum contractions to 10(-2) mol/L CaCl2 were only reduced in left ventricles of 18-month-old SHR. 4. At concentrations ranging from 10(-7) to 3 x 10(-6) mol/L, BDF 9148 increased the amplitude and prolonged the duration of action potentials and augmented the force in WKY rat left ventricles. The augmenting effects of BDF 9148 at 3 x 10(-6) mol/L were smaller than at 10(-6) mol/L, possibly because the high concentration of BDF 9148 was also blocking calcium channels. Similar effects were observed with BDF 9148 in the early stages of hypertension (14-week-old SHR). 5. In the presence of persistent hypertension-associated hypertrophy of the SHR left ventricle at > or = 6 months, the effects of BDF 9148 on action potentials and contractions were significantly reduced to a small extent. This impairment of the response to BDF 9148 may reflect the reduced contractility of the SHR left ventricle and/or it may indicate that the response to the opening of sodium channels is altered from 6 months of age. 6. In summary, most of the response of BDF 9148 is maintained in the presence of hypertrophy and failure. Thus, BDF 9148 may have some potential for the treatment of heart failure.

Reduced Effects of Isoprenaline on the Membrane Potential of Aortic Smooth Muscle from Rats Pre- and During Hypertension

“…This study con®rms that the SHR in our Auckland colony are prehypertensive at 5 weeks (Doggrell & Liang 1998;Nand & Doggrell 1999). Hypertension is apparent in SHR after 14 weeks and the gain in weight of the aorta at this time is probably indicative of hypertrophy.…”

Effects of Tedisamil on Cardiovascular Tissues Isolated from Normoand Hypertensive Rats

“…We have previously shown that the maximum responses to CaCl2 on the 18-month-old SHR left ventricle are reduced (25), and this suggests that there is a nonspecific loss of contractility in SHR heart failure.…”

Combined Inotropic and Bradycardic Effects of a Sodium Channel Enhancer in Conscious Dogs with Heart Failure: A Mechanism for Improved Myocardial Efficiency Compared with Dobutamine

“…Numerous studies in vitro have demonstrated that Na ϩ channel enhancers, including LY341311, elicit positive inotropic effects on isolated cardiac papillary and ventricular muscles from rats, from guinea pigs, and from normal and failed human hearts (Brasch and Iven, 1991;Ravens et al, 1991;Flesch et al, 1996;Nand and Doggrell, 1999). Studies in vivo have also shown that Na ϩ channel enhancers increase cardiac contractile performance in anesthetized dogs with acute ischemia (Baumgart et al, 1994) and in the chronic microembolization-induced failing heart model (Taniumra et al, 2000).…”