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RWJ-24517, a positive inotropic agent, has novel effects on action potentials in guinea pig myocardium
A Kawamura1, G M Wahler, R J Solaro
1Department of Physiology and Biophysics, University of Illinois at Chicago 60680.
Abstract:
RWJ-24517 is a positive inotropic agent whose mechanism of action is under investigation. We examined the effects of RWJ-24517 on guinea pig papillary muscle action potentials and myofilament response to Ca2+. RWJ-24517 increased the fast action potential duration (APD) in a dose-dependent fashion but had no effect on the myofilament response. Tetraethylammonium (TEA 10 mM), which in itself slightly prolonged the control AP, completely blocked the increase in APD75 (APD at 75% of repolarization) and suppressed the increase in APD25 induced by RWJ-24517 (10 microM). Verapamil (5 microM) had little effect on control APs but did decrease the prolongation of the AP induced by RWJ-24517. The increase in APD25 induced by RWJ-24517 was not completely blocked by TEA even with addition of verapamil or 4-aminopyridine (2 mM). RWJ-24517 enhanced Ca(2+)-dependent slow APs elicited by 0.1 microM isoproterenol in preparations depolarized by high extracellular K+ (25 mM), but had no effects on slow APs elicited by 10 mM TEA. These results suggest that the primary electrophysiologic effect of RWJ-24517 is a substantial AP prolongation, which appears to occur largely through a mechanism which is likely to involve inhibition of Ca(2+)-dependent K+ channels. It also appears to have additional effects on some other channels (possibly Na+ channels), which may contribute to the positive inotropic action of RWJ-24517.
Insights
RWJ-24517, a positive inotropic agent, significantly prolongs action potential duration in guinea pig papillary muscles, likely by inhibiting calcium-dependent potassium channels. Its effects on other channels may contribute to its inotropic action.
Area of Science:
- Pharmacology
- Electrophysiology
- Cardiovascular Science
Background:
- RWJ-24517 is a positive inotropic agent with an unelucidated mechanism of action.
- Understanding the electrophysiological effects of novel inotropic agents is crucial for cardiovascular drug development.
Purpose of the Study:
- To investigate the effects of RWJ-24517 on guinea pig papillary muscle action potentials.
- To determine the impact of RWJ-24517 on myofilament response to calcium.
- To elucidate the ion channel mechanisms underlying RWJ-24517's action.
Main Methods:
- Electrophysiological recordings of guinea pig papillary muscle action potentials.
- Dose-response assessments of RWJ-24517.
- Pharmacological blockade experiments using tetraethylammonium (TEA), verapamil, and 4-aminopyridine.
- Assessment of myofilament response to calcium (Ca2+).
Main Results:
- RWJ-24517 dose-dependently increased action potential duration (APD), particularly APD75 and APD25.
- Tetraethylammonium (TEA) significantly blocked RWJ-24517-induced APD prolongation.
- Verapamil partially reduced RWJ-24517's AP prolongation effect.
- RWJ-24517 enhanced isoproterenol-induced slow action potentials but not TEA-induced slow action potentials.
- No effect of RWJ-24517 on the myofilament response to Ca2+ was observed.
Conclusions:
- The primary electrophysiologic effect of RWJ-24517 is significant action potential prolongation.
- This prolongation is likely mediated by the inhibition of Ca2+-dependent K+ channels.
- Additional effects on other channels, potentially Na+ channels, may contribute to RWJ-24517's positive inotropic effect.