Abstract
We examined the effects of the cardiotonic agent RWJ 24517 (Carsatrin, racemate) and its (S)- and (R)-enantiomers on action potential duration, Na+ current (INa), and delayed rectifier K+ current (IK) of guinea pig ventricular myocytes. RWJ 24517 (0.1 and 1 μM) prolongation of action potential duration could not be accounted for by suppression of either the rapid (IKr) or slow (IKs,) component of IK, although RWJ 24517 did reduce IKr at concentrations of 1 μM. A more dramatic effect of RWJ 24517 (0.1–1 μM) and the (S)-enantiomer of RWJ 24517 (0.1–3 μM) was an increase in peak INa and slowing of the rate of INa decay, eliciting a large steady-state current. Neither RWJ 24517 nor the (S)-enantiomer affected the fast time constant for INa decay, but both significantly increased the slow time constant, in addition to increasing the proportion of INa decaying at the slow rate. Both agents elicited a use-dependent decrease of peak INa (3–10 μM), which probably resulted from a slowing of both fast and slow rates of recovery from inactivation. In contrast, the (R)-enantiomer of RWJ 24517 did not induce a steady-state component INa or increase peak INaup to 10 μM, but it decreased peak INa at 30 μM. The (R)-enantiomer displayed little use-dependent reduction of INa during trains of repetitive pulses and had no effect on rates of inactivation or recovery from inactivation. These actions of the racemate and the (S)-stereoisomer to slow inactivation and to prolong both Na+ influx and action potential duration may contribute to the positive inotropic actions of these agents because the resulting accumulation of intracellular Na+ would increase intracellular Ca2+ via Na+/Ca2+ exchange.
Footnotes
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Send reprint requests to: Dr. J. Andrew Wasserstrom, Division of Cardiology-S203, Northwestern University Medical School, 303 E. Chicago Ave., Chicago, IL 60611. E-mail:ja-wasserstrom{at}nwu.edu
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↵1 This work was supported by grants from the Robert Wood Johnson Foundation; American Heart Association, Metropolitan Chicago; and National Heart, Lung, and Blood Institute (Grant HL30724 to J.A.W.). R.G.T. was supported by a postdoctoral fellowship from the Medical Research Council of Canada.
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↵2 Present address: Department of Medicine, University of Toronto, Toronto, Canada M5S 1A8.
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↵3 Present address: Merck Research Laboratories, West Point, PA 19486.
- Abbreviations:
- AP
- action potential
- APD
- action potential duration
- DPI 201-106
- DPI
- 4-[3-(4-benzhydryl-1-piperazinyl)-2-hydroxypropoxy]-1H-indole-2-carbonitrile
- RWJ 24517, Carsatrin, 6-[1-[1-bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine
- (S)-RWJ
- (S)-enantiomer of RWJ 24517
- (R)-RWJ
- (R)-enantiomer of RWJ 24517
- I-V
- current-voltage
- INa
- sodium current
- τF
- fast time constant
- τS
- slow time constant
- STX
- saxitoxin
- ICa
- L-type calcium
- IKtail
- tail current amplitude
- IK1
- inward rectifying K+ current
- IK
- delayed rectifier K+ current
- Received April 20, 1999.
- Accepted July 30, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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