Abstract
The effects of cocaine on the acetylcholine(ACh)-activated muscarinic K+ current (IK(ACh)) were assessed with the whole-cell patch-clamp technique in single atrial and left ventricular myocytes enzymatically isolated from adult ferret hearts. The density of IK(ACh) is almost 5 times greater in atrial cells than in left ventricular myocytes. Cocaine reversibly blocked IK(ACh) in a dose-dependent manner. Methylecgonidine (MEG), the major product of pyrolysis of cocaine base, also produced similar effects onIK(ACh). The concentration to produce 50% inhibition of IK(ACh) was 25 μM and 12 μM for cocaine and MEG, respectively. Cocaine at micromolar concentrations also significantly inhibited the adenosine-activated purinergic K+ current (IK(Ado)), which has the same electrophysiological properties asIK(ACh). Furthermore, cocaine inhibitedIK(ACh) activated by GTPγS, which evokesIK(ACh) by bypassing the muscarinic receptor and directly activating the G-protein, GK. These results suggest that cocaine-induced suppression ofIK(ACh) is caused by its interactions beyond the binding site of muscarinic receptors. The antimuscarinic effect of cocaine may play an important role in cocaine cardiotoxicity by reducing the membrane electrical stability and acting synergistically with other actions of cocaine to facilitate the occurrence of lethal cardiac arrhythmias.
Footnotes
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Send reprint requests to: Yong-Fu Xiao, M.D., Ph.D., Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Boston, MA 02215.
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↵1 This work was supported by NIH grant HL51307 (to J.P.M).
- Abbreviations:
- ACh
- acetylcholine
- IK(ACh)
- acetylcholine-activated muscarinic K+ channel
- IK(Ado)
- adenosine-activated purinergic K+ channel
- MEG
- methylecgonidine
- EGTA
- ethyleneglycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
- HEPES
- N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
- Received March 20, 1997.
- Accepted September 3, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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