Blockade of a cardiac K+ channel by tacrine: interactions with muscarinic and adenosine receptors.
The centrally acting anticholinesterase drug tacrine has been shown to block K+ channels in guinea pig left atrium. It competitively blocks the negative inotropic effects of adenosine, 2-chloroadenosine and carbachol. Ka values obtained from dose ratio plots were 2.5, 3.5 and 2.9 microM respectively. It was also able to antagonize the shortening of the action potential due to these compounds. Doses of tacrine ranging from 1 to 4 microM restored the AP configuration close to control values. Tacrine also antagonized the binding of 1-quinuclidinyl[phenyl-4-3H]benzilate ([3H]QNB) to membranes derived from the atrium and cerebral cortex. Ki values of 1.8 +/- 0.33 and 1.3 +/- 0.47 microM were obtained respectively. Tacrine was a weak competitor of [3H]phenylisopropyladenosine ([3H]L-PIA) binding in brain membranes. Its diverse pharmacological effects may be relevant to its use in Alzheimer's disease.
Freeman
S E
SE
Materials Research Laboratory, Defence Science and Technology Organization, Melbourne, Victoria, Australia.
Lau
W M
WM
Szilagyi
M
M
D000200:Action Potentials / Q000187:drug effects; D000241:Adenosine / Q000494:pharmacology; D000544:Alzheimer Disease / Q000188:drug therapy; D000609:Aminoacridines / Q000494:pharmacology*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D010660:Phenylisopropyladenosine / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects*; D011983:Receptors, Purinergic / Q000187:drug effects*; D013619:Tacrine / Q000494:pharmacology* / Q000627:therapeutic use
D000609:Aminoacridines; D015221:Potassium Channels; D011976:Receptors, Muscarinic; D011983:Receptors, Purinergic; D010660:Phenylisopropyladenosine; D013619:Tacrine; D011813:Quinuclidinyl Benzilate; D002217:Carbachol; D000241:Adenosine