The role of muscarinic K(+) channels in the negative chronotropic effect of a muscarinic agonist.
Acetylcholine causes bradycardia through M2 muscarinic receptors in sinoatrial node cells. I examined with electrocardiogram how the muscarinic K(+) (K(ACh)) channel participates in the sinus bradycardia induced by a muscarinic agonist in the Langendorff preparation of rabbit hearts. In the presence of 100 nM propranolol, 1 nM to 10 microM carbachol (CCh) induced sinus bradycardia in a concentration-dependent manner. Tertiapin (100 or 300 nM), which selectively blocks K(ACh) channels in cardiac myocytes, significantly inhibited the effect of > or =300 nM but not < or =100 nM CCh. The effect of CCh was divided into tertiapin-sensitive and -insensitive components. The former component was induced by >100 nM CCh in a concentration-dependent manner and accounted for approximately 75% of the maximum effect of CCh. The K(ACh) channel in atrial myocytes was also activated by this range of concentrations of CCh as measured with the patch-clamp method. The tertiapin-insensitive component was induced by 1 to 300 nM CCh in a concentration-dependent manner and accounted for approximately 25% of the maximum effect of CCh. The sinus rate in the presence of 1 microM CCh and 300 nM tertiapin was similar to that in the presence of 2 mM CsCl, a blocker of the hyperpolarization-activated I(f) current. Furthermore, no tertiapin-insensitive component existed in the presence of 2 mM CsCl. Therefore, the negative chronotropic effect of > or =300 nM CCh is mainly mediated by K(ACh) channels, whereas that of < or =100 nM CCh may result from suppression of the I(f) current.
Yamada
Mitsuhiko
M
Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Osaka, Japan. yamadacp@ri.ncvc.go.jp
D000818:Animals; D001514:Bee Venoms / Q000494:pharmacology*; D001919:Bradycardia / Q000139:chemically induced; D002217:Carbachol / Q000494:pharmacology; D002586:Cesium / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009206:Myocardium / Q000166:cytology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*
D001514:Bee Venoms; D002712:Chlorides; D018721:Muscarinic Agonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011976:Receptors, Muscarinic; D002586:Cesium; C029738:tertiapin; D002217:Carbachol; D000242:Cyclic AMP; C028019:cesium chloride