Effects of K+ channel modulators on the relationship between action potential duration and Ca2+ transients in single ventricular myocytes of the guinea pig.
Effects of K+ channel modulators, cromakalim and E4031 [1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4-methylsulfonylaminobenzoyl) piperidine], on the relationship between the action potential duration (APD) and Ca2+ transients were examined in single myocytes isolated from guinea pig cardiac left ventricle. Application of cromakalim decreased APD at 90% repolarization (APD90) and Ca2+ transient elicited at 0.5 Hz (IC50s=0.6 and 3 microM, respectively). Application of 0.3 microM E4031 increased these parameters by 110% and 45%, respectively. Under voltage-clamp, the relation between the duration of depolarization to 0 mV and Ca2+ transients could be described by the sum of two exponential components; the time constants were approximately 5 and 280 msec, respectively. The first component was abolished by 10 microM ryanodine, suggesting the involvement of Ca2+-induced Ca2+ release (CICR). Neither cromakalim nor E4031 directly affected Ca2+ current and Ca2+ transients under voltage clamp. When APD was changed by K+ channel modulators, the relation between APD90 and Ca2+-transients was almost similar to that obtained by changing the depolarization duration under voltage-clamp. CICR was changed significantly only when APD90 was markedly shortened by cromakalim. The extensively prolonged AP and Ca2+ transient in the presence of E4031 were reduced by an addition of cromakalim. It is concluded that these two K+ channel modulators can significantly alter the AP-induced Ca2+ transient mainly by changing APD, which regulates both Ca2+ influx and extrusion.
Tokuno
T
T
Department of Pharmacology & Therapeutics, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
Muraki
K
K
Watanabe
M
M
Imaizumi
Y
Y
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000503:physiopathology / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism*; D019806:Cromakalim / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D011725:Pyridines / Q000494:pharmacology; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D007004:Hypoglycemic Agents; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; D014665:Vasodilator Agents; D019806:Cromakalim; C063968:E 4031; D005905:Glyburide; D002118:Calcium