Inhibition of Na(+)-K+ pump alleviates the shortening of action potential duration caused by metabolic inhibition via blockade of KATP channels in coronary perfused ventricular muscles of guinea-pigs.
The Na(+)-K+ pump is a consumer of intracellular ATP. We therefore examined whether blockade of the Na(+)-K+ pump by cardiac glycosides could inhibit ATP-sensitive K+ (KATP) channels and prolong the action potential duration (APD) of the guinea-pig ventricular muscles perfused with Tyrode's solution via the coronary artery and stimulated at 3 Hz. The metabolic inhibition (MI) achieved by application of 0.1 microM carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (a mitochondrial uncoupler) shortened the APD in a time-dependent manner. When dihydroouabain (DHO, 5 microM) was introduced 5 min but not 10 min after introduction of MI, the APD shortening was significantly attenuated. Application of glibenclamide (1 microM), a blocker of KATP channels, introduced both 5 and 10 min after MI also alleviated the APD shortening: DHO did not alleviate the APD shortening effect produced by cromakalim (5 microM), a KATP-channel opener. In separate experiments using whole-cell patch-clamp techniques, we found that this concentration of DHO (5 microM) depressed the Na(+)-K+ pump current of the guinea-pig ventricular myocytes from 210 to 100 pA (at 0 mV) or by 49.5%. We conclude that, during early phase (approximately 5 min) of MI, the APD shortening mostly results from the activation of KATP channels, and that even a approximately 50% inhibition of the Na(+)-K+ pump by DHO leads to the blockade of KATP channels and eventual lengthening of the APD.
Abe
T
T
Department of Physiology, Oita Medical University, Japan.
Sato
T
T
Kiyosue
T
T
Saikawa
T
T
Sakata
T
T
Arita
M
M
D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D019806:Cromakalim / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010042:Ouabain / Q000031:analogs & derivatives / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010477:Perfusion; D015221:Potassium Channels / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology; D016276:Ventricular Function
D015221:Potassium Channels; D014665:Vasodilator Agents; D019806:Cromakalim; C000977:dihydroouabain; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase; D005905:Glyburide