Inhibition of cardiac contractility by 5-hydroxydecanoate and tetraphenylphosphonium ion: a possible role of mitoKATP in response to inotropic stress.
This study investigates the role of the mitochondrial ATP-sensitive K+ channel (mitoKATP) in response to positive inotropic stress. In Langendorff-perfused rat hearts, inotropy was induced by increasing perfusate calcium to 4 mM, by adding 80 microM ouabain or 0.25 microM dobutamine. Each of these treatments resulted in a sustained increase in rate-pressure product (RPP) of approximately 60%. Inhibition of mitoKATP by perfusion of 5-hydroxydecanoate (5-HD) or tetraphenylphosphonium before induction of inotropic stress resulted in a marked attenuation of RPP. Inhibition of mitoKATP after induction of stress caused the inability of the heart to maintain a high-work state. In human atrial fibers, the increase in contractility induced by dobutamine was inhibited 60% by 5-HD. In permeabilized fibers from the Langendorff-perfused rat hearts, inhibition of mitoKATP resulted, in all cases, in an alteration of adenine nucleotide compartmentation, as reflected by a 60% decrease in the half-saturation constant for ADP [K1/2 (ADP)]. We conclude that opening of cardiac mitoKATP is essential for an appropriate response to positive inotropic stress and propose that its involvement proceeds through the prevention of stress-induced decrease in mitochondrial matrix volume. These results indicate a physiological role for mitoKATP in inotropy and, by extension, in heart failure.
Portland State University, Portland, Oregon, USA.
Keith D
KD
Garlid
Paolo E
PE
Puddu
Philippe
P
Pasdois
Alexandre D T
AD
Costa
Bertrand
B
Beauvoit
Anna
A
Criniti
Liliane
L
Tariosse
Philippe
P
Diolez
Pierre
P
Dos Santos
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D003652:Decanoic Acids / Q000008:administration & dosage*; D005080:Exercise Test; D005240:Feasibility Studies; D006880:Hydroxy Acids / Q000008:administration & dosage*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007477:Ions; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology*; D009861:Onium Compounds / Q000008:administration & dosage*; D009943:Organophosphorus Compounds / Q000008:administration & dosage*; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002316:Cardiotonic Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D007477:Ions; D009861:Onium Compounds; D009943:Organophosphorus Compounds; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; C052853:5-hydroxydecanoic acid; C013289:tetraphenylphosphonium