Protection of human myocardium in vitro by K(ATP) activation with low concentrations of bimakalim.
We investigated whether the adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channel activation by bimakalim, at concentrations devoid of both negative inotropic and action-potential duration (APD) shortening effects, might exhibit myocardial protection after hypoxia and reoxygenation in human atrial myocardium by using 112 preparations. The recovery of contractility of human atrial trabeculae, subjected either to short-duration (5 min) or to long-duration (60 min) and severe (high pacing rate) hypoxia followed by reoxygenation, was assessed by challenging with dobutamine. Treated preparations were exposed to 10 or 100 nM bimakalim, 1 microM glibenclamide, or both before hypoxia. Variations of isometric developed tension (%DT) or APD90 were studied. At concentrations <100 nM, bimakalim showed no negative inotropic effects and did not modify significantly APD90 either in normoxia or in hypoxic conditions. In the short-duration hypoxia protocol, preparations treated with bimakalim showed a dobutamine-induced %DT increase significantly higher (p < 0.001) than in controls and similar to that observed in the absence of hypoxia. This bimakalim effect was blocked by glibenclamide. In the long-duration hypoxia protocol, %DT after dobutamine was 50% of that observed in normoxic preparations. Preparations treated with bimakalim showed after dobutamine %DT more than twofold above controls (p < 0.001), whereas in the glibenclamide group, recovery of DT with dobutamine remained 50% of what observed in normoxia (p < 0.001). In conclusion, exposure to hypoxia (either short- or long-lasting) and reoxygenation affects contractility of human atrial myocardium with pronounced reduction of the positive inotropic action of dobutamine. Pretreatment with bimakalim restores the response expected in the absence of hypoxia, and glibenclamide blocks the effect of bimakalim or further impairs the response to dobutamine when used alone before long-duration hypoxia. Evidence is provided for protective effects of the K(ATP) opener bimakalim on the human myocardial contractile function in conditions of hypoxia/reoxygenation, at concentrations at which negative inotropism and APD90 shortening are not contributory.
Department of Cardiac Surgery, University La Sapienza, Rome, Italy.
S
S
Picard
A
A
Criniti
K
K
Iwashiro
R
R
Rouet
F
F
Monti
E
E
Tonelli
G
G
Ruvolo
P
P
Ducouret
F
F
del Monte
U
U
Papalia
P E
PE
Puddu
D000255:Adenosine Triphosphate / Q000502:physiology*; D000328:Adult; D001578:Benzopyrans / Q000627:therapeutic use*; D004095:Dihydropyridines / Q000627:therapeutic use*; D004280:Dobutamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005905:Glyburide / Q000494:pharmacology; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D009119:Muscle Contraction; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D013997:Time Factors
D001578:Benzopyrans; D004095:Dihydropyridines; D015221:Potassium Channels; D004280:Dobutamine; C061050:bimakalim; D000255:Adenosine Triphosphate; D010100:Oxygen; D005905:Glyburide