Hyperkalemic cardioplegia-induced myocyte swelling and contractile dysfunction: prevention by diazoxide.
BACKGROUND
Hyperkalemic cardioplegia (9 degrees C) results in significant myocyte swelling and reduced contractility, representing a possible mechanism of myocardial stunning. Adenosine triphosphate-sensitive potassium channel (KATP) openers have been shown to ameliorate stunning. This study evaluated the hypothesis that a KATP opener would prevent hyperkalemic cardioplegia-induced myocyte swelling and reduced contractility.


METHODS
Isolated rabbit myocytes were perfused with 37 degrees C Tyrode's solution for 20 minutes, followed by test solution (9 degrees C or 37 degrees C) including control Tyrode's, Tyrode's + 100 micromol/L diazoxide (KATP opener), St. Thomas's solution; or 9 degrees C St. Thomas's + 100 micromol/L diazoxide or St. Thomas's + 100 micromol/L diazoxide + 20 micromol/L HMR1098 or 50 micromol/L 5-hydroxydeconoate (KATP blockers) for 20 minutes (n = 8 per group). Myocytes were then reexposed to 37 degrees C Tyrode's solution for 20 minutes. Volume and contractility were measured by videomicroscopy and video-based edge detection, respectively.


RESULTS
St. Thomas's solution (9 degrees C) caused significant myocyte swelling and associated reduced contractility (p < 0.05). The addition of diazoxide abolished myocyte swelling (p < 0.0001), and eliminated the associated reduced contractility (p < 0.05). Findings were unchanged by the addition of HMR 1098 and 5-hydroxydeconoate.


CONCLUSIONS
Diazoxide prevented myocyte swelling and reduced contractility secondary to hyperkalemic cardioplegia, and this was unchanged by the addition of either KATP channel blocker. Prevention of myocyte swelling was associated with improved contractility, consistent with the hypothesis that myocyte swelling may be a mechanism of myocardial stunning. Diazoxide may play a role in myocyte volume homeostasis by means of a mechanism separate from opening the KATP channel.
Mizutani
Shinichi
S
Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110-1013, USA.
Al-Dadah
Ashraf S
AS
Bloch
Jeffrey B
JB
Prasad
Sandip M
SM
Diodato
Michael D
MD
Schuessler
Richard B
RB
Damiano
Ralph J
RJ
Lawton
Jennifer S
JS
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001639:Bicarbonates / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D002122:Calcium Chloride / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D002314:Cardioplegic Solutions / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D048429:Cell Size / Q000187:drug effects; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology*; D005260:Female; D006880:Hydroxy Acids / Q000494:pharmacology; D007552:Isotonic Solutions / Q000494:pharmacology; D008274:Magnesium / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D018715:Microscopy, Video; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects*; D017682:Myocardial Stunning / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D009997:Osmotic Pressure; D011188:Potassium / Q000633:toxicity*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000502:physiology; D011189:Potassium Chloride / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D011817:Rabbits; D012965:Sodium Chloride / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D000099161:Kcnj11 Channel
D001549:Benzamides; D001639:Bicarbonates; D002122:Calcium Chloride; D002314:Cardioplegic Solutions; D003652:Decanoic Acids; D003981:Diazoxide; D006880:Hydroxy Acids; D007552:Isotonic Solutions; D008274:Magnesium; D011188:Potassium; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011189:Potassium Chloride; D012965:Sodium Chloride; D000099161:Kcnj11 Channel; C041711:St. Thomas' Hospital cardioplegic solution; C037692:Tyrode's solution; C052853:5-hydroxydecanoic acid; C410297:HMR 1098