Parenteral administration of glipizide sodium salt, an inhibitor of adenosine triphosphate-sensitive potassium channels, prolongs short-term survival after severe controlled hemorrhage in rats.
OBJECTIVE
Recent experimental evidence suggests that activation of adenosine triphosphate (ATP)-sensitive potassium channels contributes to vascular failure and early mortality after hemorrhagic shock. The present investigation evaluated the effects of the water-soluble sodium salt of glipizide, an inhibitor of ATP-sensitive potassium channels, in anesthetized and awake rats subjected to severe controlled hemorrhage.


METHODS
Prospective, randomized, controlled study.


METHODS
Animal research laboratory.


METHODS
Male Wistar rats.


METHODS
Anesthetized rats were subjected to bleeding to reduce mean arterial pressure to either 40 or 35 mm Hg, which was maintained constant for 60 mins. In addition, awake rats underwent blood withdrawal of 4.25 mL/100 g over 20 mins. At the end of the hemorrhage period and 30 mins later, the animals received intravenous (5 and 20 mg/kg) or intramuscular (10 and 40 mg/kg) injections of glipizide sodium salt or vehicle.


RESULTS
In anesthetized rats subjected to pressure-controlled hemorrhage, glipizide sodium salt improved mean arterial pressure in a dose-dependent manner. Compared with the vehicle-treated animals, mean arterial pressure increased from 41.6 +/- 4.6 to 63.1 +/- 3.1 mm Hg in the 20 mg/kg intravenous group and from 33.2 +/- 4.9 to 54.0 +/- 4.7 mm Hg in the 40 mg/kg intramuscular group 60 mins after a 40-mm Hg shock. Furthermore, the drug did not affect the hemorrhage-induced changes in blood glucose concentrations. However, the higher doses of glipizide sodium salt attenuated the increments in plasma concentrations of lactate, alanine aminotransferase, creatinine, and amylase. Moreover, the higher doses markedly improved short-term survival after pressure- and volume-controlled bleeding. Overall, the intramuscular injections of the drug exerted salutary effects that were comparable to the intravenous administration.


CONCLUSIONS
In rats, parenteral administration of the water-soluble glipizide sodium salt attenuates vascular and end-organ dysfunction associated with severe hemorrhagic shock and prolongs short-term survival. The intramuscular administration provides comparable benefits as obtained by the intravenous injection.
Evgenov
Oleg V
OV
Inotek Corporation, Beverly, MA, USA.
Pacher
Pál
P
Williams
William
W
Evgenov
Natalia V
NV
Mabley
Jon G
JG
Cicila
James
J
Sikó
Zsombor B
ZB
Salzman
Andrew L
AL
Szabó
Csaba
C
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005913:Glipizide / Q000008:administration & dosage / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects*; D006470:Hemorrhage / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007263:Infusions, Parenteral; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008297:Male; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007004:Hypoglycemic Agents; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D005913:Glipizide