Effects of the cannabinoid antagonist AM281 on systemic hemodynamics and mortality rate in streptozotocin-induced diabetic rats with endotoxic shock: comparison between non-diabetic and diabetic rats.
OBJECTIVE
On the basis of previous findings that the anandamide antagonist AM281, an endogenous cannabinoid receptor antagonist, could restore the hemodynamic and cerebral blood flow changes and improve the mortality rate in non-diabetic rats during sepsis, this study was conducted to examine whether AM281 could restore the hemodynamic variables and improve the mortality rate in streptozotocin-induced diabetic rats during sepsis.


METHODS
The study was designed to include three sets of experiments, each set of experiment being conducted in both diabetic and non-diabetic animals: (1) measurement of changes in systemic hemodynamics and carotid artery blood flow, (2) measurement of biochemical variables and (3) assessment of mortality rate. Systemic hemodynamics, carotid artery blood flow changes and biochemical variables were assessed at pre-treatment and 1, 2 and 3 h after the treatment was performed.


RESULTS
In both non-diabetic and diabetic rats, administration of lipopolysaccharide (LPS) induced a reduction in hemodynamic variables, these reductions being greater in diabetic than in non-diabetic rats. In diabetic rats, administration of AM281 could only partially prevent these hemodynamic changes, these changes being insufficient to elevate these variables to control values. Significant differences were observed in mortality rates at 6 and 12 h between non-diabetic and diabetic groups with the same treatment. At 12 h, only non-diabetic AM281 group rats were still alive (mortality rate 50%).


CONCLUSIONS
Administration of AM281 only partially prevented the hemodynamic, biochemical and carotid artery blood flow changes associated with LPS-induced septicemia in diabetic rats, as compared with non-diabetic rats in whom these changes were prevented to a greater extent.
Kadoi
Y
Y
Department of Anesthesiology, Gunma University Hospital, Gunma, Japan. kadoi@med.gunma-u.ac.jp
Hinohara
H
H
Kunimoto
F
F
Saito
S
S
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D063387:Cannabinoid Receptor Antagonists; D002343:Carotid Artery, Internal / Q000187:drug effects* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D053583:Interleukin-1beta / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D012772:Shock, Septic / Q000188:drug therapy* / Q000503:physiopathology; D012977:Sodium Nitrite / Q000097:blood; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
D001786:Blood Glucose; D063387:Cannabinoid Receptor Antagonists; D053583:Interleukin-1beta; D009025:Morpholines; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D012977:Sodium Nitrite; C109925:AM 281