TY - JOUR
T1 - 4-Aminopyridine, A Blocker of Voltage-Dependent K+ Channels, Restores Blood Pressure and Improves Survival in the Wistar Rat Model of Anaphylactic Shock
AU - Bellou, Abdelouahab
AU - Al-Hammadi, Suleiman
AU - Aburawi, Elhadi H.
AU - Dhanasekaran, Subramanian
AU - Nemmar, Abderrahim
AU - Oulhaj, Abderrahim
AU - Shafiuallah, Mohamed
AU - Zerrouki, Moufida
AU - Yasin, Javed
AU - Bellou, Leila
AU - Alper, Seth L.
AU - Bellou, Sirine
AU - Kazzam, Elsadig
N1 - Publisher Copyright:
Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - Objectives: Anaphylactic shock is associated with severe hypotension. Potassium channel blockers, such as 4-aminopyridine, induce vasoconstriction. The objective of this study was to test the ability of 4-aminopyridine to restore blood pressure and increase survival in anaphylactic shock. Design: Experimental study. Setting: Physiology laboratory. Subjects: Adult male Wistar rats. Interventions: Rats were sensitized with ovalbumin (1 mg SC), and anaphylactic shock was induced by IV injection of ovalbumin (1 mg). Experimental groups included non-allergic rats (NA) (n = 6); allergic rats (Controls) (n = 6); allergic rats treated with 4-aminopyridine (4-aminopyridine) (1 mg/kg) (n = 6); and allergic rats treated with epinephrine (EPI) (10 μg/kg) (n = 6). Treatments were administered 1 minute after induction of anaphylactic shock. Measurements and Main Results: Mean arterial blood pressure, heart rate, and survival were measured for 60 minutes. Plasma levels of histamine, leukotriene B4, prostaglandin E2, prostaglandin F2, pH, and Hco3 were measured. Mean arterial blood pressure was normal in the NA group; severe hypotension and high mortality were observed in controls; normalization of mean arterial blood pressure, heart rate, and increased survival were observed in 4-aminopyridine and EPI groups. All allergic 4-aminopyridine-treated rats survived after the induction of anaphylactic shock. Histamine level was higher in controls and the 4-aminopyridine group but reduced in the EPI group. Prostaglandin E2 increased in controls and EPI group and decreased in 4-aminopyridine group; prostaglandin F2 increased in controls but decreased in 4-aminopyridine and EPI groups. Leukotriene B4 decreased in 4-aminopyridine and EPI groups. Metabolic acidosis was prevented in the 4-aminopyridine group. Conclusions: Our data suggest that voltage-dependent K+ channel inhibition with 4-aminopyridine treatment restores blood pressure and increases survival in the Wistar rat model of anaphylactic shock. 4-aminopyridine or related voltage-dependent K+ channel blockers could be a useful additional therapeutic approach to treatment of refractory anaphylactic shock.
AB - Objectives: Anaphylactic shock is associated with severe hypotension. Potassium channel blockers, such as 4-aminopyridine, induce vasoconstriction. The objective of this study was to test the ability of 4-aminopyridine to restore blood pressure and increase survival in anaphylactic shock. Design: Experimental study. Setting: Physiology laboratory. Subjects: Adult male Wistar rats. Interventions: Rats were sensitized with ovalbumin (1 mg SC), and anaphylactic shock was induced by IV injection of ovalbumin (1 mg). Experimental groups included non-allergic rats (NA) (n = 6); allergic rats (Controls) (n = 6); allergic rats treated with 4-aminopyridine (4-aminopyridine) (1 mg/kg) (n = 6); and allergic rats treated with epinephrine (EPI) (10 μg/kg) (n = 6). Treatments were administered 1 minute after induction of anaphylactic shock. Measurements and Main Results: Mean arterial blood pressure, heart rate, and survival were measured for 60 minutes. Plasma levels of histamine, leukotriene B4, prostaglandin E2, prostaglandin F2, pH, and Hco3 were measured. Mean arterial blood pressure was normal in the NA group; severe hypotension and high mortality were observed in controls; normalization of mean arterial blood pressure, heart rate, and increased survival were observed in 4-aminopyridine and EPI groups. All allergic 4-aminopyridine-treated rats survived after the induction of anaphylactic shock. Histamine level was higher in controls and the 4-aminopyridine group but reduced in the EPI group. Prostaglandin E2 increased in controls and EPI group and decreased in 4-aminopyridine group; prostaglandin F2 increased in controls but decreased in 4-aminopyridine and EPI groups. Leukotriene B4 decreased in 4-aminopyridine and EPI groups. Metabolic acidosis was prevented in the 4-aminopyridine group. Conclusions: Our data suggest that voltage-dependent K+ channel inhibition with 4-aminopyridine treatment restores blood pressure and increases survival in the Wistar rat model of anaphylactic shock. 4-aminopyridine or related voltage-dependent K+ channel blockers could be a useful additional therapeutic approach to treatment of refractory anaphylactic shock.
KW - 4-aminopyridine
KW - anaphylactic shock
KW - histamine
KW - leukotrienes
KW - prostaglandins
KW - voltage-dependent K channel
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UR - http://www.scopus.com/inward/citedby.url?scp=84973321149&partnerID=8YFLogxK
U2 - 10.1097/CCM.0000000000001822
DO - 10.1097/CCM.0000000000001822
M3 - Article
C2 - 27270180
AN - SCOPUS:84973321149
SN - 0090-3493
VL - 44
SP - e1082-e1089
JO - Critical Care Medicine
JF - Critical Care Medicine
IS - 11
ER -