4-Aminopyridine, A Blocker of Voltage-Dependent K+ Channels, Restores Blood Pressure and Improves Survival in the Wistar Rat Model of Anaphylactic Shock.
OBJECTIVE
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.


METHODS
Experimental study.


METHODS
Physiology laboratory.


METHODS
Adult male Wistar rats.


METHODS
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.


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.
1Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. 2Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. 3Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. 4Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. 5Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. 6Department of Nephrology, Polyclinic Gentilly, Nancy, France. 7Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. 8Department of Biochemistry, Simmons College, Boston, MA. 9Division of Nephrology, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA. 10Department of Biological Chemistry, Northeastern University, Boston, MA.
Abdelouahab
A
Bellou
Suleiman
S
Al-Hammadi
Elhadi H
EH
Aburawi
Subramanian
S
Dhanasekaran
Abderrahim
A
Nemmar
Abderrahim
A
Oulhaj
Mohamed
M
Shafiuallah
Moufida
M
Zerrouki
Javed
J
Yasin
Leila
L
Bellou
Seth L
SL
Alper
Sirine
S
Bellou
Elsadig
E
Kazzam
D015761:4-Aminopyridine / Q000494:pharmacology*; D000138:Acidosis / Q000517:prevention & control; D000707:Anaphylaxis / Q000188:drug therapy*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D015237:Dinoprost / Q000097:blood; D015232:Dinoprostone / Q000097:blood; D004195:Disease Models, Animal; D004837:Epinephrine / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006632:Histamine / Q000097:blood; D007975:Leukotriene B4 / Q000097:blood; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D017208:Rats, Wistar; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D026902:Potassium Channel Blockers; D014662:Vasoconstrictor Agents; D007975:Leukotriene B4; D006632:Histamine; D015237:Dinoprost; D015761:4-Aminopyridine; D015232:Dinoprostone; D004837:Epinephrine