Treatment with an endothelin type A receptor-antagonist after cardiac arrest and resuscitation improves cerebral hemodynamic and functional recovery in rats.
OBJECTIVE
Successful resuscitation of the brain after cardiac arrest requires unimpaired microcirculatory reperfusion. Postischemic cerebral hypoperfusion presumably is mediated through activation of endothelin type A receptors (ET(A)). The effect of the selective ET(A) antagonist BQ123 on cerebral blood flow and function was studied in a rat model of cardiac arrest.


METHODS
Prospective, randomized trial.


METHODS
Experimental animal laboratory.


METHODS
Twelve male Sprague-Dawley rats (290-350 g).


METHODS
Cardiac arrest for 12 mins was induced by electrical fibrillation of the heart, followed by standardized cardiopulmonary resuscitation. BQ123 (0.8 mg/kg; n = 6) or its vehicle (saline; n = 6) was injected intravenously at 15 mins after the return of spontaneous circulation.


METHODS
Cortical blood flow was measured by laser-Doppler flowmetry, electrophysiological function by recording the amplitude of somatosensory evoked potentials, vascular reactivity by ventilation with 6% CO2, and the functional coupling of blood flow by recording the laser-Doppler flow (LDF) changes during somatosensory stimulation. Hemodynamic and functional cerebral recovery was monitored for 3 hrs after the return of spontaneous circulation.


RESULTS
Forty-five minutes after the return of spontaneous circulation, postischemic hypoperfusion developed in both groups, as reflected by a decrease of the LDF signal to about 60% of the preischemic level. In untreated animals, hypoperfusion persisted throughout the observation time, but in animals receiving BQ123, LDF gradually returned to normal. CO2 reactivity in untreated animals was severely reduced for 2-3 hrs after the onset of recirculation, whereas after BQ123 treatment it returned to normal and after 2 hrs even above normal. The ET(A) antagonist also induced a more rapid recovery of the somatosensory evoked potentials amplitude and of the functional blood flow response to somatosensory stimulation, but these parameters did not recover completely within the observation period.


CONCLUSIONS
Application of the ET(A) antagonist BQ123 during the early reperfusion period after cardiac arrest shortens postischemic cerebral hypoperfusion and accelerates the restoration of the cerebrovascular CO2 reactivity and the recovery of electrophysiologic function.
Krep
H
H
Max-Planck Institute for Neurological Research, Department of Experimental Neurology, Cologne, Germany.
Brinker
G
G
Pillekamp
F
F
Hossmann
K A
KA
D000818:Animals; D002245:Carbon Dioxide / Q000494:pharmacology; D016887:Cardiopulmonary Resuscitation; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists; D006323:Heart Arrest / Q000503:physiopathology / Q000628:therapy*; D006439:Hemodynamics; D008297:Male; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D002245:Carbon Dioxide; C072247:cyclo(Trp-Asp-Pro-Val-Leu)