The effects of H1 and H2 histamine receptor antagonists on the development of endotoxemia in the conscious, unrestrained rat.
This study was designed to use the H2 antagonist cimetidine and the H1 antagonist diphenhydramine alone and in combination to clarify the role of histamine in the development of endotoxin shock. The jugular vein and the carotid artery of male Sprague-Dawley rats were cannulated during enflurane anesthesia. After recovery, blood pressure, heart rate, and respiration rate were continuously monitored. Animals were pretreated with saline, a combination of the H1 and H2 receptor antagonists diphenhydramine (20 mg/kg) and cimetidine (80 mg/kg), or individual doses of diphenhydramine or cimetidine. After pretreatment an endotoxin bolus (40 mg/kg) was given. Arterial blood samples (0.35 ml) were taken before endotoxin and after endotoxin at 60 and 240 min for measurement of pH, PO2, PCO2, hematocrit, glucose, and lactate. Pathological examinations were made at 240 min. Four additional groups of animals (N = 10) were studied for the effect of each of the treatment modes on 24-hr survival rate. Treatment with cimetidine plus diphenhydramine prevented the endotoxin-induced blood pressure fall, increase in heart rate, and hypoglycemia; increased the 24-hr survival rate from 10 to 60%; and inhibited the small intestinal pathology found in control rats. Treatment with diphenhydramine alone produced similar results except that there was a gradual blood pressure decrease later in shock. The results obtained from the cimetidine-treated groups were much the same but there was a slight, transient decrease in blood pressure early after endotoxin and the survival rate was increased to 90%. These results demonstrate that in the conscious rat antagonism of the H1 and/or H2 receptors modifies hemodynamic and metabolic responses and the subsequent pathology, altering the course of endotoxin shock and survival. This study provides substantial evidence to implicate histamine as one of the key vasoactive mediators in the development of endotoxin shock.
D J
DJ
Brackett
C F
CF
Schaefer
M F
MF
Wilson
D000704:Analysis of Variance; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D002927:Cimetidine / Q000494:pharmacology; D004155:Diphenhydramine / Q000494:pharmacology; D004737:Enflurane; D006339:Heart Rate / Q000187:drug effects; D006636:Histamine Release; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011968:Receptors, Histamine / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000378:metabolism*; D012119:Respiration / Q000187:drug effects; D012772:Shock, Septic / Q000503:physiopathology*; D013997:Time Factors
D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D002927:Cimetidine; D004155:Diphenhydramine; D004737:Enflurane