Peritoneal leucocytes from spontaneously hypertensive rats have reduced chemiluminescence response and lowered sensitivity to dexamethasone in vivo.
The genetically altered hypothalamo-pituitary-adrenocortical axis in the spontaneously hypertensive rat (SHR) suggests altered phagocyte function in this strain. We therefore compared luminol-amplified chemiluminescence in peritoneal leucocytes from 10- to 12-week-old SHRs and age-matched Wistar-Kyoto rats (WKYs) activated by serum-opsonized zymosan particles (SOZ), N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) or phorbol 12-myristate 13-acetate (PMA). While the number of peritoneal monocytes/macrophages was increased by 49% in SHRs relative to WKYs, activator-induced chemiluminescence per cell in SHRs was only 14-42% of that in WKYs. FMLP responses were especially low in SHRs. Treatment of rats with dexamethasone in the drinking water for 48 h prior to ex vivo experiments reduced chemiluminescence dose-dependently in WKYs as well as in SHRs. ED50 of dexamethasone in SHRs was, however, increased compared to WKYs, indicating lowered sensitivity to dexamethasone in SHRs. No evidence was found of strain differences in differential distribution of peritoneal cells or in pharmacokinetics of dexamethasone. Plasma ACTH levels were significantly higher in SHRs than in WKYs, while basal plasma corticosterone concentrations in SHRs and WKYs were not significantly different. The results suggest that production of reactive oxygen compounds by peritoneal mononuclear phagocytes is reduced in SHRs compared with WKYs, and that the phagocyte respiratory burst is modulated differently by endogenous glucocorticoids in the two strains. We propose that reduced activity of the phagocyte NADPH oxidase-myeloperoxidase system is a major contributory cause of the altered chemiluminescence responses in SHRs. The data indicate that species differences may also be present at earlier steps in the signal transduction pathways activated by SOZ, fMLP and PMA.
Norwegian Defence Research Establishment, Kjeller, Norway.
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Skrede
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Røshol
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Aerø
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D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000188:drug therapy*; D007962:Leukocytes / Q000187:drug effects*; D008163:Luminescent Measurements; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012680:Sensitivity and Specificity
D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone