D-Arg-[Hyp3-D-Phe7]-bradykinin, a bradykinin antagonist, reduces mortality in a rat model of endotoxic shock.
The kallikrein-kinin system is activated during endotoxic shock, suggesting that bradykinin plays a role in the pathology of this disease. To test this hypothesis, a bradykinin antagonist, D-Arg-Hyp3-D-Phe7-bradykinin (NPC 567), was studied in conscious, chronically catheterized rats undergoing lipopolysaccharide (LPS)-induced endotoxic shock. LPS treatment resulted in an increase in circulating bradykinin from less than 23 pg/ml to 144 +/- 18 pg/ml at 1 hr. Intravenous administration of LPS resulted in a 38% drop in mean arterial pressure at 1 hr which was partially reversed by NPC 567. NPC 567 did not affect the moderate tachycardia observed following LPS. NPC 567 infusion at 8 nmol/kg/min dramatically reduced mortality from 100% to 50% at 24 hr (P less than 0.01). In response to LPS, blood thromboxane B2 (TXB2) rose from less than 200 pg/ml to 2,298 +/- 64 pg/ml, while 6-keto-prostaglandin-F1 alpha (6kPGF1 alpha) rose from 289 +/- 23 pg/ml to 7,927 +/- 822 pg/ml. NPC 567 reduced the rise in 6kPGF1 alpha by 42% (P less than 0.05), without affecting TXB2. In summary, NPC 567 reduced mortality in rats treated with LPS, reduced the rise in 6kPGF1 alpha and partially reversed the hypotensive effects. These results suggest that bradykinin plays a significant role in the pathology of endotoxic shock.
Wilson
D D
DD
Nova Pharmaceutical Corporation, Baltimore, Maryland 21224.
de Garavilla
L
L
Kuhn
W
W
Togo
J
J
Burch
R M
RM
Steranka
L R
LR
D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000032:analysis / Q000627:therapeutic use; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D011460:Prostaglandins F / Q000032:analysis; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D012772:Shock, Septic / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D013929:Thromboxane B2 / Q000032:analysis
D000700:Analgesics; D008070:Lipopolysaccharides; D011460:Prostaglandins F; D013929:Thromboxane B2; C053010:NPC 567; D001920:Bradykinin; C100006:prostaglandin F1