Bradykinin Generation Research Articles

Disseminated Intravascular Coagulation and Hypotension After Intravasation of Barium

Prolonged hypotension and disseminated intravascular coagulation were seen in a patient after intravasation of barium sulfate contrast medium during a barium enema examination. High endotoxin levels were measured in the contrast material. In vitro, this material induced generation of bradykinin. The clinical features observed may be explained by contact activation of the Hageman factor-dependent pathways caused by the contrast material and/or by circulating endotoxins. Treatment of this rare but severe complication occurring during a barium enema procedure should be directed against the endotoxic shock.

Generation of bradykinin during incubation of hereditary angioedema plasma

Generation of bradykinin during incubation of hereditary angioedema plasma

An inhibitor from corn blocks the hypotensive action of plasma protein fraction and active Hageman factor

Rapid infusion of certain lots of plasma protein fraction (PPF) into surgical patients can cause a severe fall in blood pressure. It has been reported that these lots contain the ∼ 30,000 dalton Hageman factor fragment (HF f), a potent activator of prekallikrein. Thus, the hypotensive effect of PPF could be due to the generation of bradykinin from the patients' kininogen. Strong evidence supporting the theory that HF f is the hypotensive agent in PPF has been obtained by the use of a specific inhibitor of HF f isolated from corn. Intravenous infusion of implicated lots of PPF or purified HF f causes a pronounced fall in the blood pressure of anesthetized rats pretreated with the kininase inhibitor SQ14225. The hypotensive effect of both PPF and HF f is blocked when they are preincubated with the specific HF f inhibitor. It is concluded that HF f is at least the trigger, if not the sole agent, responsible for the hypotensive action of implicated lots of PPF.

Hypotension associated with prekallikrein activator (Hageman-factor fragments) in plasma protein fraction.

Thirteen lots of plasma protein fraction made by one manufacturer were implicated in 23 recent reports of hypotension in surgical patients. Four of these patients required resuscitation after rapid administration of the product in the postoperative period. All implicated lots had prekallikrein-activator activity but low levels of bradykinin and kallikrein. The prekallikrein activator was identified as Hageman-factor fragments by molecular weight (35,000 as estimated by gel chromatography), isoelectric point (4.2 to 4.4), and inhibition by antibody to Hageman factor. These data suggest that Hageman-factor fragments are potent hypotensive agents, presumably because they trigger the generation of bradykinin in recipients. Prekallikrein-activator activity, usually at levels lower than those in the initial 13 implicated lots, was frequently detected in plasma protein fraction made by other manufactures. Several of these lots were associated with additional reports of hypotension. Prekallikrein-activator activity rarely occurred in albumin.

Androgen Therapy in Hereditary Angioneurotic Edema

Under normal conditions, an alpha globulin designated as C1̄ inhibitor (C1̄-INH) inhibits the activated first component of complement (C1̄). In hereditary angioneurotic edema, which is transmitted as classic Mendelian autosomal dominant, the serum of affected persons either contains a nonfunctional alpha globulin or lacks the inhibitor altogether. This deficiency was identified independently by Landerman et al.,1 who found the plasma of a patient unable to inhibit kallikrein generation of bradykinin, and by Donaldson and Evans,2 who reported on the inability of another patient's plasma to inhibit C1̄. Both observations were shown to be correct when Kagan and Becker3 demonstrated that . . .

Cardiovascular and metabolic effects of whole or fractionated gram-negative bacterial endotoxin in the unanesthetized Rhesus monkey.

Rhesus monkeys were infused with endotoxin lipopolysaccharide (LPS) (10 mg/kg [LPS 10 ] or 2.5 mg/kg [LPS 2.5 ]) or with fractions of LPS containing 6.3% lipid (PS 1 ) or 0.5% lipid (PS 2 ) (2.5 mg/kg). Systemic and regional hemodynamics, leukocyte counts, blood gases, pH, and plasma bradykinin concentration were measured. Monkeys receiving LPS 10 , LPS 2.5 , or PS 1 became hypotensive (mean blood pressure -37 ± 10 mm Hg) and had decreased peripheral vascular resistance (-10% to -24% of the base line), compensated metabolic acidosis, and elevated plasma bradykinin concentrations (14 ± 6 ng/ml) 2 hours after infusion. Vasodilation occurred in coronary, hepatic, and splanchnic vasculature; vasoconstriction occurred in the spleen. Cardiac output was diverted from muscle to viscera. Monkeys receiving PS 2 were normotensive with elevated peripheral vascular resistance (+46%) and no measurable plasma bradykinin concentration. By 6 hours, marked elevation of peripheral vascular resistance developed in monkeys given LPS 10 (+113%) and LPS 2.5 (+57%). Monkeys receiving PS 1 returned to base-line values, but monkeys receiving PS 2 remained unchanged. Leukopenia (-50% to -65%) was persistent only in monkeys receiving LPS or PS 1 . Toxicity of LPS apparently depends on the lipid portions of the molecule. Vasodilation and bradykinin generation are correlated with persistent granulocytopenia. Late toxicity may be independent of early cardiovascular events.

Biochemical mechanisms of generation of bradykinin by endotoxin.

The vasodilatory properties of bradykinin are compatible with a pathogenetic role in man and subhuman primates during endotoxemia. The peptide is generated during endotoxemia when peripheral vascular resistance is decreased. A number of mechanisms of kinin generation can be recruited by endotoxin. In plasma containing complement and 19S antibody to endotoxin, the polysaccharide moiety of endotoxin activates plasma kallikreins. Similar quantities of bradykinin are generated in all species tested. Therefore, species-related variation in production of the peptide in vivo depends on the interaction of endotoxin with other tissues. Granulocytes of primates (as opposed to those of rabbits) contain a cytoplasmic kallikrein or kallikrein activator. Granulocytes release their cytoplasmic enzymes (and presumably kallikreins) when phagocytizing endotoxin. In-vitro phagocytosis requires complement and lipid-rich endotoxin. Polysaccharide fractions of endotoxin do not produce effects on granulocytes, their kinin generation, or the cardiovascular system. We suggest that differences in endotoxin effect among species are largely related to effects of the lipid moiety of endotoxin and the chemical machinery of the cells this moiety penetrates.