Are cardiovascular and sympathoadrenal effects of human “new pressor protein” preparations attributable to human coagulation β-FXIIa?

Abstract

“New pressor protein” (NPP) derived from normal human plasma is an extra renal enzyme that shares strong sequence homology with human coagulation β-FXIIa. Under our bioassay conditions, human NPP (10–20 μl plasma equivalent/∼300 g rat iv) can raise the systolic blood pressure (SBP) by 40–50 mmHg, the diastolic blood pressure (DBP) by 15–20 mmHg, and the heart rate (HR) by 70–90 beats/min. Plasma epinephrine (of adrenal medullary origin) and norepinephrine rise by about 50- and 10-fold, respectively. Because β-FXIIa is not normally associated with pressor properties, we endeavored to substantiate that the hypertensive effects of impure NPP preparations used in our experiments are attributable to their content of β-FXIIa. We carried out comparisons with highly purified (>90%) commercial human β-FXIIa and found that by gel filtration (Sephadex G-100 and G-75), NPP bioactivity appeared in the ∼30-kDa elution zone, consistent with the molecular mass of β-FXIIa. Retention time using fast-protein liquid chromatography anion exchange chromatography was identical. Molecular mass and comigration were confirmed by SDS-PAGE gel electrophoresis, and the recovered ∼30-kDa protein bands yielded β-FXIIa fragments identified by mass spectrometry. Matched doses of the NPP preparations produced dose-response curves very similar to those elicited by β-FXIIa with respect to increments of SBP, DBP, and HR, whereas plasma catecholamine increments were generally comparable. We propose that β-FXIIa is substantially, if not exclusively, responsible for the observed effects of our NPP preparations and that this points to a novel axis connecting the FXII coagulation cascade and the sympathoadrenal gland to other cardiovascular regulatory mechanisms.