Submitted on July 18, 2003
Accepted on October 20, 2003
Are the cardiovascular and sympathoadrenal effects of human "New Pressor Protein" preparations attributable to human coagulation 
-FXIIa?
Peter C. Papageorgiou1, Ali Pourdjabbar2, Akis A. Amfilochiadis1, Eleftherios P. Diamandis3, Frans Boomsma4, and Daniel H. Osmond5*
1 Departments of Physiology and Medicine, University of Toronto, Toronto, ON, Canada; Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
2 Departments of Physiology and Medicine, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
3 Department of Laboratory Medicine and Pathobiology, University of Toronto and Mount Sinai Hospital, Toronto, ON, Canada
4 Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
5 Departments of Physiology and Medicine, University of Toronto, Toronto, ON, Canada; Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada
* To whom correspondence should be addressed. E-mail: daniel.osmond{at}utoronto.ca.
"New Pressor Protein" (NPP) derived from normal human plasma is an extra renal enzyme that shares strong sequence homology with human coagulation 
-FXIIa. Under our bioassay conditions, human NPP (10-20 µL plasma
equivalent/~300g rat i.v.), can raise the systolic blood pressure (SBP) by 40-50 mmHg, the diastolic (DBP) by 15-20 mmHg and the heart rate (HR) by 70-90 beats/min. Plasma epinephrine (of adrenal medullary origin) and nor-
epinephrine rise by about 50- and 10-fold, respectively. Since -FXIIa is not normally associated with pressor properties we endeavoured to substantiate that the hypertensive effects of impure NPP preparations used in our experiments are attributable to their content of -FXIIa. We carried out comparisons with highly purified (>90%) commercial human -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 weight of -FXIIa. Retention time using FPLC anion exchange chromatography was identical. Molecular weight and co-migration were confirmed by SDS-PAGE gel electrophoresis, and the recovered ~30 kDa protein bands yielded -FXIIa fragments, identified by mass spectrometry. Matched doses of the NPP preparations produced dose response curves very similar to those elicited by -FXIIa with respect to increments of SBP, DBP and HR, while plasma catecholamine increments were generally comparable. We propose that -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.
