Angiotensin converting enzyme-regulated, noncholinergic sympathoadrenal catecholamine release mediates the cardiovascular actions of human 'new pressor protein' related to coagulation beta-factor XIIa

Background: Human 'new pressor protein' (NPP), related to coagulation beta-factor XIIa (beta-FXIIa), potently releases sympathoadrenal catecholamines in bioassay rats, with concurrent elevation of systolic and diastolic blood pressure (SBP/DBP) and heart rate (HR). Elevated plasma NPP/beta-FXIIa levels in hypertensive anephric pediatric patients on hemodialysis associated with fluid status and blood pressure changes were previously reported, suggesting that NPP/beta-FXIIa contributed to their hypertension.

Objective: To investigate the mechanism of action of NPP/beta-FXIIa.

Methods: Hemodynamic and sympathoadrenal responses to NPP (20 microL plasma equivalent/rat) or coagulation beta-FXIIa (300 ng/kg intravenously) were measured in rats treated with pentolinium (ganglion blockade [+GB]) and/or captopril (+CAP; angiotensin converting Enzyme [ACE] inhibition).

Results: In controls not receiving GB or CAP (-GB-CAP), NPP/beta-FXIIa raised plasma epinephrine (E) sixfold, SBP/DBP by 14/8 mmHg and HR by 15 beats/min. With blockade of the cholinergic pathway to the sympathoadrenal system (+GB), basal E, norepinephrine (NE), SBP, DBP and HR all dropped. However NPP/beta-FXIIa remained capable of raising E 20-fold, NE fourfold, SBP/DBP by 27/11 mmHg and HR by 20 beats/min, suggesting that it acted through a 'noncholinergic' mechanism. With +CAP alone, NPP/beta-FXIIa raised plasma E 18-fold, NE threefold, SBP/ DBP by 29/8 mmHg and HR by 73 beats/min, implicating an ACE-regulated 'peptidergic' mechanism. Combining +GB with +CAP potentiated NPP/beta-FXIIa actions further by raising E 50-fold, NE sevenfold, SBP/DBP by 55/20 mmHg and HR by 87 beats/min, strengthening the efficacy of this alternate pathway.

Conclusions: The cardiovascular effects of NPP/beta-FXIIa are considerably mediated by a noncholinergic (peptidergic) ACE-regulated mechanism for sympathoadrenal Catecholamine release that is enhanced by +GB and/or +CAP. Under inflammatory procoagulant conditions, endogenously produced NPP/beta-FXIIa may interfere with the antihypertensive effects of ACE inhibition therapy.