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

• Published in: Canadian journal of cardiology Vol. 25; no. 4; pp. e100 - e108
• Main Authors: Papageorgiou, Peter C., PhD, Simos, Demetrios, MSc MD, Boomsma, Frans, PhD, Rojkjaer, Rasmus, PhD, Osmond, Daniel H., PhD
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.04.2009; Pulsus Group Inc
• Subjects: ACE inhibitors; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Autonomic Nervous System - physiology; Blood Pressure - drug effects; Blood Proteins - pharmacology; Bradykinin; Captopril - pharmacology; Cardiovascular; Cardiovascular System - drug effects; Catecholamines - blood; Coagulation β-FXIIa; Experimental Studies; Factor XII; Factor XIIa - pharmacology; Ganglionic Blockers - pharmacology; Heart Rate - drug effects; Hypertension; Male; Pentolinium Tartrate - pharmacology; Rats; Rats, Wistar; Sympathoadrenal; Hypertension; Coagulation β-FXIIa; ACE inhibitors; Factor XII; Bradykinin; Sympathoadrenal
• ISSN: 0828-282X; 1916-7075
• DOI: 10.1016/S0828-282X(09)70067-4

Background Human ‘new pressor protein’ (NPP), related to coagulation beta-factor XIIa (β-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/β-FXIIa levels in hypertensive anephric pediatric patients on hemodialysis associated with fluid status and blood pressure changes were previously reported, suggesting that NPP/β-FXIIa contributed to their hypertension. Objective To investigate the mechanism of action of NPP/β-FXIIa. Methods Hemodynamic and sympathoadrenal responses to NPP (20 μL plasma equivalent/rat) or coagulation β-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/ β-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/β-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/β-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/β-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/β-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/β-FXIIa may interfere with the antihypertensive effects of ACE inhibition therapy.