Activated coagulation Factor XII (FXIIa) elevates blood pressure (BP) acutely by stimulating adrenomedullary catecholamine (CA) release in Brown Norway (BN) bioassay rats. These effects are absent in kininogen-deficient BN Katholiek (BNK) bioassay rats, indicating that these FXIIa-induced responses require an intact kallikrein-kinin system (KKS). In three hypertensive anephric pediatric patients, ΔFXIIa concentrations tracked peri-dialytic ΔBP. We hypothesized that FXIIa exerts a vasoconstrictor pro-hypertensive action, via the KKS, particularly evident in chronic renal failure (CRF). In CRF patients (n=11) receiving conventional hemodialysis, mean plasma FXIIa concentrations were 3-fold (p<0.05) greater than in healthy controls. Although conversion from conventional to nocturnal hemodialysis did not change mean FXIIa concentrations there was intra-session variation within individuals, such that ΔFXIIa concentrations correlated with changes in mean arterial pressure (MAP, r=0.66, p=0.026) and total peripheral resistance (TPR, r=0.75, p=0.007). In normotensive BN rats, FXIIa infusion (85 ng/min/kg for 60 mins) increased MAP (10±1 mmHg), TPR (0.5±0.1 Units), and CA, whilst left-ventricular end-diastolic volume (LVEDV) and heart rate decreased (all p<0.05). After adrenalectomy, FXIIa infusion decreased MAP (5±1 mmHg), did not raise CA or induce sustained vasoconstriction, and caused a greater fall in LVEDV (all p<0.05). In the 5/6 nephrectomized (NX) rodent CRF model, MAP and TPR were significantly greater in BN NX (n=16) than in BNK NX (n=15) (147±4 vs. 133±2 mmHg, 2.8±0.2 vs. 2.3±0.2 Units; all p<0.05). Plasma FXIIa measured using our semi-quantitive ELISA was 3-fold higher in both BN NX and BNK NX than in controls (p<0.01), but only correlated with MAP (r=0.48, p=0.01) in the BN NX. Plasma CA were elevated in the BN NX (p<0.05) but not in BNK NX. Infusion of a specific FXIIa inhibitor into BN NX decreased MAP (-12 mmHg) and TPR (-0.5 Units) proportionally to baseline FXIIa (ΔMAP: r=-0.72, p=0.002; ΔTPR: r=-0.57, p=0.021), and plasma CA fell by 40-67% (all p<0.05). No such changes occurred in the BNK NX. In summary, a significant component of the hypertension of CRF can be attributed to FXIIa-induced vasoconstriction mediated via the KKS and stimulated CA release. In normal rats, FXIIa appears also to directly or indirectly decrease preload and heart rate.

Activated coagulation Factor XII (FXIIa) elevates blood pressure (BP) acutely by stimulating adrenomedullary catecholamine (CA) release in Brown Norway (BN) bioassay rats. These effects are absent in kininogen-deficient BN Katholiek (BNK) bioassay rats, indicating that these FXIIa-induced responses require an intact kallikrein-kinin system (KKS). In three hypertensive anephric pediatric patients, ΔFXIIa concentrations tracked peri-dialytic ΔBP. We hypothesized that FXIIa exerts a vasoconstrictor pro-hypertensive action, via the KKS, particularly evident in chronic renal failure (CRF). In CRF patients (n=11) receiving conventional hemodialysis, mean plasma FXIIa concentrations were 3-fold (p<0.05) greater than in healthy controls. Although conversion from conventional to nocturnal hemodialysis did not change mean FXIIa concentrations there was intra-session variation within individuals, such that ΔFXIIa concentrations correlated with changes in mean arterial pressure (MAP, r=0.66, p=0.026) and total peripheral resistance (TPR, r=0.75, p=0.007). In normotensive BN rats, FXIIa infusion (85 ng/min/kg for 60 mins) increased MAP (10±1 mmHg), TPR (0.5±0.1 Units), and CA, whilst left-ventricular end-diastolic volume (LVEDV) and heart rate decreased (all p<0.05). After adrenalectomy, FXIIa infusion decreased MAP (5±1 mmHg), did not raise CA or induce sustained vasoconstriction, and caused a greater fall in LVEDV (all p<0.05). In the 5/6 nephrectomized (NX) rodent CRF model, MAP and TPR were significantly greater in BN NX (n=16) than in BNK NX (n=15) (147±4 vs. 133±2 mmHg, 2.8±0.2 vs. 2.3±0.2 Units; all p<0.05). Plasma FXIIa measured using our semi-quantitive ELISA was 3-fold higher in both BN NX and BNK NX than in controls (p<0.01), but only correlated with MAP (r=0.48, p=0.01) in the BN NX. Plasma CA were elevated in the BN NX (p<0.05) but not in BNK NX. Infusion of a specific FXIIa inhibitor into BN NX decreased MAP (-12 mmHg) and TPR (-0.5 Units) proportionally to baseline FXIIa (ΔMAP: r=-0.72, p=0.002; ΔTPR: r=-0.57, p=0.021), and plasma CA fell by 40-67% (all p<0.05). No such changes occurred in the BNK NX. In summary, a significant component of the hypertension of CRF can be attributed to FXIIa-induced vasoconstriction mediated via the KKS and stimulated CA release. In normal rats, FXIIa appears also to directly or indirectly decrease preload and heart rate.