Adrenomedullary catecholamine, pressor and chronotropic responses to human coagulation beta-FXIIa mediated by endogenous kinins.

OBJECTIVES: There is increasing evidence that blood coagulation factors can influence blood pressure. In the present study, we tested the hypothesis that the beta fragment of human coagulation factor XIIa (beta-FXIIa) induces adrenal catecholamine-mediated pressor and chronotropic responses via bradykinin generated from the plasma kallikrein-kinin system. METHODS AND RESULTS: In anaesthetized bioassay rats with blocked autonomic reflexes, in the Brown Norway strain a bolus injection of beta-FXIIa (1 microg/kg, administered intravenously) elicited a 170-fold rise in plasma epinephrine (from 0.12 +/- 0.02 to 20.58 +/- 2.42 nmol/l; P < 0.001) and a fivefold increase in plasma norepinephrine (from 0.11 +/- 0.02 to 0.57 +/- 0.09 nmol/l; P < 0.01), concurrent increases in systolic blood pressure (from 70 +/- 5 to 101 +/- 4 mmHg; P < 0.01) and heart rate (from 315 +/- 11 to 408 +/- 15 bpm; P < 0.01), and a doubling of bradykinin concentrations (P < 0.05). Bilateral adrenal medullectomy abolished both the catecholamine and the haemodynamic responses to beta-FXIIa. Catecholamine, bradykinin and haemodynamic responses to beta-FXIIa were absent in plasma kininogen-deficient Brown Norway Katholiek (BNK) rats. Exogenous bradykinin dose-dependently reproduced these catecholamine and haemodynamic responses in Brown Norway and BNK rats, but not in Brown Norway adrenal medullectomized rats. CONCLUSION: The pressor and chronotropic responses to beta-FXIIa in this bioassay preparation are mediated exclusively through adrenal catecholamine release, and require plasma kininogens for their full expression. These observations suggest that interaction between the coagulation, kallikrein-kinin and sympatho-adrenal systems can exert important pressor effects in the absence of counterregulatory autonomic reflexes.

Role of bradykinin B2-receptor in the sympathoadrenal effects of 'new pressor protein' related to human blood coagulation factor XII fragment.

BACKGROUND: Human plasma new pressor protein (NPP) increases blood pressure, heart rate and plasma adrenal medullary catecholamines in bioassay rats - all potentiated by angiotensin-converting enzyme (ACE) inhibition. High plasma NPP activity has been found in haemodialysis patients with hypertension. OBJECTIVE: To investigate whether the bradykinin B2-receptor mediates the effects of NPP. METHODS AND RESULTS: Male Wistar bioassay rats were anaesthetized with inactin, ganglion blocked with pentolinium and injected intravenously (i.v.) with human NPP (20 microl plasma equivalent) or bradykinin (100 ng/kg). Both NPP and bradykinin increased systolic (SBP) and diastolic (DBP) blood pressures, heart rate and plasma adrenaline and noradrenaline concentrations. All these responses were potentiated by the ACE inhibitor, captopril (10 mg/kg i.v.), but not by antagonism of the angiotensin II type 1 receptor with losartan (10 mg/kg i.v.). Administration of the bradykinin B2-receptor antagonist, HOE-140 (20 microg/kg i.v.), significantly attenuated the peak NPP responses as follows: SBP from 58 +/- 3 to 40 +/- 4 mmHg (decrease of 30%; P < 0.05); DBP from 22 +/- 4 to 10 +/- 1 mmHg (decrease of 55%; P < 0.05); heart rate from 124 +/- 8 to 28 +/-6 beats/min (decrease of 77%; P < 0.05); plasma adrenaline from 14297 +/- 2477 to 3318 +/- 1105 pg/ml (decrease of 77%; P < 0.05) and noradrenaline from 505 +/- 66 to 77 +/-29 pg/ml (decrease of 85%; P < 0.05). CONCLUSIONS: The haemodynamic and sympathoadrenal effects of NPP involve substantial mediation by the bradykinin B2-receptor, in addition to other mechanisms.

Are cardiovascular and sympathoadrenal effects of human "new pressor protein" preparations attributable to human coagulation beta-FXIIa?

"New pressor protein" (NPP) derived from normal human plasma is an extra renal enzyme that shares strong sequence homology with human coagulation beta-FXIIa. Under our bioassay conditions, human NPP (10-20 microl plasma equivalent/ approximately 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 beta-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 beta-FXIIa. We carried out comparisons with highly purified (>90%) commercial human beta-FXIIa and found that by gel filtration (Sephadex G-100 and G-75), NPP bioactivity appeared in the approximately 30-kDa elution zone, consistent with the molecular mass of beta-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 approximately 30-kDa protein bands yielded beta-FXIIa fragments identified by mass spectrometry. Matched doses of the NPP preparations produced dose-response curves very similar to those elicited by beta-FXIIa with respect to increments of SBP, DBP, and HR, whereas plasma catecholamine increments were generally comparable. We propose that beta-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.

Possible role of new pressor protein in hypertensive anephric hemodialysis patients.

Unexplained hypertension was observed in three anephric children on hemodialysis. We investigated the possible involvement of a novel hypertensive extra-renal enzyme new pressor protein (NPP), related to coagulation beta-FXIIa. Currently, NPP activity can only be determined by a rat bioassay model. On study day 1, pre dialysis, patients 1, 2, and 3 were hypertensive and their plasmas raised rat systolic blood pressure (SBP) by 45, 34, and 9 mmHg, respectively. Post dialysis, patients 1 and 2 reached their estimated dry body weight and their systemic pressures dropped, while patient 3 remained hypertensive and hypervolemic. Their post-dialysis plasmas raised rat SBP by 22, 14, and 9 mmHg, respectively. On day 2, similar relationships between patient SBP, volume status, and plasma NPP-like activity in rats were observed. The characteristic rat BP responses, lack of inhibition by captopril (ruling out a renin-mediated effect), and inhibition by soybean trypsin inhibitor support co-identity with NPP. Plasma FXIIa (combined alpha-FXIIa and beta-FXIIa) was measured by immunoassay and found to be elevated in all patients. This investigation suggests that there is high endogenous NPP activity in the plasmas of these hypertensive hemodialysis patients, it changes with SBP and fluid volume, and is a possible contributor to their hypertension. Further studies are required to examine the wider applicability of these novel findings.