ecallantide and Hypertension

Plasma kallikrein (PK) is a serine protease generated from plasma prekallikrein, an abundant circulating zymogen expressed by the Klkb1 gene. The physiological actions of PK have been primarily attributed to its production of bradykinin and activation of coagulation factor XII, which promotes inflammation and the intrinsic coagulation pathway. Recent genetic, molecular, and pharmacological studies of PK have provided further insight into its role in physiology and disease. Genetic analyses have revealed common Klkb1 variants that are association with blood metabolite levels, hypertension, and coagulation. Characterisation of animal models with Klkb1 deficiency and PK inhibition have demonstrated effects on inflammation, vascular function, blood pressure regulation, thrombosis, haemostasis, and metabolism. These reports have also identified a host of PK substrates and interactions, which suggest an expanded physiological role for this protease beyond the bradykinin system and coagulation. The review summarises the mechanisms that contribute to PK activation and its emerging role in diabetes and metabolism.

Topics: Adipogenesis; Animals; Blood Coagulation; Blood Pressure; Bradykinin; Diabetes Mellitus; Factor XII; Gene Expression Regulation; Genetic Variation; Glucose; Hemostasis; Humans; Hypertension; Inflammation; Mice; Plasma Kallikrein; Prekallikrein; Thrombosis

The aim of this study was to investigate the effect of short-term treatment with losartan, a selective and competitive angiotensin II (AngII) receptor blocker, on vascular endothelial growth factor (VEGF), active renin and kallikrein activity (KA) in patients with essential hypertension and primary aldosteronism. Nine patients with primary aldosteronism (5 with Conn adenoma and 4 with idiopathic hyperaldosteronism) and 9 patients with essential hypertension were included in the study. Systolic and diastolic blood pressure decreased significantly after losartan treatment in both patient groups. Plasma and urinary Kallikrein activity were significantly higher in primary aldosteronism in comparison with essential hypertension. There were no significant changes in the active renin and aldosterone in patients with primary aldosteronism after treatment. Plasma and urinary KA decreased significantly after losartan administration in both groups. Serum VEGF levels in primary aldosteronism were not significantly different from those in essential hypertension and did not change significantly after treatment in either group. In conclusion, losartan, in usual therapeutic doses, lowers blood pressure in patients with primary aldosteronism and essential hypertension. This marked antihypertensive effect in primary aldosteronism could be explained predominantly by blockade of tissue renin-angiotensin system (RAS). The variations in KA could be due to hemodynamic changes. VEGF is not likely to be involved in the action of losartan.

Topics: Administration, Oral; Age Factors; Aldosterone; Angiotensin Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Endothelial Growth Factors; Female; Humans; Hyperaldosteronism; Hypertension; Kallikreins; Losartan; Lymphokines; Male; Matched-Pair Analysis; Middle Aged; Plasma Kallikrein; Receptor, Angiotensin, Type 1; Renin; Sex Factors; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Plasma kallikrein (PKa) has been implicated in contributing to hemorrhage following thrombolytic therapy; however, its role in spontaneous intracerebral hemorrhage is currently not available. This report investigates the role of PKa on hemorrhage and hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were fed with a high salt-containing stroke-prone diet to increase blood pressure and induce intracerebral hemorrhage. The roles of PKa on blood pressure, hemorrhage, and survival in SHRSP were examined in rats receiving a PKa inhibitor or plasma prekallikrein antisense oligonucleotide (PK ASO) compared with rats receiving control ASO. Effects on PKa on the proteolytic cleavage of atrial natriuretic peptide (ANP) were analyzed by tandem mass spectrometry. We show that SHRSP on high-salt diet displayed increased levels of PKa activity compared with control rats. Cleaved kininogen was increased in plasma during stroke compared to SHRSP without stroke. Systemic administration of a PKa inhibitor or PK ASO to SHRSP reduced hemorrhage and blood pressure, and improved neurological function and survival compared with SHRSP receiving control ASO. Since PKa inhibition was associated with reduced blood pressure in hypertensive rats, we investigated the effects of PKa on the cleavage of ANP. Incubation of PKa with ANP resulted in the generation fragment ANP

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cerebral Hemorrhage; Hypertension; Plasma Kallikrein; Rats; Rats, Inbred SHR; Stroke

Hematoma expansion (HE) aggravates brain injury after intracerebral hemorrhage (ICH) and hypertension is a key contributor to HE. Plasma kallikrein (PK) is involved in hemorrhagic transformation in ischemic stroke mice. This study was conducted to explore the role of PK in HE in hypertensive ICH.. Hypertension was achieved by continuous infusion of angiotensin II (Ang II) with an osmotic pump in C57BL/6 mice. ICH was achieved by stereotactic intrastriatal injection of blood. PK-specific antibody and platelet glycoprotein VI (GPVI) agonists were administered to intervene in hematoma expansion. The hematoma volume was indicated by the erythrocyte components hemoglobin and carbonic anhydrase-1 in the ipsilateral brain hemisphere.. Ang II-induced hypertensive mice showed enhanced hematoma expansion and worsened neurologic deficits after ICH modeling. Moreover, intrastriatal injection of blood from Ang II-treated mice into normal mice increased the area of secondary hemorrhage more than blood from untreated mice. Mechanistically, elevated PK was found in Ang II-infused mice whereas, inhibition of PK and administration of the GPVI agonist convulxin decreased hematoma expansion and improved neurologic deficits after ICH.. These findings suggest that PK inhibition and GPVI agonist treatment might serve as potential methods to intervene in HE after ICH.

Topics: Angiotensin II; Animals; Blood Pressure; Cerebral Hemorrhage; Crotalid Venoms; Disease Models, Animal; Hypertension; Lectins, C-Type; Male; Mice; Plasma Kallikrein; Treatment Outcome

Topics: Adult; Antihypertensive Agents; Blood Glucose; Humans; Hypertension; Imidazoles; Insulin; Kinins; Male; Metabolic Syndrome; Middle Aged; Plasma Kallikrein; Thromboxanes