Effects of orally administered glandular kallikrein on urinary kallikrein and prostaglandin excretion, plasma immunoreactive prostanoids and platelet aggregation in essential hypertension

Abstract

The effects of orally administered glandular kallikrein on urinary kallikrein, aldosterone and prostaglandin E (PGE) excretion, plasma renin activity (PRA), immunoreactive 6-keto PGF1 alpha and thromboxane B2 concentrations and platelet aggregation were studied in 12 patients with essential hypertension (EH). After a 2-week control period, each patient was given orally 450 KU/day of hog glandular kallikrein for 8 weeks. Urinary kallikrein, aldosterone and PGE excretion, and plasma 6-keto PGF1 alpha and thromboxane B2 concentrations were measured by radioimmunoassay. Platelet aggregation was measured by the addition of ADP, collagen or ristocetin with an aggregometer. Urinary kallikrein excretion and plasma 6-keto PGF1 alpha concentration were significantly decreased in patients with EH. There were no significant differences in PRA, urinary aldosterone excretion and plasma thromboxane B2 concentrations between control subjects and patients with EH. There was a significant decrease in blood pressure in patients with EH coinciding with significant increases of urinary kallikrein and PGE excretion and plasma immunoreactive 6-keto PGF1 alpha concentration after administration of glandular kallikrein. There was also a significant inhibition of platelet aggregation induced by collagen in these patients. Thus, a suppression of the kallikrein-kinin-prostaglandin system in patients with EH was found, and a decrease in blood pressure with an increment of urinary kallikrein, PGE excretion, plasma immunoreactive 6-keto PGF1 alpha and inhibition of platelet aggregation in vivo by the administration of glandular kallikrein.

Inhibition of bradykinin‐induced vasodilation in human forearm vasculature by icatibant, a potent B2‐receptor antagonist.

“…In rat models of hypertension studies have shown both reduced urinary excretion of tissue kallikrein and also increased inactivation of circulating kinins [23,24]. Decreased urinary excretion of tissue kallikrein has also been reported in human hypertension, and hog pancreatic kallikrein administered orally to hypertensive patients not only corrects decreased urinary excretion of kallikrein but also lowers blood pressure [25].…”

Regression of Glomerular Injury by Kallikrein Infusion in Dahl Salt-Sensitive Rats Is a Bradykinin B₂-Receptor-Mediated Event

“…There is evidence that orally administered kallikrein indeed increases plasma kinin concentration in humans [27, 28]. Since the efferent arterioles in glomeruli are very sensitive to kinins, the low-dose of kallikrein probably reduces intraglomerular blood pressure through balancing the afferent and efferent arterioles, thereby improving glomerular sclerosis.…”

Direct gene delivery of human tissue kallikrein reduces blood pressure in spontaneously hypertensive rats.

“…These findings suggest that low renal kallikrein levels may contribute to hypertension and high urinary kallikrein could have a protective effect against hypertension. Clinical studies have shown that the blood pressure of hypertensive patients can be temporarily lowered by oral administration of pig pancreatic kallikrein ( 16,17). However, to achieve this hypotensive effect, a large quantity and repeated administration of purified tissue kallikrein are required.…”

“…Oral administration of pig pancreatic kallikrein has been shown to cause a temporary lowering of blood pressure in hypertensive patients ( 16,17). Recently, oral kallikrein therapy on salt-sensitive essential hypertensive patients has been reported (39 (40).…”