High sensitivity to salt in kininogen-deficient brown Norway Katholiek rats.

Abstract

Brown Norway Katholiek rats, which have very low levels of plasma kininogens, excreted a much smaller amount of kinin in the urine than normal rats of the same strain. The systolic blood pressure of 7-week-old kininogen-deficient rats fed low (0.3%) NaCI diets (131±4 mm Hg, n=12) was not different from that in normal rats. Two percent NaCI diets given from 7 weeks of age for 4 weeks caused rapid increases in blood pressure (167±4 mm Hg, n=12, 9 weeks old) in deficient rats, although the same diets induced no blood pressure increase in normal rats. Urinary excretion of active kallikrein and prokallikrein remained constant in both rat groups throughout NaCI loading. During this period, the deficient rats secreted less urine (9 weeks old, P<.05) and less urinary sodium (11 weeks old, P<.05). Serum levels of sodium in deficient rats were higher (/ > <.O5) than in normal rats at 9 weeks of age. Intracellular concentrations of sodium in the erythrocytes of deficient rats were higher (P<.05) than in normal rats throughout NaCI loading. Subcutaneous infusion of bovine low molecular weight kininogen with an osmotic pump in NaCI-loaded deficient rats induced a reduction (P<.01) in blood pressure and increases (P<.05) in urine volume and urinary sodium and kinin levels. By contrast, subcutaneous infusion of the bradykinin antagonist Hoe 140 or of aprotinin in NaCI-loaded normal rats induced a hypertensive response. This antagonist treatment reduced urine volume and urinary sodium. These results indicate that the lack of kinin generation observed in the kininogen-deficient rats was related through sodium retention to the hypertensive response to NaCI loading. (Hypertension. 1993;22:705-714.) KEY WORDS • hypertension, sodium-dependent • sodium, dietary • kininogens • bradykinin • aprotininT he blood pressure-lowering effects of urinary kallikrein injected intravenously have been described for more than six decades,' and bradykinin is well known to induce vasodilatation and an increase in renal blood flow and excretion of water and sodium from the kidney.2 Urinary kallikrein therefore has been thought to be involved in hypertension, and its reduction has been reported in human 36 and animal 717 experiments. On the other hand, it is widely accepted that sodium retention may be related to the pathogenesis of hypertension, although the precise mechanisms of its contribution to the elevation of blood pressure are still unclear. The causal relation between these three factors -urinary kallikrein, sodium retention, and hypertension-has not been verified. Recently, we reported that the kallikrein-kinin system may play a suppressive role in deoxycorticosterone acetate (DOCA)-salt hypertension.18 Using kininogendeficient Brown Norway Katholiek (BN-Ka) rats and normal rats of the same strain (Brown Norway Kitasato [BN-Ki]), we were able to demonstrate that the urinary kallikrein-kinin system may contribute to lowering of systemic blood pressure in the initial phase of the development of DOCA-salt hypertension in uninephrectomized ...

Human Kininogen Gene Is Transactivated by the Farnesoid X Receptor

“…The short-lived vasodilator bradykinin stimulates the bradykinin B2 receptor on endothelial cells to produce nitric oxide (32,33). Bradykinin was reported to significantly affect renal hemodynamic and excretory function (34).…”

Diuretic and Natriuretic Effect of Ebelactone B in Anesthetized Rats by Inhibition of a Urinary Carboxypeptidase Y-Like Kininase.

“…These results strongly suggest that urinary kinin induces diuresis and natriuresis and inhibition of degradation of BK by compounds such as EB may accelerate the excretion of urine volume and urinary sodium, since the BK receptor (B2) is present mainly on the collecting tubules (14), which is different from the site of action of loop diuretics or thiazide derivatives. As we reported that the lack or reduced activity of urinary kallikrein-kinin system acceler ated the development of hypertension through reduced ex cretion of sodium and water in several models (8,9,15), EB or other kininase inhibitor in the urine may be a candi date for a novel type of anti-hypertensive drug.…”

“…Physiological saline was in fused (6 ml/kg/hr) via the jugular vein throughout the experimental period. Urine volume was estimated by its weight, and urinary sodium and potassium levels were as sayed by flame photometry (8). For the assay of kinin in the urine, urine was collected directly into plastic tubes containing absolute ethanol through a polyethylene can nula inserted into both ureters under pentobarbital anesthesia, since kinin is rapidly degraded during its stay in the bladder.…”

The Kallikrein-Kinin System as a Regulator of Cardiovascular and Renal Function

“…Moreover, wild-type mice or mice with the TK gene deleted exhibited a similar increase in blood pressure when renovascular hypertension was induced (129), further supporting the concept that the KKS plays no more than a minor role in blood pressure regulation either under normal conditions or during hypertension. In kininogen-deficient Brown Norway Katholiek rats (BNK), administration of mineralocorticoids and salt or angiotensin II reportedly increased blood pressure to the same degree as rats with a normal KKS (229), contradicting reports by other investigators (150)(151)(152). Thus, taken together the published data would suggest that kinins are not critical for blood pressure regulation, nor are they required for the development of hypertension, save perhaps in salt-sensitive animals.…”

“…Chronic blockade of B 2 receptors with a potent and selective antagonist, icatibant, did not increase blood pressure under normal conditions or in situations that favor hypertension in rats, such as (i) chronic infusion of a subpressor or pressor dose of angiotensin II (Ang II), (ii) a high salt diet, or (iii) mineralocorticoids and salt (148,229). However, other researchers have had entirely different results, who found that lack circulating kininogen or blockade of B 2 receptors are associated with significant increases in blood pressure under normal conditions or when animals are challenged with a pressor agent or diet (147,(150)(151)(152).…”