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 ...

Brown Norway kininogen-deficient rats had very low levels of plasma kininogens and lower levels of plasma prekallikrein, compared with those of normal rats of the same strain. Systolic blood pressure, determined by the tail-cuff method, of 5-week-old kininogen-deficient rats (106±0.4 mm Hg, n=l) and the rate of systolic blood pressure increase with age were not different from those in normal rats. Weekly injections of deoxycorticosterone acetate (5 mg/kg s.c) with 1% sodium chloride solution in drinking water after uninephrectomy at 7 weeks of age caused a gradual increase in the blood pressure of normal rats, reaching a plateau at 18 weeks of age, whereas that of deficient rats rose rapidly to 158 ±6 mm Hg 2 weeks after the start of treatment and continued to increase slightly, becoming significantly higher than normal rats at 8, 9,10,11, and 12 weeks of age (p<0.05 or 0.01). The levels of urinary prokallikrein and active kallikrein were slightly higher in deficient rats before deoxycorticosterone acetate-salt treatment but were not significantly increased after this treatment, whereas these levels in normal rats were increased 3.6-and 4.7-fold by this treatment Urinary free kinin, collected from the ureter in untreated deficient rats, was below the detection limit The plasma level of low molecular weight kininogen, the substrate of glandular kallikrein, was decreased in normal rats during the treatment Continuous subcutaneous injection of aprotinin by an osmotic pump to normal rats induced significant increase in blood pressure. These results indicate that glandular kallikrein may play a suppressive role in deoxycorticosterone acetate-salt hypertension. {Hypertension 1991;17:806-813) I t was pointed out early on that kallikrein may be related to hypertensive diseases. 1 Recently, urinary kallikrein levels were reported to be lower in patients with essential hypertension than in normotensive controls 2 " 5 but were normal in renal artery stenosis and raised in pheochromocytoma and primary aldosteronism.2 Spontaneously hypertensive rats and rats with deoxycorticosterone acetate (DOCA)-salt hypertension showed greater increases in urinary kallikrein excretion than normotensive Wistar control rats from the National Institutes of Health.3 However, the role of the endogenous kallikrein-kinin system in development of hypertension remains unclear. The kallikrein-kinin system is a system for generating vasodilating peptides, bradykinin, or kallidin, by means of proteolytic enzymes, plasma, or glandular kallikrein, from its own precursor protein, high molecular weight (HMW) or low molecular weight (LMW) kininogen. Brown Norway Katholiek (BNKa) rats have been reported to have a congenitally abnormal kallikrein-kinin system 6 -8 and have been extensively studied and compared with normal rats of the same strain (BN-Kitasato [BN-Ki]). 9- 19 In a previous study, it was reported that not only HMW but also LMW kininogens were lacking in plasma from mutant BN-Ka rats, and only T-kininogen was present. -12 Because of the lack of...

Brown Norway Katholiek rats with 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 (132±2 mm Hg, n=7) was not different from that of normal rats. Angiotensin II (Ang II) (20 jig/d SC) from 7 weeks of age for 2 weeks with a micro-osmotic pump caused significant increases in blood pressure (181 ±5 mm Hg, n=7, 9 weeks old) in the deficient rats, although the same treatment induced no blood pressure increase in the normal rats. Also during this period, the deficient rats had significantly higher heart rates, tended to excrete less urinary sodium, and showed significantly higher sodium levels in serum, erythrocytes, and cerebrospinal fluid compared with the normal rats. Ang II increased urinary excretion of aldosterone in both deficient and normal rats (P<.05). Spironolactone treatment (50 mg/kg per day) for 7 days in deficient rats restored blood pressure and heart rate to T he biologically active peptide bradykinin is well known to induce increases in renal blood flow and water and sodium excretions. Kinin is generated by the action of kallikrein secreted in the distal tubules, and its receptors are distributed on the tubular cells of the distal tubules.12 It has been claimed that urinary kallikrein may be involved in hypertension in humans 3 " 6 and animal models of hypertension. 7 ' 17Using kininogen-deficient Brown Norway Katholiek (BN-Ka) rats that excreted little kinin in the urine 18 and normal rats of the same strain (Brown Norway Kitasato [BN-Ki]), we previously reported that the urinary kallikrein-kinin system may contribute to lowering systemic blood pressure in the initial phase of the development of deoxycorticosterone acetate (DOCA)-salt hypertension in uninephrectomized rats by acceleration of the excretion of sodium and water. This was confirmed in DOCA-salt-treated Sprague-Dawley rats with the use of a potent and selective bradykinin antagonist, Hoe 140.iy Hypertension was also induced as a result of sodium retention 20 in mutant BN-Ka rats by loading a low concentration (2%) of sodium in the diet, whereas the same treatment did not increase systemic blood pressure in normal BN-Ki rats. These results indicated Received September 22, 1993; accepted in revised form March 23, 1994.From the Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, and the Department of Pharmacology (S.O.), Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan.Correspondence to Dr Masataka Majima, MD, PhD, Department of Pharmacology, Kitasato University School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa 228, Japan.© 1994 American Heart Association, Inc.normal levels and significantly reduced sodium levels in erythrocytes and cerebrospinal fluid. Subcutaneous infusion of bovine low-molecular-weight kininogen with an osmotic pump in Ang II-treated deficient rats induced significant reductions in blood pressure, heart ra...

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Kininogen-deficient Brown Norway Katholiek (deficient BN-Ka) rats excreted a small amount of kinin in their urine, compared with normal BN Kitasato (normal BN-Ki) rats from the same strain. Intraarterial (i.a.) infusion (6 ml/kg/hr) of conscious deficient BN-Ka rats with 0.15 M NaCI did not increase mean arterial blood pressure (MBP) [from 103±2 (pre) to 93±6 mmHg (day 4)] and did not cause sodium accumulation in the serum, cerebrospinal fluid or erythrocytes, but 0.3 M NaCI infusion significantly increased MBP from 104 ± 3 (pre) to 130 ± 5 mmHg (day 4) with increased sodium levels in the serum, cerebrospinal fluid and erythrocytes. Infusion of 0.3 M NaCI in normal BN-Ki rats neither increased MBP nor accumulated sodium. The dose-response curve of the increase in MBP for angiotensin II injection (i.a., bolus, 1-1000 pmol/kg) in 0.3 M NaCI-infused deficient BN-Ka rats shifted to the left by a factor of 10 compared with that in 0.15 M NaCI-infused deficient BN-Ka rats, and that for norepinephrine injection shifted to the left by a factor of 30. Normal BN-Ki rats did not show any enhancement in MBP elevation with 0.3 M NaCI. These results suggest that the sodium accumulation attributable to a lack of kinin generation may be related to increased vascular reactivity to angiotensin II and norepinephrine.