Hypertension induced by a nonpressor dose of angiotensin II in kininogen-deficient rats.

Abstract

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...

Effect of ACE Inhibitor on DOCA-Salt– and Aortic Coarctation–Induced Hypertension in Mice

“…12 In this regard, Majima et al 13 found that DOCA-salt induced a faster rise in systolic pressure in kinin-deficient rats (Brown Norway Katholiek, BNK) than controls; moreover, BNK given a high-salt diet or chronic infusion of Ang II become hypertensive compared with controls. 14,15 On the other hand, using a different approach, Madeddu et al 16,17 reported that chronic blockade of B 2 receptors with icatibant made rats hypertensive when given a high-salt diet or chronically infused with Ang II. Both Majima and Madeddu concluded that kinins prevent the chronic hypertensinogenic effect of DOCA-salt, high salt or Ang II.…”

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).…”

The Management of Antiphospholipid Antibodies Affected Pregnancy

“…Tissue kallikrein cleaves lowmolecular-weight kininogen substrate to produce the vasodilator Lys-bradykinin, whereas plasma kallikrein forms bradykinin (BK) from high-molecular-weight kininogen (HMWK). Kininogen-deficient rats are susceptible to the development of salt-induced hypertension (28), and the in vivo angiogenesis is suppressed (29). The proangiogenic effect of BK and HMWK has been demonstrated in both in vitro and in vivo studies (30).…”