Angiotensin II-induced hypertension in bradykinin B2 receptor knockout mice.

The present study was performed to examine the role of endogenous bradykinin (BK) in the development of angiotensin II (Ang II)-induced hypertension in mice. BK B2receptor knockout (B2R-/-) and wild-type (B2R+/+) mice (22to 26 g) were infused with either saline (SAL) or Ang II (40ng/min) via an osmotic minipump implanted intraperitoneally. On day 12after implantation, there was no difference in systolic blood pressure (SBP, tail-cuff plethysmography) between SAL/B2R+/+ and SAL/B2R-/- mice(128+/-5 versus 133+/-6 mm Hg, n=24/group). In contrast, SBP was higher on day 12 of infusion in Ang II/B2R-/- than in Ang II/B2R+/+ mice (173+/-6versus 156+/-5 mm Hg; P<0.05, n=27 and 28). Mean arterial pressure (MAP)was also higher in anesthetized Ang II/B2R-/- mice than in Ang II/B2R+/+mice (139+/-3 versus 124+/-3 mm Hg; P<0.05, n=16 and 14). Unlike Ang II, long-term norepinephrine (NE) infusion via an osmotic minipump (45ng/min) caused equivalent increases in SBP in B2R+/+ and B2R-/- mice measured on day 12 after implantation (151+/-4 versus 149+/-5 mm Hg, n=9and 8). MAP also did not differ on day 13 after implantation between NE/B2R+/+ and NE/B2R-/- mice (120+/-6 versus 122+/-4 mm Hg, n=9 and 8). There were no differences in glomerular filtration rate and urinary sodium excretion among the groups. However, renal plasma flow (RPF) was lower in Ang II/B2R-/- mice than in Ang II/B2R+/+ mice (2.34+/-0.06 versus 4.33+/-0.19 mL x min-1 x g-1; P<0.05). Acute inhibition of NO synthase (NOS)with nitro-L-arginine-methyl ester (0.5 microg x g-1 x min-1) in SAL/B2+/+ and SAL/B2-/- mice caused equal increases in MAP (142+/-1 versus 145+/-1 mmHg) and decreases in RPF (2.06+/-0.06 versus 2.12+/-0.15 mL x min-1 x g-1).However, short-term NOS inhibition caused a greater increase in MAP of Ang II/B2R+/+ mice than of Ang II/B2R-/- mice, such that MAP after NOS inhibition in Ang II/B2R+/+ approached that of Ang II/B2R-/- mice (156+/-2versus 159+/-2 mm Hg). These changes were associated with a decrease in RPF in Ang II/B2R+/+ mice to values similar to those of Ang II/B2R-/- mice before NOS inhibition (2.12+/-0.09 versus 2.34+/-0.06 mL x min-1 x g-1). These results demonstrate that the kallikrein-kinin system selectively buffers the vasoconstrictor activity of Ang II. Furthermore, the enhanced susceptibility of B2R-/- mice to Ang II-induced hypertension and renal vasoconstriction is likely due to an impaired ability to release NO by endogenous kinins.

Long-term effect on blood pressure of early brief treatment by different antihypertensive agents: a study in the prague hypertensive rat.

In the Prague hypertensive rat (PHR), a strain of genetic hypertension derived from Wistar, administration of various antihypertensive drugs (AHD) during the developmental phase of hypertension (weeks 5-9 of life) prevents the rise of blood pressure. However, only drugs blocking the renin-angiotensin system (RAS, i.e. AT1-antagonist losartan and ACE inhibitor perindopril) have a long-term effect on blood pressure leading to values of systolic blood pressure (SBP) of 174.5+/-14.5 and 169.8+/-15.3 mmHg, respectively, at week 30. At this time, control, untreated PHR have a SBP of 222.0+/-16.6 mmHg (p<0.01 for both groups); age-matched PNR (Prague normotensive rat, bred in parallel with PHR from the same parent pair) exhibit values as low as 123.3+/-11.7 mmHg (p<0.01 from all other values). When losartan was administered to another group of PHR not only at weeks 5-9 but once more at weeks of 15-19 of age, the values of their SBP at week 30 were 156.8+/-12.64 mmHg, i.e., values significantly (p<0.01) different not only from 239.7+/-17.59 mmHg (value of the untreated PHR group) but also from 174.5+/-14.5 mmHg (value of PHR to which losartan was administered only once, at weeks 5-9). Thus, twice repeated administration of losartan in young age almost normalizes blood pressure deep into adult age. Proteinuria, a common finding in adult PHR, is also significantly lower in adult age in both groups receiving at weeks 5-9 drugs blocking RAS; the values at week 30 are 4.0+/-0.26 mg/24 h/rat in the losartan and 3.87+/-0.27 in the perindopril group, in contrast to 12.8+/-1.08 (p<0.01 for both groups) in control PHR. In conclusion, early brief administration (weeks 5-9 of life) of RAS-blocking agents to PHR led to long-term antihypertensive and antiproteinuric effects. These effects were significantly intensified by a second brief administration at weeks 15-19.

Losartan protects the rat kidney from ischemic injury.

Administration of losartan (L), an angiotensin II receptor antagonist, at a daily dose of 3 mg/kg body wt, lowered systolic blood pressure (SBP) in both the Prague hypertensive rat and the Prague normotensive rat (PNR). Proteinuria was markedly reduced in both strains by L. Seven days after kidney ischemia due to bilateral clamping of both renal arteries for 45 minutes, the renal function (endogenous creatinine clearance, sodium, potassium, and urea excretion rates) was completely normal in L-treated PHR and PNR, whereas distinct deterioration was observed in untreated animals. The survival rate after kidney ischemia was significantly improved by L in both PHR and PNR. Thus, L had a significant blood pressure-lowering action in both strains and exerted a distinct renal protective effect from kidney ischemia.

A transient role of the kidney in the maintenance of hypertension.

Using the Prague hypertensive rat (PHR), a model derived from the Wistar rat, in which a normotensive parallel, the Prague normotensive rat (PNR), was bred from the same parent pair (so that transplantation of organs between both these parallel rat model lines results in no distinct signs of rejection), we were able to show that hypertension travels with the kidney. Transplantation of a kidney from PHR to a bilaterally nephrectomized (BNX) PNR led to an increase in systolic blood pressure (SBP) in the recipient for 10 weeks after grafting. Similarly, a decrease in SBP was seen in BNX PHR for the same period of time after grafting a kidney from PNR. If, however, the SBP was measured over a longer period of time, because the elevated SBP slowly drops after grafting a kidney from PHR to BNX PNR, it is less than 130 mm Hg in the fourth month and thereafter. If BNX PHR receives a kidney from PNR, the decrease in SBP is permanent, amounting to 126.3 +/- 12.7 mm Hg one year after transplantation. The grafting of a heart from PHR to the abdominal aorta of PNR does not influence SBP. In conclusion, the presence of a kidney from PHR is necessary for the development, but is not sufficient for the maintenance of hypertension. The heart of PHR is not "hypertensogenic" as is the kidney.

[Ineffectiveness of ACE inhibitors (enalapril) on glomerular damage in rats after a 5/6 nephrectomy and a high-salt diet]. / Neúcinnost ACEI (enalaprilu) na prubeh glomerulárního poskození u krys po 5/6 nefrektomii, krmených vysokoslanou dietou.

Wistar rats with surgically removed 5/6 of renal parenchyma were fed either standard (0.35% salt content) or a high-salt (2%) diet. Half of the animals of each group drunk plain water while the other half was provided water enriched with the angiotensin-converting enzyme inhibitor enalapril (ENA) at a dose of 5 mg/kg/day. In rats receiving standard diet, ENA had a significant inhibitory effect on the consequences of ablation: the rats had normal blood pressure, low proteinuria, and high endogenous creatinine clearance compared to water-drinking controls. The high-salt diet significantly enhanced the sequelae of ablation: a high blood pressure and proteinuria, low clearance, which ENA was unable to prevent in these animals. No plausible explanation for the absence of ENA's beneficial effect is available: one can speculate that, under conditions of high-salt intake, the activity of the renin-angiotensin system is suppressed leaving no place for ENA to exert its effect. We also believe that the highly adverse effect of a high-salt diet in chronic renal failure is due to growth factors other than angiotensin II.

[The effect of a low-protein diet and certain pharmaceutical agents on the course of ablation nephropathy in rats]. / Vliv diety o nízkém obsahu bílkovin a nekterých farmak na prubeh ablacní nefropatie u krys.

BACKGROUND: The beneficial effect of a low-protein diet on the course of renal failure after ablation nephropathy in the rat is known; also calcium channel antagonists (CaA) and angiotensin I converting enzyme inhibitors (ACEI) have a protective effect. Because even simple energy restriction retards the development of spontaneous or ablation-induced glomerulosclerosis the authors decided to replace the lacking dietary protein in the low protein diet by starch (disaccharide) and by fat (cereal oil) and compare these two low-protein diets as to their effect on the development of chronic renal failure (CRI) caused by surgical removal of 5/6 of renal parenchyma (5/6 NX). METHODS AND RESULTS: In Wistar rats just after weaning, 5/6 of renal parenchyma were removed surgically. Thereafter, the rats were fed either a "high-protein" (21%) or two types of a "low-protein" (6%) diet, in one of the latter, the lack of protein was substituted by saccharide, in the other by fat making the substitution "isocaloric" in either case. In all three diet groups, subgroups drinking either tap water or water containing either the ACE-inhibitor enalapril (ena) or the calcium antagonist diltiazem (dil) or both (ena+dil) were formed. On the high-protein diet, an increase in the weight of kidney remnants, in proteinuria and in systolic blood pressure (SBP) was seen. This was prevented by feeding either type of the low-protein diet but also by ena and ena+dil. Ena and ena+dil not only prevented the increase in SBP but actually lowered it significantly. Dil alone also had a SBP-lowering action but offered no protection from kidney hypertrophy and it significantly. Dil alone also had a SBP-lowering action but offered no protection from kidney hypertrophy and proteinuria. No additive protective action of ena+dil or ena+low-protein or ena+dil+low-protein was seen suggesting that the lower limit of these protective actions was reached by the low-protein diet alone. There was no substantial difference between either type of low-protein diet except a small and transient decrease in body weight in the first week on a fat-rich diet. CONCLUSIONS: In the described experiments and with the set-up used the low-protein diet had no effect on the plasma creatinine and urea levels nor on creatinine clearance. The weight of the kidney remnants and proteinuria were significantly higher in animals on a high-protein diet who drank water or water with diltiazem. These changes were suppressed by administration of angiotensin converting enzyme inhibitors either alone or combined with diltiazem. A low- protein diet (both types tested) as well as angiotensin converting enzyme inhibitors improve the course of chronic renal failure in ablation nephropathy in the rat; the authors did not prove an additive effect of the combination of this diet with angiotensin converting enzyme inhibitors.

The Prague Hypertensive Rat: a new model of genetic hypertension.

Several animal models of genetic hypertension have been developed but not all of them possess a closely related control strain. Therefore, a new model based on Wistar rats is described in which both hypertensive and normotensive lines were bred from a single parental pair. Several basic data on the two lines (called the Prague Hypertensive Rat, PHR, and the Prague Normotensive Rat, PNR) are given. PNR had a longer survival compared with PHR. At the age of 7 weeks, systolic blood pressure was 161 +/- 14 mmHg in PHR males and 109 +/- 9 mmHg in PNR males. Its further increase with age was very slow in PNR but very steep in PHR. Typical left ventricular cardiac hypertrophy developed in PHR in which cardiac output was not significantly different from that of PNR but total peripheral resistance was higher. Kidney weight was also greater in PHR than in PNR. There was no difference in basic renal functions except of proteinuria which was higher in PHR than in PNR. No differences were observed in extracellular and interstitial fluid volumes whereas plasma and blood volumes were slightly but significantly greater in PHR than in PNR suggesting a shift of extracellular fluid towards the intravascular compartment. This hypertensive model the parameters of which resemble to those of human essential hypertension should be especially suitable for cross-transplantation studies.