Physiological and immunopathological consequences of active immunization of spontaneously hypertensive and normotensive rats against murine renin.

Michel, Jean‐Baptiste; Sayah, S.; Guettier, Catherine; Nussberger, Jürg; Philippe, Monique; Gonzalez, M. F.; Carelli, Claude; Galen, F. X.; Ménard, Joël; Corvol, Pierre

doi:10.1161/01.cir.81.6.1899

Cited by 60 publications

(35 citation statements)

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“…26 It is interesting to compare the results of the present study with those from the study on renin immunization in SHR. 7 The hemodynamic and the biochemical responses to renin immunization, Ang II antagonism or ACE inhibition are quite comparable, indicating that the major effects of the immunization were due to the inhibition of renin and not to the renal disease. Plasma urea concentrations were significantly increased in the immunized rats, whereas neither DuP 753 nor benazeprilat had any effects on plasma urea or creatinine concentrations.…”

Section: -21mentioning

confidence: 93%

“…7 The interpretation of this study is complicated by the development of an autoimmune disease of the kidney. Nevertheless, other recent studies have shown that blood pressure is lowered in SHR after acute administration of novel compounds blocking the RAS at levels other than ACE.…”

Section: âmentioning

confidence: 98%

“…2 In addition, a recent study has shown that active immunization of SHR against mouse renin lowers blood pressure to normotensive levels. 7 The interpretation of this study is complicated by the development of an autoimmune disease of the kidney. Nevertheless, other recent studies have shown that blood pressure is lowered in SHR after acute administration of novel compounds blocking the RAS at levels other than ACE.…”

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Prolonged angiotensin II antagonism in spontaneously hypertensive rats. Hemodynamic and biochemical consequences.

et al. 1991

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The present study examines the effects of prolonged angiotensin II antagonism in spontaneously hypertensive rats by using an angiotensin II receptor antagonist (DuP 753) that is devoid of agonistic properties and selective for the subtype 1 of the angiotensin II (AT,) receptor. The antihypertensive effects of DuP 753 and its effects on circulating parameters of the reninangiotensin system were compared with those of a converting enzyme inhibitor (benazeprilat). To minimize any influence of differences in the pharmacokinetic properties of the two blockers, administration was by continuous intravenous infusion. The experiments were performed in conscious, freely moving rats with continuous 24-hour monitoring of blood pressure. DuP 753 (10 or 30 mg/kg/day) lowered mean arterial pressure to the same extent as benazeprilat (3 or 10 mg/kg/day) during a 48-hour period. The antihypertensive effect was sustained when the treatment was extended to 7 days (DuP 753,10 mg/kg/day, benazeprilat, 3 mg/kg/day). Neither of the compounds affected the baseline or diurnal rhythm of heart rate. Plasma concentrations of renin and angiotensin II were increased sevenfold and 10-fold, respectively, in the rats treated with DuP 753. In rats treated with benazeprilat, plasma renin concentration increased threefold, whereas angiotensin II was unchanged. Heart weights were significantly reduced to a similar extent by DuP 753 and benazeprilat Both compounds also induced a smaller but significant decrease in blood pressure in Wistar-Kyoto rats. Our results indicate that the antihypertensive effects of converting enzyme inhibitors in spontaneously hypertensive rats are mainly due to the blockade of the renin-angiotensin system. In this rat model, angiotensin II appears to play an important role in the maintenance of hypertension that is mediated via the AT, receptor. {Hypertension 1991;18:278-288) T he spontaneously hypertensive rat (SHR) is an inbred strain that develops high blood pressure with increasing age and is widely used as a model of human essential hypertension.1 Similar to most patients with essential hypertension, SHR have normal or decreased plasma renin activity (PRA) and are not considered to be a renin-dependent model of hypertension. Nevertheless, angiotensin I converting enzyme (ACE) inhibitors lower blood pressure in SHR and in patients with essential hypertension. 2ÂCE inhibitors not only completely prevent the development of hypertension in SHR, if administered from an early age, but also lower blood pressure in adult SHR with established hypertension. In contrast to ACE inhibitors, peptidic angiotensin II (Ang II) antagonists 4 and Ang II antibodies 5 do not consistently lower blood pressure in SHR. In addition, the plasma renin-angiotensin system (RAS) is not elevated in SHR; these observations suggest that the effects of ACE inhibitors could be due to non-Ang II-mediated mechanisms.2 -3 However, there is also evidence indicating that the effects of ACE blockade are mediated mainly via Ang II. The antihypertensive effect...

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Section: -21mentioning

confidence: 93%

Section: âmentioning

confidence: 98%

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confidence: 98%

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Prolonged angiotensin II antagonism in spontaneously hypertensive rats. Hemodynamic and biochemical consequences.

et al. 1991

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“…8 The efficacy of interrupting the renin-angiotensin system in SHR is difficult to explain, because SHR do not have elevated plasma renin activity or elevated plasma angiotensin II (Ang II) concentrations relative to their normotensive counterpart, the Wistar-Kyoto (WKY) rat. A possible explanation for the efficacy of interrupting the renin-angiotensin system in SHR, despite normal plasma renin activity, may be that SHR have a more active vascular renin-angiotensin system than WKY rats.…”

Section: T He Spontaneously Hypertensive Rat (Shr) Ismentioning

confidence: 99%

Enhanced renal angiotensin II subtype 1 receptor responses in the spontaneously hypertensive rat.

Kost

Jackson

1993

Hypertension

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Results from renal transplantation experiments demonstrate that a renal defect is responsible for the development of hypertension in the spontaneously hypertensive rat (SHR). In addition, studies with inhibitors of the renin-angiotensin system have shown that angiotensin II (Ang II) is required for the development and maintenance of hypertension in the SHR. These observations prompted us to propose the hypothesis that hypertension in these rats is due to an enhanced renal responsiveness to Ang II. The purpose of the present study was to determine whether an enhanced renal responsiveness to Ang II exists in adult (12-to 14-week-old) SHR relative to Wistar-Kyoto control rats. To prevent hypertension-induced changes in renal function in SHR, we maintained both strains in the normotensive state from 4 weeks of age with long-term captopril treatment (100 mg/kg per day). Intrarenal Ang II infusions induced a significantly greater decrease in renal blood flow and gloraernlar filtration rate and a significantly greater increase in renal vascular resistance in SHR compared with Wistar-Kyoto rats. DuP 753 (Ang II subtype 1 [AT,] receptor antagonist), but not PD 123177 (Ang II subtype 2 receptor antagonist), blocked the renal responses to Ang II in SHR, suggesting that the enhanced renal responsiveness to Ang II was mediated solely by the AT, receptor subtype. Unlike renal responses to Ang II, renal responses to periarterial renal nerve stimulation were similar in both strains, suggesting a selective renal hyperresponsiveness to Ang II in the SHR rather than a general hyperresponsiveness toward all vasoconstrictors. From these studies in chronically captopril-treated rats, we conclude that 1) SHR have a genetically determined, enhanced renal responsiveness to Ang II; 2) the enhanced renal responsiveness to Ang II is mediated by the AT, receptor; and 3) renal responses to periarterial nerve stimulation are not significantly enhanced, suggesting a selective hyperresponsiveness to Ang II in the kidneys of SHR. (Hypertension 1993^1:420-431)

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“…9 Further studies showed that anti-renin vaccines caused a significant and sustained decrease in BP, but could also induce autoimmune renal disease in animal models. 10 A vaccine against Ang I was tested in a phase IIa clinical trial, and was found to be safe, but did not effectively cause a decrease in BP in patients with essential hypertension. 11 In contrast, the study by Tissot et al 8 using a vaccine against Ang II showed a small, but significant, decrease in both systolic and diastolic BP in patients with mild-to-moderate hypertension.…”

Section: Introductionmentioning

confidence: 99%

Vaccination against the angiotensin type 1 receptor for the prevention of L-NAME-induced nephropathy

et al. 2011

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Previous studies have shown that renin-angiotensin (Ang) system vaccines may be effective for the treatment of hypertension, but their efficacy for the prevention of renal disease is unclear. The aim of this study was to compare the effects of an Ang II type 1 (AT1) receptor vaccine with an Ang II receptor blocker (ARB) and a vasodilator on blood pressure (BP) and renal injury in the L-NAME nephropathy model. Male spontaneously hypertensive rats (SHRs) were divided into six groups and treated transiently with three injections of vehicle or AT1 receptor vaccine (0.1 mg) at age 4, 6 and 8 weeks, or continuously with candesartan cilexetil (0.1 mg kg À1 per day) or hydralazine hydrochloride (5 mg kg À1 per day), then administered NG-nitro-Larginine methyl ester (L-NAME) from age 18 to 21 weeks to induce renal injury. Vaccination against the AT1 receptor caused a significant increase in AT1 receptor titers, and a sustained decrease in BP. L-NAME treatment resulted in a marked increase in proteinuria in the control groups, which was completely suppressed in the AT1 vaccine-treated group, and glomerular injury scores were also significantly decreased. Real-time RT-PCR and immunofluorescence studies revealed increased renin mRNA, and increased glomerular expression of nephrin. Comparable results were seen in rats treated continuously with the ARB candesartan, but not with hydralazine. These results suggest that transient AT1 vaccination is as effective as continuous treatment with ARB, not only for the attenuation of hypertension, but also for the prevention of L-NAME-induced nephropathy in SHR.

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Physiological and immunopathological consequences of active immunization of spontaneously hypertensive and normotensive rats against murine renin.

Cited by 60 publications

References 47 publications

Prolonged angiotensin II antagonism in spontaneously hypertensive rats. Hemodynamic and biochemical consequences.

Prolonged angiotensin II antagonism in spontaneously hypertensive rats. Hemodynamic and biochemical consequences.

Enhanced renal angiotensin II subtype 1 receptor responses in the spontaneously hypertensive rat.

Vaccination against the angiotensin type 1 receptor for the prevention of L-NAME-induced nephropathy

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