Role of the kidney in primary hypertension: a renal transplantation study in rats

Rettig, Rainer; Folberth, Christine; Stauss, Harald M.; Kopf, Daniel; Waldherr, Rüdiger; Unger, Thomas

doi:10.1152/ajprenal.1990.258.3.f606

Cited by 93 publications

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“…Hypertension is transferred to WKY rats by transplantation of SHR kidneys and vice versa. 19 In addition, a number of abnormalities in renal function, which normalize as blood pressure increases, are observed in young SHR, indicating that an elevated blood pressure may be necessary to compensate for the decreased renal function in SHR. 20 The exact nature of the renal defect is not clear, but there is evidence to suggest that the RAS could be involved.…”

Section: Plasma Renln Concentrationmentioning

confidence: 99%

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: Plasma Renln Concentrationmentioning

confidence: 99%

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

et al. 1991

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“…One criticism of the transplantation studies is that SHR renal grafts may have been damaged secondary to the increased renal perfusion pressure of these animals before transplantation. This objection was addressed by studies in which SHR kidneys were protected from elevated pressure by long-term antihypertensive treatment before transplantation, 37 or renal grafts were obtained from young (4-week-old) SHR that were presumably prehypertensive. 36 In both cases, normotensive recipients of SHR renal grafts developed hypertension, and recipients of WKY rat renal grafts did not.…”

mentioning

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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“…4 Thus, hyperuricemia may reflect the primary role of the kidney in the pathogenesis of hypertension. 5 It has been suggested that hyperuricemia may represent an additional risk factor for the development of cardiovascular disease. 6 Excessive oxidant stress may be instrumental in the onset and maintenance of experimental hyperten-sion.…”

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confidence: 99%

Nephrotoxicity of allopurinol is enhanced in experimental hypertension.

1991

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Hyperuricemia is present in 20-40% of pediatric and adult patients with essential hypertension. This metabolic abnormality may represent an additional risk factor for the development of cardiovascular disease. Therefore, we performed the following studies to determine 1) whether hyperuricemia is more prevalent in the spontaneously hypertensive rat (SHR) and 2) whether allopurinol treatment has a beneficial effect on the development of hypertension in this strain, based on its capacity to lower the serum uric acid concentration and to act as an antioxidant agent SHR and control Wistar-Kyoto (WKY) rats were assigned to two groups, one given tap water to drink and the other provided water containing allopurinol (400 mg/1) to furnish an approximate daily dose equal to 100 mg/kg body wt. This treatment was maintained for 15 weeks. The serum uric acid levels were similar in untreated SHR and WKY rats (1.85±0.10 versus 1.66±0.14 mg/dl; p=0.2S). In the control WKY rat strain, allopurinol therapy did not adversely affect weight gain or hematocrit and did not cause an increase in mortality. It resulted in a moderate decrement in kidney function (creatinine clearance: allopurinol-treated group 0.32 ±0.09 versus control group 0.46±0.04 ml/min/100 g body wt, in conjunction with mild-to-moderate tubulointerstitial inflammation (allopurinol-treated group 0.9 ±0.4 versus control group 0). In contrast, administration of allopurinol to SHR resulted in failure to thrive, marked anemia, severe azotemia (creatinine clearance: allopurinol-treated group 0.04 ±0.01 versus control group 0.39±0.04 ml/min/100 g body wt; p<0.001), and severe tubular atrophy and interstitial fibrosis (allopurinol-treated group 2.2±0.2 versus control group 0;p<0.001). These findings indicate that hyperuricemia is not more prevalent in the SHR. Furthermore, allopurinol administration is associated with markedly increased nephrotoxicity characterized by severe tubulointerstitial injury, azotemia, and impaired growth. (Hypertension 1991;17:194-202)

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Role of the kidney in primary hypertension: a renal transplantation study in rats

Cited by 93 publications

References 0 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.

Nephrotoxicity of allopurinol is enhanced in experimental hypertension.

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