-
[show abstract]
[hide abstract]
ABSTRACT: To determine whether the persistent antihypertensive effect observed after withdrawal of angiotensin-converting enzyme inhibition was specific and whether it was associated with durable improvement of renal function. Lyon hypertensive (LH) rats were treated from 3 and 12 weeks of age with perindopril at the dose of 0.4 (P0.4) or 1.5 (P1.5) mg·kg(-1)·d(-1), with double (hydralazine 75 mg·kg(-1)·d(-1) and hydrochlorothiazide 15 mg·kg(-1)·d(-1)), or triple antihypertensive therapy (reserpine 0.75 mg·kg(-1)·d(-1) was added). Blood pressure (BP) was recorded by telemetry, and renal functions were evaluated in freely moving rats. Despite similar BP reduction after perindopril withdrawal in P0.4 and P1.5 groups, greater decrease in proteinuria was observed in P1.5 group. Double or triple therapy prevented the hypertension of LH rats, but without any persistent antihypertensive or antiproteinuric effect after its withdrawal. Salt load elicited an increase in BP that was similar in untreated LH and both perindopril-pretreated groups (+30 mm Hg), but more pronounced in double therapy–pretreated or triple therapy–pretreated groups (+50 mm Hg). The pressure–natriuresis curve shifted to lower BP levels in P0.4 and P1.5 groups, whereas it was blunted in double and triple therapy groups. Angiotensin-converting enzyme inhibition has a durable renoprotection after treatment withdrawal that is independent of BP lowing.
Journal of cardiovascular pharmacology 11/2010; 57(2):240-5. · 2.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In Lyon genetically hypertensive (LH) rats with diabetes, the effects of angiotensin converting enzyme (ACE) inhibition with perindopril on the prevention of dyslipidemia and proteinuria were evaluated by comparison with a nonspecific antihypertensive treatment.
Diabetes was induced in 2-day-old male LH rats by intraperitoneal injection of streptozotocin (75 mg/kg). Glucose tolerance (glucose 2 g/kg by gavage), blood pressure (BP), plasma lipids, and urinary protein excretion were studied in: (i) untreated diabetic LH rats, (ii) diabetic LH rats treated from 8 to 16 weeks of age with oral perindopril at a low dose (0.01 mg/kg/day), (iii) similar rats treated with oral perindopril for the same duration at a high dose (1 mg/kg/day), and (iv) similar rats treated for the same duration with a triple therapy regimen consisting of hydralazine, hydrochlorothiazide, and reserpine (75, 15, and 0.75 mg/kg/day, respectively).
The neonatal administration of streptozotocin in LH rats increased nonfasting glycemia and induced a marked glucose intolerance which was accompanied by further increases in BP, plasma cholesterol, and urinary protein excretion. None of the treatments was able to modify glucose tolerance in diabetic LH rats. The low dose of perindopril was ineffective in the prevention of hypertension, dyslipidemia, and proteinuria in diabetic LH rats, while the high dose of perindopril normalized the BP, reduced the plasma lipids, and lowered the proteinuria. However, in spite of significant reduction in BP, the triple therapy failed to improve dyslipidemia and proteinuria; on the contrary, the therapy worsened these two conditions.
In diabetic LH rats, only ACE inhibition is of benefit to the kidney and lipidemia, thereby demonstrating that antihypertensive regimens may differ in their capacity to protect the target organs and lipid metabolism in a diabetic setting.
American Journal of Hypertension 07/2008; 21(6):657-62. · 3.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A region with a major effect on blood pressure (BP) is located on rat chromosome 1. We have previously isolated this region in reciprocal congenic strains (WKY.SHR-Sa and SHR.WKY-Sa) derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY) and shown that there are 2 distinct BP quantitative trait loci, BP1 and BP2, in this region. Sisa1, a congenic substrain from the SHR.WKY-Sa animals carrying an introgressed segment of 4.3Mb, contains BP1. Here, we report further dissection of BP1 by the creation of 2 new mutually exclusive congenic substrains (Sisa1a and Sisa1b) and interrogation of candidate genes by expression profiling and targeted transcript sequencing. Only 1 of the substrains (Sisa1a) continued to demonstrate a BP difference but with a reduced introgressed segment of 3Mb. Exonic sequencing of the 20 genes located in the Sisa1a region did not identify any major differences between SHR and WKY. However, microarray expression profiling of whole kidney samples and subsequent quantitative RT-PCR identified a single gene, Spon1 that exhibited significant differential expression between the WKY and SHR genotypes at both 6 and 24 weeks of age. Western blot analysis confirmed an increased level of the Spon1 gene product in SHR kidneys. Spon1 belongs to a family of genes with antiangiogenic properties. These findings justify further investigation of this novel positional candidate gene in BP control in hypertensive rat models and humans.
Circulation Research 05/2007; 100(7):992-9. · 9.49 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Lyon hypertensive (LH) rats exhibit a mild hypertension associated with excessive body weight, spontaneous hyperlipidemia, elevated insulin/glucose ratio and exaggerated urinary protein excretion.
We aimed to develop, in LH rats and their normotensive control (LL) rats, a moderate non-insulin-dependent diabetic model to study the different consequences on metabolic and renal functions.
Non-insulin-dependent diabetes was induced by intraperitoneal injection of streptozotocin (STZ) at 2 days of age (50, 75 or 100 mg/kg for LH and 75, 100 or 125 mg/kg for LL rats). The evolution, with age, of glycemia, glucose tolerance (glucose 2 g/kg by gavage), blood pressure, plasma lipids and urinary protein and albumin excretions were studied in control and STZ-treated LH and LL rats.
Although fasting glycemia was not significantly changed, the neonatal administration of STZ increased non-fasting glycemia and induced a marked glucose intolerance that were comparable between LH rats receiving 75 mg/kg and LL rats receiving 100 mg/kg of STZ. Interestingly, in treated LH rats only, the impaired glucose tolerance was accompanied by further metabolic and renal dysfunctions characterized by additional increases in plasma cholesterol (+28%) and triglycerides (+105%) and accelerated progression of proteinuria (+36%) and albuminuria (+48%).
These observations indicate that susceptibility to diabetic metabolic disorders and renal diseases may be linked to the genetic predisposition to hypertension. This new model offers a reasonable reflection of the human situation, where hypertension and non-insulin-dependent diabetes often coincide, suitable for molecular, biochemical and pharmacological investigations.
Journal of Hypertension 03/2007; 25(2):429-38. · 4.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Early and chronic angiotensin converting enzyme (ACE) inhibition prevents hypertension and improves the pressure natriuresis in Lyon hypertensive (LH) rats. The effect of this treatment on the responses of renal medullary blood flow (MBF) to angiotensin II (Ang II) was studied.
In chronic experiments, Ang II (7.5 to 480 ng/kg, intravenous) was injected in 15-week-old anesthetized LH and normotensive (LL) control rats treated orally since weaning with perindopril (0.4 or 1.5 mg/kg/day) with or without pretreatment with indomethacin (5 mg/kg intravenous). In acute experiment, Ang II (30 to 480 ng/kg intravenous) was given in LH rats treated acutely with perindopril (1.5 mg/kg, intravenous bolus).
Administration of Ang II induced dose-dependent decreases in MBF, which were greater in LH than in LL rats. In LL rats, the initial and short-lasting (<1 min) medullary vasoconstriction evoked by Ang II was followed by a long-lasting (>2 min) and dose-dependent medullary vasodilation, which was blunted in LH rats. Chronic perindopril treatment normalized the blood pressure level in LH rats and corrected their blunted medullary vasodilation, whereas the same treatment had no significant effect in LL rats. In chronically perindopril-treated LH rats, indomethacin decreased by 90% the medullary vasodilation induced by Ang II. Acute perindopril treatment did not modify the medullary responses to Ang II in LH rats.
Chronic ACE inhibition restores the vasodilator response of MBF to Ang II in LH rats. This effect, which is not observed after acute inhibition, is mainly mediated through the release of prostaglandins.
American Journal of Hypertension 06/2006; 19(6):617-22. · 3.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aims of the present work were to determine whether a brief renin-angiotensin system blockade with AT1 receptor antagonist or angiotensin-converting enzyme inhibitor may provide long-lasting protection against hypertension and proteinuria in both young and adult Lyon hypertensive (LH) rats. Young pre-hypertensive Lyon hypertensive rats were orally treated with 5, 10, or 20 mg/kg/d of losartan, or with 0.4 mg/kg/d of perindopril from 3 to 12 weeks of age. Adult Lyon hypertensive rats were treated with 10 mg/kg/d of losartan, 0.4 mg/kg/d of perindopril, or a combination of both from 12 to 20 weeks of age. Telemetric blood pressure (BP) and urinary protein excretion were evaluated during and after treatment cessation. In young prehypertensive Lyon hypertensive rats, losartan fully prevented the hypertension and proteinuria; these effects were dose dependent and persisted long after treatment withdrawal. When renin-angiotensin system blockade was initiated in adult Lyon hypertensive rats with established hypertension, 10 mg/kg/d of losartan or 0.4 mg/kg/d of perindopril induced a significant regression in both blood pressure (15%-20%) and proteinuria (40%-50%) as did in young Lyon hypertensive rats; the combination treatment produced an additional effect only on blood pressure. After treatment cessation, a reduction in blood pressure persisted in all the pretreated adult Lyon hypertensive rats whereas the effect on proteinuria was less marked. In conclusion, whatever the blocker used, an early renin-angiotensin system blockade in prehypertensive Lyon hypertensive rats induces a durable prevention of hypertension and associated renal alterations. The similar renin-angiotensin system blockade in adult Lyon hypertensive rats provides a regression of hypertension and proteinuria, but the persistence of these beneficial effects is less pronounced than in young Lyon hypertensive rats, thus suggesting that the treatment with renin-angiotensin system blockers should be initiated as early as possible before the full expression of hypertension, to achieve the maximal long-lasting effects in mature stage.
Journal of Cardiovascular Pharmacology 01/2006; 46(6):740-5. · 2.29 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In Lyon genetically hypertensive (LH) rats, an early and long-term angiotensin-converting enzyme (ACE) inhibition with perindopril prevents their hypertension and renal alterations. The present work aimed to determine whether: 1) these effects persist after treatment withdrawal; 2) a short-term additional angiotensin II type 1 (AT1) receptor blockade with losartan potentiates these effects; and 3) an early combination of low doses of perindopril and losartan produces the same prolonged effects as monotherapy with a higher dose of perindopril.
Perindopril (0.4 or 3 mg/kg/day orally) was given from 3 to 12 weeks of age to male LH rats. In other perindopril-treated LH rats, losartan (10 mg/kg/day orally) was added 1 week before perindopril withdrawal and during a 3-week period. In another group of LH rats, perindopril (0.1 mg/kg/day) and losartan (2.5 mg/kg/day) were given together from 3 to 12 weeks. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were monitored using radio-telemetry and renal function studied in anesthetized rats.
Eight weeks after perindopril withdrawal, a significant reduction (P < .05) in SBP and DBP was observed with the both doses (SBP: 135 +/- 3, 139 +/- 5 v 157 +/- 4; DBP: 89 +/- 4, 93 +/- 5 v 111 +/- 3 mm Hg for 0.4 and 3 mg/kg/day v untreated LH rats). This was accompanied by a persistent decrease in urinary protein excretion and a long-lasting improvement in pressure natriuresis. The persistent antihypertensive effect was not improved by short-term addition of losartan. Interestingly, the early combination of perindopril with losartan at fourfold lower doses produced similar persistent antihypertensive and renoprotective effects.
The blood pressure reduction produced by an early ACE inhibition in LH rats persists long after treatment withdrawal and is associated with an improvement in renal function. The combination of low doses of perindopril and losartan reveals a long-term effect similar to that of a monotherapy with a higher dose of perindopril.
American Journal of Hypertension 06/2005; 18(5 Pt 1):699-706. · 3.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In Lyon hypertensive (LH) rats, a model of low-renin genetic hypertension, we investigated adrenal sensitivity to angiotensin II in terms of angiotensin II receptor (AT1 and AT2 receptors) regulation, morphological changes, and aldosterone and corticosterone secretion. Twelve-week-old LH rats, compared with normotensive LN and LL rats, were either untreated or treated for 4 weeks with AT1 receptor antagonist irbesartan (50 mg/kg/d), angiotensin-converting enzyme inhibitor perindopril (3 mg/kg/d), or perindopril (3 mg/kg/d) plus angiotensin II infusion (200 ng/kg/min). At 16 weeks, untreated LH rats had high systolic blood pressure (P<0.05), low aldosterone (P<0.05), and increased corticosterone (P<0.05) plasma levels. AT1-receptor binding density in the zona glomerulosa was similar in the three strains. In LH rats, angiotensin II infusion increased the relative adrenal weight from 10.5+/-0.3 to 16.7+/-0.7 mg/100g (P<0.05), whereas this change was very modest in normotensive rats. Zona glomerulosa enlarged and plasma aldosterone increased after angiotensin II infusion in the 3 strains, but more markedly in LH versus normotensive rats (2.4- versus 1.3- and 1.6-fold, respectively; 20- versus 10-fold in normotensive rats, P<0.05). Surprisingly, after angiotensin II infusion, despite the absence of angiotensin II receptors in the three strains, the zona fasciculata-reticularis enlarged 1.5-fold and plasma corticosterone increased 1.7-fold only in LH rats (P<0.05), suggesting an indirect control of this compartment by angiotensin II. The hypertrophy and hypersecretory activity of both zona glomerulosa and zona fasciculata-reticularis in LH rats in response to angiotensin II point to the adrenal cortex as a pivotal tissue in the pathophysiology of hypertension in LH rats.
Hypertension 01/2004; 43(1):87-93. · 6.21 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The present study evaluated the acute effects of ANG II (5-480 ng/kg iv) and phenylephrine (PE; 0.2-146 microg/kg iv) on total renal (RBF) and medullary blood flow (MBF) in anesthetized Lyon hypertensive (LH) and low-blood-pressure (LL) rats. ANG II and PE induced dose-dependent decreases in both RBF and MBF, which were greater in LH than in LL rats. Interestingly, after ANG II, but not after PE, the initial medullary vasoconstriction was followed by a long-lasting and dose-dependent vasodilation that was significantly blunted in LH compared with LL rats. The mechanisms of the MBF effects of ANG II were studied in LL rats only. Blockade of AT(1) receptors with losartan (10 mg/kg) abolished all the effects of ANG II, whereas AT(2) receptor blockade with PD-123319 (50 microg x kg(-1) x min(-1) iv) did not change these effects. Indomethacin (5 mg/kg) decreased by approximately 90% the medullary vasodilation induced by the lowest doses of ANG II (from 15 ng/kg). In contrast, N(G)-nitro-l-arginine methyl ester (10 mg/kg and 0.1 mg. kg(-1). min(-1) iv) and the bradykinin B(2)-receptor antagonist HOE-140 (20 microg/kg and 10 microg x kg(-1) x min(-1) iv) markedly lowered the medullary vasodilation at the highest doses of ANG II only. In conclusion, this study shows that LH rats exhibit an altered MBF response to ANG II compared with LL rats and indicates that the AT(1) receptor-mediated medullary vasodilator response to low doses of ANG II is mainly due to the release of PGs, whereas the dilator response to high doses of ANG II has additional nitric oxide- and kinin-dependent components.
American journal of physiology. Renal physiology 03/2003; 284(2):F365-72. · 3.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This paper reviews the data which demonstrate that Lyon genetically hypertensive (LH) rats exhibit a low renin form of hypertension. Since when compared to normotensive controls, LH rats exhibit a low renin release and are salt-sensitive. Despite this, the blockade of the renin-angiotensin system normalizes the blood pressure level and the regional blood flows in LH rats. Such a discrepancy between the compulsory presence of angiotensin II for the hypertension to develop and the low level of renin release seen in LH rats led to two hypotheses: 1) the existence of an early, short lasting increase of renin release which would be sufficient for the occurrence of a stable hypertension; 2) an hypersensitivity to the effects of angiotensin II. The study of the long-term effects of early short lasting blockades of the renin-angiotensin system allowed to exclude the first hypothesis. Concerning a hypersensitivity to the effects of angiotensin II, it was found to exist in the preglomerular vessels of LH rats. This increased response of renal vessels to angiotensin II may well explain the low renin form of hypertension of our model and therefore represents an important field for further research.
Acta Pharmacologica Sinica 02/2003; 24(1):1-6. · 1.95 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The present work aimed to assess, in Lyon hypertensive (LH) rats, whether an early and prolonged inhibition of the renin-angiotensin system (RAS) could result in a blood pressure (BP) lowering and nephroprotection that persist after its withdrawal. Male LH rats received orally from 3 to 12 wk of age either an angiotensin-converting enzyme inhibitor perindopril at the doses of 0.4 and 3 mg x kg(-1) x day(-1) or an AT(1) receptor antagonist losartan at the dose of 10 mg x kg(-1) x day(-1). BP, histological changes in the kidney, and urinary protein excretion were examined during and 10 wk after cessation of the treatments. Both perindopril and losartan decreased BP, prevented renal lesions, and limited urinary protein excretion. After cessation of the treatment, BP returned to the level of never-treated LH rats in rats having received 3 mg x kg(-1) x day(-1) of perindopril while it remained slightly lower in those treated with 0.4 mg x kg(-1) x day(-1) of perindopril or with losartan. This lack of marked persistent antihypertensive effect contrasted with a durable decrease in urinary protein excretion and improvement of the renal histological lesions. In conclusion, it is possible to separate the BP-lowering effects of RAS blockade from those on glomerulosclerosis and urinary protein excretion.
AJP Regulatory Integrative and Comparative Physiology 12/2002; 283(5):R1041-5. · 3.34 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: One or more quantitative trait locus (QTL) for blood pressure (BP) exists on rat chromosome 1, in the vicinity of the Sa gene. The present work examined whether this QTL region: 1) alters pressure-natriuresis relationship and 2) affects the BP response to salt load. Male spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY) rats, and rats from an SHR congenic strain that contains a WKY chromosome 1 segment spanning the BP QTL region (SHR. WKY-Sa) were used. In an acute study in anesthetized animals, renal function was measured at several levels of renal perfusion pressure. In a chronic study, BP was measured in freely moving rats using telemetry during normal and high sodium intake (2% NaCl as drinking water for 2 wk). WKY rats showed a significantly higher glomerular filtration rate and increased pressure-natriuresis compared with SHR. SHR.WKY-Sa also demonstrated an increased glomerular filtration rate and enhanced pressure-natriuresis, associated with a lower tubular sodium reabsorption, compared with SHR. These modifications were accompanied by a lower basal BP in SHR.WKY-Sa compared with SHR and a markedly reduced BP response to salt load. These findings suggest that the BP QTL(s) present in this region of chromosome 1 influences BP and salt sensitivity, at least partly, by modulating pressure-natriuresis.
Physiological Genomics 03/2002; 8(1):15-21. · 2.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The present work studied renal medullary blood flow (MBF) and its response to salt load in Lyon hypertensive (LH) rats to understand the mechanisms underlying the abnormal renal sodium excretion exhibited by LH rats. Experiments were conducted in uninephrectomized, anesthetized, and volume-expanded 15-week-old male LH and their normotensive (LL) controls. Under standard diet, LH rats exhibited a blunted pressure diuresis and natriuresis associated with an absence of pressure-induced increase in MBF compared to LL rats. One week of salt load (2% NaCl as drinking water) induced a significant increase in blood pressure (BP) in LH (+11 mm Hg) than in LL (+6 mm Hg) rats associated with a decrease in MBF in LH rats only (from 182 +/- 25 to 122 +/- 20 perfusion units, P < .001). Finally, despite the salt load-induced increase in pressure natriuresis, it remained significantly lower in LH than in LL rats. The results show an alteration in MBF regulation in LH rats and suggest that this abnormality may be involved in their blunted pressure natriuresis and their enhanced salt sensitivity.
American Journal of Hypertension 03/2002; 15(3):212-6. · 3.18 Impact Factor
-
Madeleine Vincent,
El Habib Boussaïri,
Régine Cartier, Ming Lo,
Agnès Sassolas,
Catherine Cerutti,
Christian Barrès,
Marie-Paule Gustin,
Guy Cuisinaud,
Nilesh J. Samani,
G. Mark Lathrop,
Jean Sassard
[show abstract]
[hide abstract]
ABSTRACT: Objective: A large population of F2 rats, obtained from a cross between male Lyon hypertensive (LH) rats and female Lyon normotensive (LN) rats, was studied in order to assess the relationship between increased body weight, hyperlipidaemia and high blood pressure which characterize LH rats.
Methods: Mean arterial pressure (MAP) was recorded in male, conscious, freely moving LH, LN, F1 and F2 rats aged 30 weeks. Plasma total cholesterol, high-density lipoprotein-, low-density lipoprotein- and very low-density lipoprotein-cholesterol, phospholipids, triglycerides, insulin and glucose were measured.
Results: In the F2 cohort it was observed that high MAP was a recessive trait that depends on several genes and was unrelated to body weight. The left ventricular weight, corrected for tibia length, was correlated with MAP. Plasma total and high-density lipoprotein-cholesterol and phospholipids concentrations were lower in the F1 rats than in the LN rats, suggesting an overdominance of the LN alleles. In the F2 rats MAP was related to total, high-density lipoprotein- and low-density lipoprotein-cholesterol. Plasma triglycerides, insulin and the insulin: glucose ratio, which were higher in the LH rats than in the LN rats, were also correlated with MAP in the F2 cohort. Using stepwise multiple regression analysis, MAP remained correlated with plasma total cholesterol, insulin and the insulin: glucose ratio, but not with triglycerides.
Conclusions: Hypertension in LH rats is a recessive trait that is independent of body weight. In addition, the cosegregation of blood pressure with plasma cholesterol and, to a lesser degree, with insulin levels, which was observed in the present study provides the first direct evidence that these phenotypes are associated and are not due simply to genetic drift in the Lyon model.
(C) Lippincott-Raven Publishers.
Journal of Hypertension 10/1993; 11(11). · 4.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 1. Because we previously observed that angiotensin AT2 receptor stimulation decreased pressure-natriuresis, in the present study we examined the possible involvement of these receptors in altered sodium excretion shown by Lyon hypertensive (LH) rats. 2. In 9-week-old male anaesthetized LH rats and normotensive (LL) controls pretreated with an angiotensin-converting enzyme inhibitor (quinapril; 10 mg/kg) and an AT1 receptor antagonist (losartan; 10 mg/kg), angiotensin (Ang) II was infused (30 ng/kg per min) to stimulate AT2 receptors. In other groups of rats, an AT2 receptor antagonist (PD123319; 50 micro g/kg per min) was added before AngII infusion. 3. During AT2 receptor stimulation, LH differed from LL rats by significantly reduced renal blood flow (RBF), glomerular filtration rate and pressure diuresis and natriuresis. The addition of PD123319 did not change total RBF, whereas it did increase pressure diuresis and natriuresis in both strains. However, the effects of PD123319 were less marked in LH rats than in LL rats. 4. These findings confirm that, under the present experimental conditions, AT2 receptors are antinatriuretic and are not of greater functional importance in hypertensive animals of the Lyon strain.
Clinical and Experimental Pharmacology and Physiology 30(5-6):413-8. · 1.85 Impact Factor
