Physiological Impact of a Synthetic Elastic Protein in Arterial Diseases Related to Alterations of Elastic Fibers: Effect on the Aorta of Elastin-Haploinsufficient Male and Female Mice.

Elastic fibers, made of elastin (90%) and fibrillin-rich microfibrils (10%), are the key extracellular components, which endow the arteries with elasticity. The alteration of elastic fibers leads to cardiovascular dysfunctions, as observed in elastin haploinsufficiency in mice (Eln+/-) or humans (supravalvular aortic stenosis or Williams-Beuren syndrome). In Eln+/+ and Eln+/- mice, we evaluated (arteriography, histology, qPCR, Western blots and cell cultures) the beneficial impact of treatment with a synthetic elastic protein (SEP), mimicking several domains of tropoelastin, the precursor of elastin, including hydrophobic elasticity-related domains and binding sites for elastin receptors. In the aorta or cultured aortic smooth muscle cells from these animals, SEP treatment induced a synthesis of elastin and fibrillin-1, a thickening of the aortic elastic lamellae, a decrease in wall stiffness and/or a strong trend toward a reduction in the elastic lamella disruptions in Eln+/- mice. SEP also modified collagen conformation and transcript expressions, enhanced the aorta constrictive response to phenylephrine in several animal groups, and, in female Eln+/- mice, it restored the normal vasodilatory response to acetylcholine. SEP should now be considered as a biomimetic molecule with an interesting potential for future treatments of elastin-deficient patients with altered arterial structure/function.

Dietary Supplementation with Silicon-Enriched Spirulina Improves Arterial Remodeling and Function in Hypertensive Rats.

Vascular aging is characterized by increase in arterial stiffness and remodeling of the arterial wall with a loss of elastic properties. Silicon is an essential trace element highly present in arteries. It is involved in the constitution and stabilization of elastin fibers. The nutritional supply and bioavailability of silicon are often inadequate. Spirulina (Sp), micro algae have recognized nutritional properties and are able to incorporate minerals in a bioavailable form. We evaluated the effects of nutritional supplementation with silicon-enriched spirulina (SpSi) on arterial system structure and function in hypertension. Experiments were performed on hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats supplemented with SpSi or Sp over a period of three months. Arterial pressure, vascular function and morphometric parameters of thoracic aorta were analyzed. SpSi supplementation lowered arterial pressure in SHR and minimized morphometric alterations induced by hypertension. Aortic wall thickness and elastic fibers fragmentation were partially reversed. Collagen and elastin levels were increased in association with extracellular matrix degradation decrease. Vascular reactivity was improved with better contractile and vasorelaxant responses to various agonists. No changes were observed in SHR supplemented with Sp. The beneficial effects of SpSi supplementation evidenced here, may be attributable to Si enrichment and offer interesting opportunities to prevent cardiovascular risks.

Durable improvement of renal function after perindopril withdrawal in Lyon hypertensive rats.

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 therapy­pretreated or triple therapy­pretreated groups (+50 mm Hg). The pressure­natriuresis 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.

Effect of perindopril on renal medullary hemodynamics in genetically hypertensive rats.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Acute pressure-natriuresis function shows early impairment in Lyon hypertensive rats.

OBJECTIVE: This study aimed to determine whether the alteration of the pressure natriuresis seen in Lyon genetically hypertensive (LH) rats occurs early, and the possible involvement in this alteration of the most important extra-renal factors that influence natriuresis. METHODS: In LH rats and their normotensive (LL) controls, acute pressure natriuresis was studied in denervated kidneys with or without controlling extra-renal influence; that is, adrenalectomy and an intravenous infusion of vasopressin, norepinephrine, hydrocortisone and aldosterone. RESULTS: With controlling the cited extra-renal influence, LH rats already exhibited, at 5 weeks of age, a slightly higher blood pressure (+9%) and a markedly reduced renal blood flow (-33%) compared with LL rats; their pressure-diuresis and pressure-natriuresis curves were significantly blunted. Between 16 and 50 weeks of age, although BP levels did not change, renal blood flow and glomerular filtration rate declined in LH rats while their pressure-diuresis and pressure-natriuresis curves continued to shift to higher pressures. When studied without controlling extra-renal influence, the values of pressure diuresis and natriuresis were significantly higher than in controlled conditions both in LH and LL rats. However, in 16-week-old rats, the LH/LL ratios for sodium and water excretion remained close under the two experimental conditions. CONCLUSIONS: The pressure-natriuresis function in LH rat shows early impairment and aggravates with age. This alteration is observed with, as well as without, controlling the influence of the main extra-renal factors that affect natriuresis.

Persistent effects on blood pressure and renal function of perindopril alone or combined with losartan in Lyon hypertensive rats.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Lyon genetically hypertensive rats: an animal model of "low renin hypertension".

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.