Effects of Valsartan on Mechanical Properties of the Carotid Artery in Spontaneously Hypertensive Rats Under High-Salt Diet

Abstract

Abstract-The aim of this investigation was to evaluate the influence of a high-salt diet (HSD) on the effects of valsartan, an angiotensin II type 1 (AT 1 ) receptor antagonist, on carotid arterial stiffness and structure in spontaneous hypertensive rats (SHR). Carotid arterial stiffness was studied in SHR receiving a HSD or a normal-salt diet (NSD) from the 10th to 20th week of age. Within each of the 2 groups, the animals received treatment with either placebo or valsartan (30 mg · kg Ϫ1 · d Ϫ1 ) administered on the 4th to 20th week of age. Arterial pressure, wall stress, incremental elastic modulus (Einc), medial cross-sectional area, and EIIIA fibronectin isoform were significantly increased in placebo-HSD rats compared with placebo-NSD rats with no change in the ratio of collagen to elastin. Valsartan reduced mean arterial pressure in both NSD and HSD rats but reduced pulse pressure only in NSD rats. In NSD rats, valsartan reduced Einc and medial cross-sectional area. In HSD, valsartan increased Einc and did not modify medial cross-sectional area and fibronectin. In valsartan-treated rats, the ratio of collagen to elastin was greater in HSD than in NSD rats. In conclusion, the effects of AT 1 blockade are greatly influenced by salt intake in SHR. Despite a reduction in mean arterial pressure in HSD rats, AT 1 blockade was not able to prevent the effects of a HSD on pulse pressure, carotid artery stiffness, and hypertrophy. Key Words: salt Ⅲ angiotensin II Ⅲ AT 1 blockade Ⅲ large artery stiffness Ⅲ carotid artery P revious reports have shown that plasma renin-angiotensin activity is reduced in rats receiving a high-salt diet (HSD). 1-4 However, a long-term HSD in salt-sensitive animals-Dahl salt-sensitive rats, 5 stroke-prone hypertensive rats, 6 -8 or ANP knockout mice 9 -is known to stimulate plasma renin activity. These observations suggest that the effects observed during perturbation of the renin-angiotensin aldosterone system by a high sodium intake may depend on the animal model used. Recently, Wang and Du 10 observed an increased expression of angiotensin II type 1 (AT 1 ) receptor mRNA in arterial preparations derived from Wistar and Sprague-Dawley rats maintained on a HSD. In contrast, when Dahl rats were treated with a HSD, decreases in aortic mRNA and AT 1 receptor density were observed. 5 Together, these results suggested that 1 modification associated with high sodium intake may be at the level of the AT 1 receptor. Interestingly, in spontaneously hypertensive rats (SHR) treated with a HSD, an enhanced functional response to angiotensin II and AT 1 receptor antagonists was demonstrated, suggesting that sodium modified AT 1 activity in SHR. 11,12 Although AT 1 receptor antagonists have been shown to reduce mortality in salt-sensitive animal models (Dahl rats or stroke-prone rats), 7,[13][14][15] there is little evidence available that AT 1 receptor antagonists continually block the elevated blood pressure and arterial abnormalities observed in SHR during high sodium intake.The aim of this inves...

AT1receptor antagonism attenuates target organ effects of salt excess in SHRs without affecting pressure

“…The arterial stiffening associated with high dietary salt intake was not prevented by RAS blockade, thereby confirming a previous report (22) on the vascular effects of valsartan. These findings support the concept that dietary salt excess participates in the pathogenesis of reduced arterial distensibility and suggest that different mechanisms may operate in mediating the adverse effects of salt excess on conduit as well as resistance vessels.…”

Increased Carotid Wall Elastic Modulus and Fibronectin in Aldosterone-Salt–Treated Rats

“…We have previously shown that SHR receiving a sodium loading developed a higher level of wall stress with no upward shift of the Einc-wall stress curve. 14 In addition, administration of a high-salt diet alone for 4 weeks in uninephrectomized SD rats did not produced any significant increase in wall stress nor Einc (unpublished data). These findings indicate that in both normotensive rats and SHR, a high-salt diet does not modify the mechanical behavior of the arterial wall.…”

“…Previous reports have shown that high level of mechanical stress, 15,16 stimulation of the renin angiotensin system, 17,18 as well as high sodium intake 14,19 may stimulate Fn synthesis. Because in these studies the level of wall stress was high, it is difficult to distinguish its role from that of sodium or renin angiotensin system.…”

Sodium Intake and Vascular Stiffness in Hypertension

“…39 In vivo arguments supporting cause-and-effect relationships between integrins and Fn and their impact on arterial stiffness were also obtained from studies on spontaneously hypertensive rats fed different levels of dietary sodium. 38 On a normal-sodium diet, AngII inhibition reduced mean BP, aortic Fn, and ␣ 5 ␤ 1 integrin, together with increased isobaric vascular distensibility. Under AngII blockade and a high-salt diet, mean BP was lowered significantly, but arterial distensibility and aortic Fn remained elevated and unmodified during the experiment.…”

“…1 ECM attachment molecules interact with VSM cells, VSM cells and glycosaminoglycans, or various collagen fibers (collagen cross-links). 1,37 Because integrins transmit insideout and outside-in signals capable of modulating changes of vascular responses, Lacolley and colleagues [37][38][39] showed that adhesion molecules such as fibronectin (Fn) and its ␣ 5 ␤ 1 integrin receptor may contribute greatly to this modulation of wall stiffness. Results of studies conducted on young and old spontaneously hypertensive rats, and using aortic Fn and integrin immunolabel, suggested that more attachment sites between VSM cells and the ECM might be responsible for enhanced arterial rigidity.…”