Inhibition of Platelet Activation in Stroke-Prone Spontaneously Hypertensive Rats: Comparison of Losartan, Candesartan, and Valsartan

Am, Jiménez; Montón, Mercedes; Garcı́a, R.; Núñez, Antonio; Gómez, Juan; Rico, Luís; García-Colis, Elena; Ls, de Miguel; Mm, Arriero; Cabestrero, Fernando; Farré, Jerónimo; Casado, Santos; López‐Farré, Antonio

doi:10.1097/00005344-200104000-00007

Cited by 23 publications

(11 citation statements)

References 28 publications

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“…This was not confirmed in the present study, because the reduction in BP by AT 1 R blockade with losartan administered was not altered by a concomitant treatment with C21 in the present study. However, it should be noted that the dose of losartan was not maximal, because a greater decrease in BP (45-100 mm Hg) has been observed with higher doses in SHRsp, 26,27 and the rats were still hypertensive at the end of the experiment. Thus, there was not complete prevention of genetic hypertension.…”

Section: Discussionmentioning

confidence: 93%

Angiotensin Type 2 Receptor Agonist Compound 21 Reduces Vascular Injury and Myocardial Fibrosis in Stroke-Prone Spontaneously Hypertensive Rats

et al. 2012

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Abstract-Angiotensin type 2 receptor-mediated effects of angiotensin II appear to counteract many of the effects mediated via the angiotensin type 1 receptor. Compound 21 (C21), a selective angiotensin type 2 receptor agonist, has demonstrated beneficial effects on cardiac function after myocardial infarction in rodents. We hypothesized that C21 alone or in combination with an angiotensin type 1 receptor antagonist would blunt the development of hypertension and vascular damage in stroke-prone spontaneously hypertensive rats. Six-week-old stroke-prone spontaneously hypertensive rats received C21 (1 mg/kg per day), the angiotensin type 1 receptor antagonist losartan (10 mg/kg per day), C21 plus losartan, or vehicle PO for 6 weeks. Systolic blood pressure was lower in losartan and C21-losartan combination groups (PϽ0.001). Endotheliumdependent relaxation was enhanced (PϽ0.001) in the C21-losartan combination group at lower acetylcholine concentrations. C21 or C21-losartan combination reduced vascular stiffness, aortic medial and myocardial interstitial collagen content, and aortic fibronectin (PϽ0.05). C21 and losartan decreased the expression of 2 genes associated with cardiac hypertrophy, myosin heavy chain-␤ (myh7) by 30 to 50%, and ␣-skeletal muscle actin by 30% to 35% (PϽ0.05). C21-losartan combination caused an additional 40% reduction in myh7 compared with C21 (PϽ0.01). Aortic superoxide generation was reduced equally by the 3 treatments (PϽ0.001). Monocyte/macrophage infiltration in the aorta and kidney (PϽ0.001) and T-lymphocyte infiltration in the renal cortex (PϽ0.05) were lowered similarly by the 3 treatments. These data suggest that C21 alone or in combination with losartan may improve endothelial function and vascular composition and mechanics by reducing oxidative stress, collagen content, fibronectin, and inflammatory cell infiltration in stroke-prone spontaneously hypertensive rats. hronic hypertension results in vascular remodeling and inflammation, endothelial dysfunction, and accelerated development of atherosclerosis. 1,2 Of the many factors implicated in hypertensive vascular remodeling, angiotensin (Ang) II, the main effector hormone of the renin-Ang-aldosterone system, seems to be one of the most important. 3 Ang II exerts its effects by binding to 2 membrane-bound, G proteincoupled receptors, Ang II type 1 (AT 1 R) and type 2 receptors (AT 2 R). Most well-known effects of Ang II that contribute to unfavorable vascular remodeling and consequent hypertensive complications are mediated via AT 1 R, whereas those exerted via AT 2 R are less well known and appear to counteract many of its effects exerted via AT 1 R. 4,5 AT 2 Rmediated effects seem to exert vasculoprotective actions via vasodilation, NO production, 6 -8 and apoptosis and inhibition of growth and fibrosis. 5,9,10 Beneficial vascular effects of AT 1 R blockade have been at least partially attributed to unopposed AT 2 R stimulation. 7,11,12

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Section: Discussionmentioning

confidence: 93%

Angiotensin Type 2 Receptor Agonist Compound 21 Reduces Vascular Injury and Myocardial Fibrosis in Stroke-Prone Spontaneously Hypertensive Rats

et al. 2012

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“…[36][37][38][39][40] 28,30,33 and especially in elderly patients with isolated systolic hypertension. 29,31 Other mechanisms by which ARBs could reduce the incidence of new or recurrent stroke include the beneficial effects of some ARBs on blood glucose control by increasing insulin sensitivity, 49,50 their platelet antiaggregating effects, [51][52][53][54] their hypouricemic effects 66,67 and their atrial antifibrillatory effects. [69][70][71] All these actions of ARBs could add to their AII-mediated stroke protective effects.…”

Section: Discussionmentioning

confidence: 99%

“…Treatment of platelets from these animals with losartan decreased their adhesiveness to surfaces, whereas treatment with candesartan or valsartan had no significant effect on platelet adhesiveness. 52 These studies indicated that the action of losartan on platelet adhesion was not mediated through the AT 1 receptor because neither the losartan's metabolite EXP 3174, nor the other ARBs, candesartan and valsartan were able to prevent platelet adhesion or significantly suppress the expression of P-selectin on platelet surface. The increased expression of P-selectin on the platelet surface of SHR-SP has been blamed for the increased thrombogenicity and the higher incidence of strokes seen in these animals.…”

Section: Aii-mediated Effects Of Arbsmentioning

confidence: 99%

Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: clinical and experimental evidence

Chrysant

2005

J Hum Hypertens

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Stroke is a major cause of death and disability and its incidence increases linearly with age and the level of systolic and diastolic blood pressure. Stroke, besides being a cause of long-term disability for the affected person, also imposes a significant burden on society and healthcare costs. Although good blood pressure control is very critical for stroke prevention, angiotensin receptor blockers (ARBs) may be superior to angiotensin-converting enzyme inhibitors (ACEIs) for the same degree of blood pressure control. This hypothesis has clinical and experimental support. ARBs prevent stroke incidence by blocking the angiotensin II (AII), AT 1 receptors preventing brain ischaemia and allowing AII to stimulate the unoccupied AT 2 receptors, which improve brain ischaemia. ACEIs, by reducing AII generation, are less effective in preventing stroke. This hypothesis provides evidence that AII plays an important role in the prevention of stroke. Certain ARBs like losartan, and telmisartan, irbesartan and candesartan possess additional properties which may play a role in stroke prevention, which is independent of AII. These include antiplatelet aggregating, hypouricemic, antidiabetic and atrial antifibrillatory effects. However, the most critical factor in stroke prevention is good blood pressure control irrespective of drug used.

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“…S2-S4). The most likely cause was that hypertension activated platelets and thrombus formation (28,29) and led to intravasal thrombi.…”

Section: Aii Induces Cardiac Hypertrophy In the Absence And Presence Ofmentioning

confidence: 99%

Roles of cGMP-dependent protein kinase I (cGKI) and PDE5 in the regulation of Ang II-induced cardiac hypertrophy and fibrosis

Patrucco

Domes

Sbroggiò

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Conflicting results have been reported for the roles of cGMP and cGMP-dependent protein kinase I (cGKI) in various pathological conditions leading to cardiac hypertrophy and fibrosis. A cardioprotective effect of cGMP/cGKI has been reported in whole animals and isolated cardiomyocytes, but recent evidence from a mouse model expressing cGKIβ only in smooth muscle (βRM) but not in cardiomyocytes, endothelial cells, or fibroblasts has forced a reevaluation of the requirement for cGKI activity in the cardiomyocyte antihypertrophic effects of cGMP. In particular, βRM mice developed the same hypertrophy as WT controls when subjected to thoracic aortic constriction or isoproterenol infusion. Here, we challenged βRM and WT (Ctr) littermate control mice with angiotensin II (AII) infusion (7 d; 2 mg·kg −1 ·d −1 ) to induce hypertrophy. Both genotypes developed cardiac hypertrophy, which was more pronounced in Ctr animals. Cardiomyocyte size and interstitial fibrosis were increased equally in both genotypes. Addition of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, in the drinking water had a small effect in reducing myocyte hypertrophy in WT mice and no effect in βRM mice. However, sildenafil substantially blocked the increase in collagen I, fibronectin 1, TGFβ, and CTGF mRNA in Ctr but not in βRM hearts. These data indicate that, for the initial phase of AII-induced cardiac hypertrophy, lack of cardiomyocyte cGKI activity does not worsen hypertrophic growth. However, expression of cGKI in one or more cell types other than smooth muscle is necessary to allow the antifibrotic effect of sildenafil.PKGI | PDE | cardiac failure | hypertension | NO/cyclic GMP system

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Inhibition of Platelet Activation in Stroke-Prone Spontaneously Hypertensive Rats: Comparison of Losartan, Candesartan, and Valsartan

Cited by 23 publications

References 28 publications

Angiotensin Type 2 Receptor Agonist Compound 21 Reduces Vascular Injury and Myocardial Fibrosis in Stroke-Prone Spontaneously Hypertensive Rats

Angiotensin Type 2 Receptor Agonist Compound 21 Reduces Vascular Injury and Myocardial Fibrosis in Stroke-Prone Spontaneously Hypertensive Rats

Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: clinical and experimental evidence

Roles of cGMP-dependent protein kinase I (cGKI) and PDE5 in the regulation of Ang II-induced cardiac hypertrophy and fibrosis

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