Prenatal and postnatal hydralazine treatment does not prevent renal vessel wall thickening in SHR despite the absence of hypertension.

Smeda, John S.; Lee, R. M. K. W.; Forrest, James B.

doi:10.1161/01.res.63.3.534

Cited by 60 publications

(36 citation statements)

References 11 publications

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“…Also, in prehypertensive young SHR, there is increased reactivity of the renal vasculature to vasoconstrictors and decreased medullary blood flow, supporting a role in the development of HTN (139,180). Furthermore, in SHR, preglomerular arterial wall hypertrophy is not reversed by antihypertensive treatment, which is not the case in other vascular beds (158). The presence of structural and functional changes in preglomerular and afferent arterioles before the development of HTN and the persistence of structural changes, despite normalization of BP, suggest that these renal vascular changes are not a mere consequence of elevated BP, but may be involved in the pathogenesis of HTN.…”

Section: Renal Vascular Dysfunction As a Cause Or Consequence Of Htnmentioning

confidence: 88%

Cellular mediators of renal vascular dysfunction in hypertension

Ponnuchamy¹,

Khalil²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Ponnuchamy B, Khalil RA. Cellular mediators of renal vascular dysfunction in hypertension. Am J Physiol Regul Integr Comp Physiol 296: R1001-R1018, 2009. First published February 18, 2009 doi:10.1152/ajpregu.90960.2008.-The renal vasculature plays a major role in the regulation of renal blood flow and the ability of the kidney to control the plasma volume and blood pressure. Renal vascular dysfunction is associated with renal vasoconstriction, decreased renal blood flow, and consequent increase in plasma volume and has been demonstrated in several forms of hypertension (HTN), including genetic and salt-sensitive HTN. Several predisposing factors and cellular mediators have been implicated, but the relationship between their actions on the renal vasculature and the consequent effects on renal tubular function in the setting of HTN is not clearly defined. Gene mutations/ defects in an ion channel, a membrane ion transporter, and/or a regulatory enzyme in the nephron and renal vasculature may be a primary cause of renal vascular dysfunction. Environmental risk factors, such as high dietary salt intake, vascular inflammation, and oxidative stress further promote renal vascular dysfunction. Renal endothelial cell dysfunction is manifested as a decrease in the release of vasodilatory mediators, such as nitric oxide, prostacyclin, and hyperpolarizing factors, and/or an increase in vasoconstrictive mediators, such as endothelin, angiotensin II, and thromboxane A 2. Also, an increase in the amount/activity of intracellular Ca 2ϩ concentration, protein kinase C, Rho kinase, and mitogenactivated protein kinase in vascular smooth muscle promotes renal vasoconstriction. Matrix metalloproteinases and their inhibitors could also modify the composition of the extracellular matrix and lead to renal vascular remodeling. Synergistic interactions between the genetic and environmental risk factors on the cellular mediators of renal vascular dysfunction cause persistent renal vasoconstriction, increased renal vascular resistance, and decreased renal blood flow, and, consequently, lead to a disturbance in the renal control mechanisms of water and electrolyte balance, increased plasma volume, and HTN. Targeting the underlying genetic defects, environmental risk factors, and the aberrant renal vascular mediators involved should provide complementary strategies in the management of HTN. blood pressure; dietary salt; oxidative stress; cytokines; kidney; endothelium; vascular smooth muscle; extracellular matrix; matrix metalloproteinases THE ROLE OF THE KIDNEY IN the regulation of sodium and water balance and blood pressure (BP) is well recognized (53,55,128). A decrease in plasma volume and renal blood flow (RBF) stimulates renin release from the juxtaglomerular cells (JGCs) and activates the renin-angiotensin system (RAS). Renin transforms angiotensinogen to angiotensin I (ANG I), and angiotensin-converting enzyme (ACE) transforms ANG I to ANG II. ANG II stimulates the adrenal cortex to release aldosterone (Aldo), which acts on the rena...

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Section: Renal Vascular Dysfunction As a Cause Or Consequence Of Htnmentioning

confidence: 88%

Cellular mediators of renal vascular dysfunction in hypertension

Ponnuchamy¹,

Khalil²

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…36 - 37 In SHR, hydralazine was not able to prevent the development of mesenteric or renal artery hypertrophy despite a significant decrease in blood pressure. 37 - 38 However, Owens 34 showed that in the aorta the efficacy of hydralazine and captopril in preventing the development of medial hypertrophy was the same as their efficacy in lowering blood pressure. These discrepancies are consistent with the observation that the aorta, a rather elastic artery, is mainly sensitive to blood pressure changes, 2 whereas in peripheral arteries, which are rather muscular, hypertrophy may be modulated mainly by nonhemodynamic factors 37 -38 such as autonomic nervous system activity.…”

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confidence: 99%

Angiotensin converting enzyme inhibition prevents the increase in aortic collagen in rats.

et al. 1994

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Four groups of 4-week-old spontaneously hypertensive rats were treated during 4 months with the angiotensin converting enzyme inhibitor quinapril at 1 mg/kg per day (Ql) or 10 mg/kg per day (Q10), hydralazine at 15 mg/kg per day (H), or placebo (P). In the first set of experiments, blood pressure was measured in conscious rats, and plasma and aortic angiotensin converting enzyme activities were evaluated. In the second set of experiments, histomorphometric parameters of the thoracic aorta were evaluated. Mean blood pressure was lower in the Q10 and H groups (136±16 and 149±11 mm Hg) compared with the P group (190±23 mm Hg) (P<.01). The Ql group showed mean blood pressure values (171 ±15 mm Hg) lower than the P group (P<.05) but significantly higher than the Q10 and H groups (P<.01 and P<.05, respectively). Aortic medial cross-sectional area was significantly lower in the H and Q10 groups (455 ±61 and 487±57 x 10 3 jun 2 ) than in the P group (636±72 /mm of aorta). Aortic angiotensin converting enzyme activity was inhibited by approximately 60% in both groups treated with quinapril, whereas plasma angkrtension converting enzyme activity was reduced only in the Q10 rats. These results show that, whereas both hydralazine and quinapril prevented the development of aortic hypertrophy in a pressure-dependent manner, the prevention of the increase in aortic collagen was observed only after quinapril treatment. This latter effect of angiotensin converting enzyme inhibition was not related to the blood pressure reduction but was associated with the reduction of aortic and not plasma converting enzyme.

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“…In addition, the amiRNA interference had no effect on improving the remodeling of the main renal artery, which is supported by the findings that anti-hypertension treatment in SHR did not prevent renal vessel wall thickening but reversed the hypertrophy of other arterial vessel walls. 22 On the other hand, we found that the blood pressure returned to the higher level but the modeling partially reverted 6 weeks after viral injection.…”

Section: Discussionmentioning

confidence: 62%

Artificial microRNA interference targeting AT1a receptors in paraventricular nucleus attenuates hypertension in rats

Zhang

Shi

et al. 2011

Gene Ther

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Excessive sympathetic activity has a crucial role in the initiation and progression of chronic structural alterations in the heart and vessels associated with hypertension. Angiotensin II type 1a receptors (AT 1a R) in paraventricular nucleus (PVN) are involved in sympathetic overdrive and hypertension. The present study was designed to investigate the cardiovascular beneficial effects of the AT 1a R gene silence in the PVN in hypertension. The PVN microinjection of recombinant adenoviral vectors expressing either artificial microRNA (amiRNA) targeting AT 1a receptors (Ad-miR-AT 1a ) or control microRNA (Ad-miR-Con) were carried out in spontaneously hypertensive rats (SHR) and normotensive Wistar rats. The vectors were labels with green fluorescent protein (GFP). The successful amiRNA interference was confirmed by the AT 1 receptors reduction and the GFP expression in the PVN. Significant depressor effects were observed from day 5 to day 20 after Ad-miR-AT 1a treatment in SHR. Ad-miR-AT 1a treatment decreased the ratio of left ventricular weight to body weight, cross-sectional areas of myocytes, myocardial fibrosis, media thickness, and the media/lumen ratio of the aorta and the mesenteric artery in SHR. The amiRNA interference reduced the basal sympathetic activity, cardiac sympathetic afferent reflex, plasma norepinephrine and plasma angiotensin II in SHR. These results indicate that amiRNA interference targeting AT 1a R in the PVN decreases arterial blood pressure, blunts sympathetic activity and improves myocardial and vascular remodeling in SHR.Gene Therapy ( Keywords: RNA interference; AT 1 receptors; hypertension; sympathetic activity; myocardial fibrosis; vascular remodeling INTRODUCTION As a worldwide challenge, hypertension is a powerful independent risk factor for the development of cerebrovascular disease, myocardial infarction, heart failure and peripheral artery disease. Sympathetic overdrive has a key role in the progression of hypertension and related pathological changes. 1,2 Sympathectomy surgery in spontaneously hypertensive rats (SHR) attenuates cardiac fibrosis and hypertension. 3 Central sympathetic deactivation has been considered as an important strategy for arresting hypertension and regressing-related cardiac structural alterations. 4,5 Paraventricular nucleus (PVN) is critical in the integration of sympathetic outflow and cardiovascular activity via its projections to rostral ventrolateral medulla and intermediolateral column of spinal cord. 6 Inhibiting the PVN dramatically reduces sympathetic vasomotor tone, 7 whereas activating the PVN increases sympathetic outflow in SHR. 8 Bilateral electrolytic lesions of the PVN attenuate the sympathetic activity and the development of hypertension in SHR. 9,10 These results indicate the importance of the PVN in the development and progression of hypertension in SHR.It has been found that the angiotensin II type 1 receptors (AT 1 R) in the PVN are increased in SHR 11 and renovascular hypertensive rats. 12 Our recent studies have shown that angio...

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Prenatal and postnatal hydralazine treatment does not prevent renal vessel wall thickening in SHR despite the absence of hypertension.

Cited by 60 publications

References 11 publications

Cellular mediators of renal vascular dysfunction in hypertension

Cellular mediators of renal vascular dysfunction in hypertension

Angiotensin converting enzyme inhibition prevents the increase in aortic collagen in rats.

Artificial microRNA interference targeting AT1a receptors in paraventricular nucleus attenuates hypertension in rats

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