Defective G protein activation of the cAMP pathway in rat kidney during genetic hypertension.

Chatziantoniou, Christos; Ruan, Xiaoping; Arendshorst, William J.

doi:10.1073/pnas.92.7.2924

Cited by 64 publications

(52 citation statements)

References 25 publications

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“…The enhanced renal sensitivity to Ang II in SHR is in part due to defects in the G s (Chatziantoniou et al, 1995) and G i (Jackson, 1994;Gao et al, 2003) signal transduction pathways but apparently is independent of changes in the number of angiotensin receptors (Gao et al, 2003). The findings of the present study strongly suggest that enhanced renal sensitivity to Ang II in SHR is also independent of renal degradation of Ang II.…”

Section: Discussionsupporting

confidence: 66%

Renal Extraction of Angiotensin II

Jackson

Herzer²

2003

J Pharmacol Exp Ther

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Angiotensin II regulates many aspects of renal function and thereby influences long-term blood pressure. The effects of angiotensin II on the kidney have been exhaustively studied; however, the converse (i.e., effects of the kidney on angiotensin II) has received little attention. Accordingly, the focus of this study was to determine whether renal degradation of angiotensin II is regulated by chronic levels of angiotensin II or long-term levels of blood pressure. Twenty hypertensive rats and 22 normotensive rats were treated for 1 week with either vehicle, angiotensin II (50 ng/kg/min, subcutaneously) or captopril (100 mg/kg/day, orally). Right kidney vascular resistance was measured during infusions of angiotensin II into the left renal artery or vena cava at the level of left renal vein. Dose-response data were curve-fitted, and the extraction of angiotensin II by the left kidney was calculated by comparing the doses of angiotensin II required to elicit equal increases in right renal vascular resistance during intravenous versus left intrarenal artery infusions. Renal extraction of angiotensin II was high (mean, 81%) and demonstrated little animal-to-animal variation (coefficient of variation, 23%; standard deviation, 19%). Renal extraction of angiotensin II was independent of hypertension (P ϭ 0.257) or previous chronic exposure to angiotensin II or captopril (P ϭ 0.270), and there was no interaction between hypertension and chronic exposure to angiotensin II or captopril (P ϭ 0.950). We conclude that renal degradation of angiotensin II is constitutively high, is unaffected by chronic levels of arterial blood pressure, and is independent of long-term changes in levels of angiotensin II.

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Section: Discussionsupporting

confidence: 66%

Renal Extraction of Angiotensin II

Jackson

Herzer²

2003

J Pharmacol Exp Ther

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“…However, fenoldopam has been reported to fail to vasodilate the kidney of some patients with essential hypertension (43). The ability of fenoldopam to counteract the renal vasoconstrictor effect of exogenous angiotensin II and inhibit tubuloglomerular feedback is also impaired in the SHR (44,45). It is possible that differences in published reports may be related to differences in classes of hypertension being studied (salt-sensitive vs. saltresistant) or different experimental conditions (basal tone vs. basal, ANOVA on ranks, Dunnet's test; ϩ, P Ͻ 0.05 vs. basal, t test; #, P Ͻ 0.05 GRK4␥ A142V vs. WT (wild-type).…”

Section: Resultsmentioning

confidence: 99%

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

Felder

Sanada

et al. 2002

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

250

419

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Essential hypertension has a heritability as high as 30 -50%, but its genetic cause(s) has not been determined despite intensive investigation. The renal dopaminergic system exerts a pivotal role in maintaining fluid and electrolyte balance and participates in the pathogenesis of genetic hypertension. In genetic hypertension, the ability of dopamine and D1-like agonists to increase urinary sodium excretion is impaired. A defective coupling between the D1 dopamine receptor and the G protein͞effector enzyme complex in the proximal tubule of the kidney is the cause of the impaired renal dopaminergic action in genetic rodent and human essential hypertension. We now report that, in human essential hypertension, single nucleotide polymorphisms of a G protein-coupled receptor kinase, GRK4␥, increase G protein-coupled receptor kinase (GRK) activity and cause the serine phosphorylation and uncoupling of the D1 receptor from its G protein͞effector enzyme complex in the renal proximal tubule and in transfected Chinese hamster ovary cells. Moreover, expressing GRK4␥A142V but not the wild-type gene in transgenic mice produces hypertension and impairs the diuretic and natriuretic but not the hypotensive effects of D1-like agonist stimulation. These findings provide a mechanism for the D1 receptor coupling defect in the kidney and may explain the inability of the kidney to properly excrete sodium in genetic hypertension.L ong-term regulation of blood pressure is vested in the organ responsible for the control of body fluid volume, the kidney (1, 2). Dopamine facilitates the antihypertensive function of the kidney because it is both vasodilatory and natriuretic (3). Dopamine (produced by renal proximal tubules) via D 1 -like receptors is responsible for over 50% of incremental sodium excretion when sodium intake is increased (3-6). The paracrine͞ autocrine dopaminergic regulation of sodium excretion is mediated by tubular but not by hemodynamic mechanisms (6). The ability of dopamine and D 1 -like agonists to decrease renal proximal tubular sodium reabsorption is impaired in genetic rodent hypertension and human essential hypertension (3,5,(7)(8)(9)(10)(11)(12)(13)(14)(15). Indeed, the aberrant D 1 -like receptor function in the kidney precedes and cosegregates with high blood pressure in spontaneously hypertensive rats. In addition, disruption of the D 1 receptor in mice produces hypertension (12, 13). The pivotal role of dopamine in the excretion of sodium after increased sodium intake has led to the hypothesis that an aberrant renal dopaminergic system is important in the pathogenesis of some forms of genetic hypertension (3,5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Several mechanisms potentially responsible for the failure of endogenous renal dopamine to engender a natriuretic effect in genetic hypertension have been investigated and ruled out, including decreased renal dopamine production and receptor expression, aberrant nephron segment distribution of dopamine receptors, defective effector enzymes (adenylyl cyclase or...

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“…Subsequent studies (4,14,31) have indicated that impaired coupling between membrane receptors and downstream signal transduction events also occurs in spontaneously hypertensive rats. The present study is the first to demonstrate that a high-salt diet alone can lead to impaired coupling between membrane receptors and downstream messenger systems.…”

Section: Effect Of High-salt Diet On Electrical and Mechanical Responmentioning

confidence: 99%

High-salt diet impairs vascular relaxation mechanisms in rat middle cerebral arteries

Lombard

Sylvester

Phillips

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

132

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. High-salt diet impairs vascular relaxation mechanisms in rat middle cerebral arteries. Am J Physiol Heart Circ Physiol 284: H1124-H1133, 2003. First published November 27, 2002 10.1152/ajpheart.00835. 2002-Male Sprague-Dawley rats were maintained on a low-salt (LS) diet (0.4% NaCl) or a high-salt (HS) diet (4% NaCl) for 3 days or 4 wk. PO2 reduction to 40-45 mmHg, the stable prostacyclin analog iloprost (10 pg/ml), and stimulatory G protein activation with cholera toxin (1 ng/ml) caused vascular smooth muscle (VSM) hyperpolarization, increased cAMP production, and dilation in cerebral arteries from rats on a LS diet. Arteries from rats on a HS diet exhibited VSM depolarization and constriction in response to hypoxia and iloprost, failed to dilate or hyperpolarize in response to cholera toxin, and cAMP production did not increase in response to hypoxia, iloprost, or cholera toxin. Low-dose angiotensin II infusion (5 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 iv) restored normal responses to reduced PO2 and iloprost in arteries from animals on a HS diet. These observations suggest that angiotensin II suppression with a HS diet leads to impaired relaxation of cerebral arteries in response to vasodilator stimuli acting at the cell membrane. salt intake; hypertension; angiotensin; hypoxia; vascular smooth muscle; endothelium PREVIOUS STUDIES (8,11,19) have demonstrated that both chronic (4-8 wk) volume expanded hypertension caused by reduced renal mass (RRM) with exposure to a high-salt diet and chronic exposure of normotensive rats to a high-salt diet lead to structural changes in arterioles, reductions in microvessel density, and an impaired relaxation of skeletal muscle resistance vessels in response to a variety of vasodilator stimuli, including reduced PO 2 , the stable prostacyclin analog iloprost, and acetylcholine. Subsequent studies demonstrated that alterations in microvessel structure, density, and reactivity in normotensive animals and RRM hypertensive rats on a high-salt diet develop quite rapidly. For example, Hansen-Smith et al. (15) demonstrated that microvascular rarefaction and profound ultrastructural alterations occur in arterioles of RRM hypertensive rats and normotensive animals after only 3 days on a high-salt diet. Other studies (10)(11)(12)38) have demonstrated that vasodilator responses to reduced PO 2 , acetylcholine, and iloprost are also impaired after short-term exposure to high-salt diet. The microvascular rarefaction and the reduced relaxation of resistance arteries to vasodilator stimuli in animals on a high-salt diet may be related to the angiotensin II (ANG II) suppression that occurs in response to elevated dietary salt intake because both the reduction of cremasteric microvessel density (16) and the impaired dilation of skeletal muscle resistance arteries in response to acetylcholine, iloprost, and reduced PO 2 in animals on a high-salt diet can be prevented by infusion of a low dose of ANG II (37,38).To date, the majority of studies investigating changes in vascular control mechanisms with a highsa...

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Defective G protein activation of the cAMP pathway in rat kidney during genetic hypertension.

Cited by 64 publications

References 25 publications

Renal Extraction of Angiotensin II

Renal Extraction of Angiotensin II

G protein-coupled receptor kinase 4 gene variants in human essential hypertension

High-salt diet impairs vascular relaxation mechanisms in rat middle cerebral arteries

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