Human Renovascular Hypertension Research Articles

Increased cellular senescence in the murine and human stenotic kidney: Effect of mesenchymal stem cells.

Cell stress may give rise to insuperable growth arrest, which is defined as cellular senescence. Stenotic kidney (STK) ischemia and injury induced by renal artery stenosis (RAS) may be associated with cellular senescence. Mesenchymal stem cells (MSCs) decrease some forms of STK injury, but their ability to reverse senescence in RAS remains unknown. We hypothesized that RAS evokes STK senescence, which would be ameliorated by MSCs. Mice were studied after 4 weeks of RAS, RAS treated with adipose tissue-derived MSCs 2 weeks earlier, or sham. STK senescence-associated β-galactosidase (SA-β-Gal) activity was measured. Protein and gene expression was used to assess senescence and the senescence-associated secretory phenotype (SASP), and staining for renal fibrosis, inflammation, and capillary density. In addition, senescence was assessed as p16+ and p21+ urinary exosomes in patients with renovascular hypertension (RVH) without or 3 months after autologous adipose tissue-derived MSC delivery, and in healthy volunteers (HV). In RAS mice, STK SA-β-Gal activity increased, and senescence and SASP marker expression was markedly elevated. MSCs improved renal function, fibrosis, inflammation, and capillary density, and attenuated SA-β-Gal activity, but most senescence and SASP levels remained unchanged. Congruently, in human RVH, p21+ urinary exosomes were elevated compared to HV, and only slightly improved by MSC, whereas p16+ exosomes remained unchanged. Therefore, RAS triggers renal senescence in both mice and human subjects. MSCs decrease renal injury, but only partly mitigate renal senescence. These observations support exploration of targeted senolytic therapy in RAS.

Fenofibrate Attenuates Hypertension in Goldblatt Hypertensive Rats: Role of 20-Hydroxyeicosatetraenoic Acid in the Nonclipped Kidney

BackgroundThere is vast evidence that the renin-angiotensin system is not the sole determinant of blood pressure (BP) elevation in human renovascular hypertension or the relevant experimental models. This study tested the hypothesis that kidney deficiency of 20-hydroxyeicosatetraenoic acid (20-HETE), a product of cytochrome P450 (CYP)-dependent ω-hydroxylase pathway of arachidonic acid metabolism, is important in the pathophysiology of the maintenance phase of 2-kidney, 1-clip (2K1C) Goldblatt hypertension. Materials and MethodsIn 2K1C Goldblatt rats with established hypertension, angiotensin II, angiotensin 1-7, 20-HETE concentrations and gene expression of CYP4A1 enzyme (responsible for 20-HETE formation) of the nonclipped kidney were determined. We examined if 14 days׳ administration of fenofibrate, a lipid-lowering drug, would increase CYP4A1 gene expression and renal 20-HETE formation, and if increased 20-HETE concentrations in the nonclipped kidney would decrease BP (telemetric measurements). ResultsCYP4A1 gene expression, 20-HETE and angiotensin 1-7 concentrations were lower and angiotensin II levels were higher in the nonclipped kidney of 2K1C rats than in sham-operated rats. Fenofibrate increased CYP4A1 gene expression and 20-HETE concentration in the nonclipped kidney and significantly decreased BP in 2K1C rats but did not restore it to normotensive range. The treatment did not change BP in sham-operated rats. ConclusionsOur results suggest that alterations in the RAS and CYP-dependent ω-hydroxylase metabolites of arachidonic acid in the nonclipped kidneys are both important in the pathophysiology of the maintenance phase of 2K1C Goldblatt hypertension. Therefore, fenofibrate treatment effectively attenuated hypertension, probably via stimulation of 20-HETE formation in the nonclipped kidney.

Development of renal atrophy in murine 2 kidney 1 clip hypertension is strain independent

The murine 2-kidney 1-clip (2K1C) model has been used to identify mechanisms underlying chronic renal disease in human renovascular hypertension. Although this model recapitulates many of the features of human renovascular disease, strain specific variability in renal outcomes and animal-to-animal variation in the degree of arterial stenosis are well recognized limitations. In particular, the C57BL/6J strain is considered to be resistant to chronic renal damage in other models. Our objectives were to determine strain dependent variations in renal disease progression and to identify parameters that predict renal atrophy in murine 2K1C hypertension.We used a 0.20mm polytetrafluoroethylene cuff to establish RAS in 3 strains of mice C57BL/6J (N=321), C57BLKS/J (N=177) and129Sv (N=156). The kidneys and hearts were harvested for histopathologic analysis after 3days or after 1, 2, 4, 6, 7, 11 or 17weeks. We performed multivariate analysis to define associations between blood pressure, heart and kidney weights, ratio of stenotic kidney/contralateral kidney (STK/CLK) weight, percent atrophy (% atrophy) and plasma renin content.The STK of all 3 strains showed minimal histopathologic alterations after 3days, but later developed progressive interstitial fibrosis, tubular atrophy, and inflammation. The STK weight negatively correlated with maximum blood pressure and % atrophy, and positively correlated with STK/CLK ratio. RAS produces severe chronic renal injury in the STK of all murine strains studied, including C57BL/6J. Systolic blood pressure is negatively associated with STK weight, STK/CLK ratio and positively with atrophy and may be used to assess adequacy of vascular stenosis in this model.

Interlobular Arteries From 2-Kidney, 1-Clip Goldblatt Hypertensive Rats’ Exhibit-Impaired Vasodilator Response to Epoxyeicosatrienoic Acids

BackgroundSmall renal arteries have a significant role in the regulation of renal hemodynamics and blood pressure (BP). To study potential changes in the regulation of vascular function in hypertension, we examined renal vasodilatory responses of small arteries from nonclipped kidneys of the 2-kidney, 1-clip Goldblatt hypertensive rats to native epoxyeicosatrienoic acids (EETs) that are believed to be involved in the regulation of renal vascular function and BP. A total of 2 newly synthesized EET analogues were also examined. Materials and MethodsRenal interlobular arteries isolated from the nonclipped kidneys on day 28 after clipping were preconstricted with phenylephrine, pressurized and the effects of a 14,15-EET analogue, native 14,15‐EET and 11,12‐ether-EET‐8ZE, an analogue of 11,12-EET, on the vascular diameter were determined and compared to the responses of arteries from the kidneys of sham-operated rats. ResultsIn the arteries from nonclipped kidneys isolated in the maintenance phase of Goldblatt hypertension, the maximal vasodilatory response to 14,15-EET analogue was 30.1 ± 2.8% versus 49.8 ± 7.2% in sham-operated rats; the respective values for 11,12-ther-EET-8ZE were 31.4 ± 6.4% versus 80.4 ± 6%, and for native EETs they were 41.7 ± 6.6% versus 62.8 ± 4.4% (P ≤ 0.05 for each difference). ConclusionsWe propose that reduced vasodilatory action and decreased intrarenal bioavailability of EETs combined with intrarenal angiotensin II levels that are inappropriately high for hypertensive rats underlie functional derangements of the nonclipped kidneys of 2-kidney, 1-clip Goldblatt hypertensive rats. These derangements could play an important role in pathophysiology of sustained BP elevation observed in this animal model of human renovascular hypertension.

Orally active epoxyeicosatrienoic acid analog does not exhibit antihypertensive and reno- or cardioprotective actions in two-kidney, one-clip Goldblatt hypertensive rats

This study examined the effects of a novel orally active 14,15-epoxyeicosatrienoic acid analog (EET-A) on blood pressure (BP) and myocardial infarct size (IS) in two-kidney, one-clip (2K1C) Goldblatt hypertensive rats during sustained phase of hypertension. Between days 31 and 35 after clip placement the rats were treated with EET-A and BP was monitored by radiotelemetry; sham-operated normotensive rats were used as controls. Tissue concentrations of epoxyeicosatrienoic acids served as a marker of production of epoxygenase metabolites. The rats were subjected to acute myocardial ischemia/reperfusion (I/R) injury and IS was determined. We found that EET-A treatment did not lower BP in 2K1C rats and did not alter availability of biologically active epoxygenase metabolites in 2K1C or in sham-operated rats. The myocardial IS was significantly smaller in untreated 2K1C rats as compared with normotensive controls and EET-A reduced it in controls but not in 2K1C rats. Our findings suggest that during the phase of sustained hypertension 2K1C Goldblatt hypertensive rats exhibit increased cardiac tolerance to I/R injury as compared with normotensive controls, and that in this animal model of human renovascular hypertension short-term treatment with EET-A does not induce any antihypertensive and cardioprotective actions.

Abstract 54: Tissue Oxygenation Using Fractional Hypoxia Correlates Inversely With Blood Flow in Human Renovascular Disease (RVD) and Essential Hypertension (EH)

Determinants of Intra-renal oxygenation in human RVD are poorly understood. Blood oxygen level-dependent (BOLD) MRI measures deoxyhemoglobin (R2*) to determine cortical and medullary R2* which have focal variations and gradients. We hypothesized that tissue fractional hypoxia (% of axial kidney area with R2*>30s -1 ) would correlate better with tissue perfusion, renal blood flow (RBF), and O2 consumption than using regions of interest (ROI). METHODS: Inpatient studies were performed in EH (n=68 kidneys), and high-grade RVD (n=18 kidneys, 71±5.5% occlusion) before and 3 months after stents. All were treated with ACE/ARB Rx and thiazides during 150 mEq/d Na+ intake. BOLD MR images were obtained at 3T before and after furosemide (20mg IV), and axial images analyzed to estimate R2* levels above 30s -1 (fractional hypoxia) over the entire kidney section. Maximal R2* levels using regions of interest (ROIs) also were determined. Single-kidney cortical and medullary RBF (ml/min) perfusion (ml/min/cc) were determined by MDCT. Results: RBF was lower in kidneys with untreated RVD than EH (285.6±141 vs. 399±159 ml/min p<0.05), as was cortical perfusion (2.58±.63 vs. 3.50±1.05, p<.05 ). Cortical and medullary R2* did not differ, but fractional hypoxia was greater in RVD as compared to EH (18.3±12 vs. 11.5±8.5%, p<.05). Fractional hypoxia was inversely correlated with blood flow (R=-.29, p<.01) and perfusion (R=-.26, p<.01). R2* fell after furosemide (p<0.01) indicating a role for O2 consumption in determining tissue hypoxia. RBF and cortical perfusion increased after stenting (285±141 vs. 318±178 ml/min and 2.58±0.6 vs. 2.9±0.7ml/min/cc, p<0.05) respectively. Fractional hypoxia, but not cortical or medullary R2* based on ROI-methods, decreased in patients 3 months after renal revascularization (18.3 ±12 vs. 10.52%, p<0.05) Conclusions: These data demonstrate for the first time that fractional hypoxia in the kidney is directly related to chronically reduced blood flow and cortical perfusion in human RVD, whereas selective ROI-based measures identified only minor changes in peak R2* gradients between cortex and medulla. The reversibility of fractional hypoxia after stenting supports the use of this new method to identify critical renovascular lesions.

Genetic deficiency of Smad3 protects the kidneys from atrophy and interstitial fibrosis in 2K1C hypertension.

Although the two-kidney, one-clip (2K1C) model is widely used as a model of human renovascular hypertension, mechanisms leading to the development of fibrosis and atrophy in the cuffed kidney and compensatory hyperplasia in the contralateral kidney have not been defined. Based on the well-established role of the transforming growth factor (TGF)-β signaling pathway in renal fibrosis, we tested the hypothesis that abrogation of TGF-β/Smad3 signaling would prevent fibrosis in the cuffed kidney. Renal artery stenosis (RAS) was established in mice with a targeted disruption of exon 2 of the Smad3 gene (Smad3 KO) and wild-type (WT) controls by placement of a polytetrafluoroethylene cuff on the right renal artery. Serial pulse-wave Doppler ultrasound assessments verified that blood flow through the cuffed renal artery was decreased to a similar extent in Smad3 KO and WT mice. Two weeks after surgery, systolic blood pressure and plasma renin activity were significantly elevated in both the Smad3 KO and WT mice. The cuffed kidney of WT mice developed renal atrophy (50% reduction in weight after 6 wk, P < 0.0001), which was associated with the development of interstitial fibrosis, tubular atrophy, and interstitial inflammation. Remarkably, despite a similar reduction of renal blood flow, the cuffed kidney of the Smad3 KO mice showed minimal atrophy (9% reduction in weight, P = not significant), with no significant histopathological alterations (interstitial fibrosis, tubular atrophy, and interstitial inflammation). We conclude that abrogation of TGF-β/Smad3 signaling confers protection against the development of fibrosis and atrophy in RAS.

Is Renal Artery Stenting the Correct Treatmentof Renal Artery Stenosis?

The case favoring renal artery stenting for individuals with renal artery hypertension is largely circumstantial. At best, the clinical evidence presented in this discussion is derived primarily from nonrandomized cohort studies. It would certainly be easier to argue that medical therapy is preferred for such individuals because there are 3 published randomized clinical trials that concluded just that and none that support renal artery intervention. Nonetheless, there is considerable evidence to support the role for revascularization in general, and stenting specifically, as an important adjunctive therapy to medical therapy in the care of patients with renal artery stenosis (RAS). The argument has 3 principal components: observations about the impact on cardiovascular physiology, end-organ effects, and natural history. Response by Dworkin and Jamerson p 270 RAS is associated with and is an important cause of secondary hypertension. RAS causes endocrine activation with release of renin from renal juxtaglomerular cells. Renin catalyzes the breakdown of angiotensinogen to angiotensin I. Angiotensin I is transformed by angiotensin-converting enzyme into angiotensin II, and angiotensin II promotes the release of aldosterone from the adrenal cortex.1 Angiotensin II is a potent vasoconstrictor,2 substantially more potent than epinephrine, and is implicated in end-organ damage in the heart3 and kidney.4 RAS is suggested to cause 2 types of hypertension. With unilateral RAS and a normally perfused and normally functioning contralateral kidney, blood pressure elevation is referred to as “renin dependent” and is characterized by increased peripheral resistance.5,6 In this circumstance, renin and angiotensin levels remain elevated, but volume expansion is limited by natriuresis of the contralateral normally functioning kidney.6 Importantly, although renin levels are elevated, the value of peripheral or even renal vein renin values is limited by substantial overlap with patients having essential hypertension.7,8 When stenoses are bilateral or when the …

F 2-Isoprostane level is associated with the angiotensin II type 1 receptor -153A/G gene polymorphism

Recent studies have shown that F 2-isoprostane levels—a marker for lipid peroxidation—are increased in human renovascular hypertension but not in essential hypertension. Angiotensin II specifically stimulates F 2-isoprostane production through activation of the AT1 receptor. The objective was to determine whether there is a relationship between the level of oxidative stress evaluated by measuring urinary F 2-isoprostanes levels and polymorphisms of genes involved in the renine angiotensin aldosterone system (RAAS) regulation. The population studied included 100 subjects, 65 of whom were healthy normotensives; the other 35 were suffering from untreated, essential hypertension. The polymorphisms studied concern the genes encoding angiotensin I-converting enzyme (ACE/in16del/ins), angiotensin II receptor type I (AGTR1/A+39C[A+1166C] and AGTR1/A-153G), angiotensinogen (AGT/M235T), and aldosterone synthase (CYP11B2/T344C). Oxidative stress was evaluated by measuring urinary F 2-isoprostanes levels. The characteristics of the population were as follows: men/women = 46 / 56; age = 50 ± 10 years; BMI = 24 ± 3 kg/m 2; SBP = 131.7 ± 17.2 mm Hg; DBP = 84.6 ± 10.4 mm Hg. In univariate analysis, urinary F 2-isoprostane levels were significantly lower in the presence of the G allele of AGTR1/A-153G (56 ± 17 vs 76 ± 39 pmol/mmol creatinine; P < 0.001, and P < 0.01 after Bonferroni correction for 10 tests). In multivariate analysis, taking into account BP, age, gender, BMI, plasma glucose, and total cholesterol, the G allele of AGTR1/A-153G is linked independently to urinary F 2-isoprostanes level ( P < 0.01). Our data suggest that F 2-isoprostane level depends at least in part on the A-153G polymorphism of the angiotensin II AT1 receptor gene. The clinical and prognostic relevance of this polymorphism requires further investigation.

Role of the sympathetic nervous system in human renovascular hypertension

The findings in humans as to whether elevated sympathetic nerve activity contributes to renovascular hypertension have been less consistent compared with the results obtained in experimental models of renovascular hypertension. Collectively, there are several lines of evidence to support the view that sympathetic nerve activity is elevated in patients with renovascular hypertension. It is uncertain, however, whether this adrenergic overactivity is specific for renovascular hypertension per se, or the cause of severe hypertension with target organ damage. Central or peripheral stimulation of sympathetic nerve activity by angiotensin II, or stimulation of central sympathetic outflow via afferent renal nerves of ischemic kidneys, are possible mechanisms to explain the elevated sympathetic nerve activity in renovascular hypertension. Therapy that diminishes the activity of the sympathetic nervous system and the renin-angiotensin system seems rational and could perhaps also improve the poor prognosis for these patients.

Noninvasive evaluation of a novel swine model of renal artery stenosis.

Intrarenal hemodynamics and excretory function distal to renal artery stenosis are difficult to quantify noninvasively. In this study, a swine model of chronic unilateral renal artery stenosis, achieved by implantation of an intravascular device that leads to a gradual and progressive luminal area narrowing, was developed and evaluated. Bilateral cortical and medullary volumes, blood flows, and segmental tubular dynamics were assessed in the intact kidneys of seven pigs using electron-beam computerized tomography before and 1 mo after implantation of the device. Within 1 mo, a 66% angiographic stenosis was significantly correlated with a 25% increase in BP. The volume and blood flow were markedly lower in the stenotic compared with the contralateral kidney and cortex, while the medulla exhibited minimal changes. In the stenotic kidney, intratubular contrast content has decreased in all nephron segments, especially in the distal tubule, where it correlated with an increase in serum creatinine and stenosis severity. In the contralateral kidney, dilution of proximal tubular fluid correlated with the increase in BP, likely due to pressure-natriuresis. In conclusion, the swine model closely resembles human renovascular hypertension. In the stenotic kidney, the hemodynamic impairment of the cortex is dissociated from the relatively preserved renal medulla, and the earliest effect on excretory function is observed in the distal nephron, where the fall in the amount of fluid reaching that segment is directly proportional to the renal arterial compromise. Electron-beam computerized tomography shows promise to noninvasively quantify, follow-up, and study changes in concurrent, in vivo intrarenal hemodynamics and segmental tubular function in renovascular hypertension.

Efficacy and safety of losartan in human renovascular hypertension

Efficacy and safety of losartan in human renovascular hypertension

Sympathetic neural mechanisms in human hypertension

This review discusses the role of the sympathetic nervous system in the pathogenesis and maintenance of human hypertension. Three points are emphasized: first, there are mechanisms by which the sympathetic nervous system can contribute to the long-term regulation of vascular resistance and arterial pressure in addition to the moment-to-moment regulation of arterial pressure; second, the microneurographic method for direct intraneural recording of sympathetic nerve activity in humans has provided mounting evidence for increased sympathetic neural activity in human essential and renovascular hypertension; and third, there are both peripheral reflex and humoral mechanisms that may contribute to sympathetic overactivity in human hypertension.

Aspirin lowers blood pressure in patients with renovascular hypertension.

To clarify the role of renal prostanoid in hyperreninemia and high blood pressure in human renovascular hypertension, we measured prostaglandin E2 and renin activity in renal venous and abdominal aortic plasma before and after the intravenous administration of the cyclooxygenase inhibitor, aspirin DL-lysine. Subjects were six patients with unilateral renovascular hypertension and six with essential hypertension. In patients with renovascular hypertension, prostaglandin E2 concentration in renal venous plasma from the stenotic kidney was 9.25 +/- 1.48 pg/ml, which was significantly higher (p less than 0.01) than the concentration in the renal venous plasma from the normal kidney (4.97 +/- 1.02 pg/ml) or in the aortic plasma (2.59 +/- 0.15 pg/ml). Plasma renin activity was also higher in the renal vein of the stenotic kidney than in the other two sites. The stenotic side/normal side ratio of the renal venous prostaglandin E2 correlated significantly with a renin ratio greater than 1.5 (r = 0.8211, p less than 0.05). Intravenous injection of aspirin DL-lysine (18 mg/kg) 30 minutes later markedly suppressed prostaglandin E2 and renin levels at all sites and clearly lowered arterial blood pressure (mean: from 120 +/- 6 to 110 +/- 5 mm Hg, p less than 0.01). The reduction in blood pressure correlated significantly with the suppression of plasma renin activity in the aorta (p less than 0.05) and in the renal vein of the stenotic kidney (p less than 0.01). Conversely, in patients with essential hypertension, aspirin had little effect on renin levels and increased mean blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Successful revascularization of an occluded renal artery after prolonged anuria

Renal atherosclerosis and fibromuscular dysplasia are the most common causes of curable human renovascular hypertension and renal failure. Vascular reconstruction often preserves renal function, but renal failure is rarely reversed, especially after days of anuria. We report a case of a 23-year-old woman who as a child underwent a nephrectomy for congenital hydroureter and renal hypoplasia. She later experienced fibror muscular dysplasia of the remaining renal artery, which ultimately progressed to a complete occlusion and 31 days of total anuria. The patient was revascularized, and within 2 months renal function returned with a blood urea nitrogen and creatinine of 9.0 and 1.0 mg/dl, respectively. After a follow-up of 6 months the patient's blood pressure remained 12080 to 13080 mm Hg without administration of hypertension medication. In this report we emphasize that under selected circumstances a kidney can survive prolonged ischemia and that delayed revascularization may reestablish renal function.

Renovascular hypertension: Etiology and pathophysiology

Evidence from animal studies demonstrates that the renin-angiotensin (ANG II) system and sodium retention play major roles in experimental renovascular hypertension (RVH). Two basic models have been described. In the first, one-clip two-kidney Goldblatt hypertension, the ischemic kidney secretes renin, which leads to increased ANG II formation and hence elevation of blood pressure (BP). As BP rises, sodium excretion by the intact contralateral kidney increases (pressure natriuresis); therefore, there is no sodium retention. In the second, one-clip one-kidney Goldblatt hypertension, the contralateral kidney is removed. In this case the pressure natriuresis can no longer occur, and sodium retention occurs. The ensuing expansion of plasma volume inhibits renin secretion, so that in this model the renin level is normal or low. Following the clipping of the renal artery, renal blood flow and pressure are maintained distal to the stenosis by an ANG II-mediated vasoconstriction. This acts preferentially on the efferent glomerular arterioles, so that the ratio of preglomerular to postglomerular resistance is reduced, which helps to maintain glomerular filtration despite the reduced renal perfusion pressure. In the contralateral kidney the afferent arteriolar resistance is increased, probably as a direct result of exposure to the higher intrarenal arterial pressure. ANG II constricts the efferent arterioles in the same way as in the ischemic kidney, so that the ratio of preglomerular to postglomerular resistance is unchanged. When an angiotensin converting enzyme (ACE) inhibitor is given, the efferent arterioles vasodilate. In the ischemic kidney this may produce a reduction of glomerular filtration rate (GFR), which is not seen in the contralateral kidney. Unilateral RVH in humans corresponds closely to the animal model of one-clip two-kidney hypertension. Plasma renin activity is usually high, and converting enzyme inhibitors lower BP effectively. The increased renin is due exclusively to increased secretion of renin by the ischemic kidney, and is completely suppressed in the contralateral kidney. It is not clear whether bilateral RVH corresponds to the one-clip one-kidney model, but there is circumstantial evidence to suggest that both renin and volume factors may be involved. The majority of cases of human RVH are caused by atheroma, which is commonly bilateral, or by fibromuscular dysplasia. The former tends to be associated with atheroma elsewhere in the arterial tree, and often progresses to complete occlusion and renal failure. The latter occurs in younger patients, and almost never progresses to complete occlusion.

Changes of Plasma Noradrenaline Levels in the Renal and Systemic Circulation After Successful Percutaneous Transluminal Angioplasty in Renovascular Hypertension

The sympathetic nervous system involvement in the pathogenesis of human renovascular hypertension was studied in 10 hypertensive patients with unilateral renal artery stenosis, who underwent percutaneous transluminal angioplasty (PTA). Before PTA, systolic/diastolic BP readings were 185.3 +/- 7.8/123.2 +/- 5.1 mmHg, peripheral PRA values were 8.63 +/- 2.27 ngAl/ml/h, the ratio RVRR was 2.15 +/- 0.27, the ratio V1-IVC/IVC was 1.00 +/- 0.23 (V1 = PRA from the renal vein of the stenotic side, IVC = PRA from the inferior vena cava) and the ratio V2-IVC/IVC was 0.04 +/- 0.02 (V2 = PRA from the renal vein of the non-stenotic side); 30 min after successful PTA the respective values of the above measured parameters were: 144.2 +/- 6.7/98.2 +/- 3.1 mmHg (p less than 0.01), 8.13 +/- 2.21 ngAl/ml/h (p less than 0.005), 1.79 +/- 0.19 (p less than 0.01), 0.68 +/- 0.18 (p less than 0.001) and 0.06 +/- 0.02 (p less than 0.005). Peripheral plasma noradrenaline levels (plNA) were 0.694 +/- 0.058 ng/ml, plNA levels from the renal vein of the stenotic side were 0.962 +/- 0.108 ng/ml and plNA levels from the renal vein of the non-stenotic side were 0.759 +/- 0.092 ng/ml; 30 min after successful PTA the respective values were 0.518 +/- 0.055 ng/ml (p less than 0.01), 0.681 +/- 0.078 ng/ml (p less than 0.005) and 0.510 +/- 0.063 ng/ml (p less than 0.005). It is suggested that the reversal of chronic renal ischaemia by PTA induced statistically significant changes in the sympathetic nervous system activity, parallel to the changes of renin secretion.

Diagnostic uses of angiotensin-converting enzyme inhibitors in renovascular hypertension.

The response to angiotensin-converting enzyme inhibitors (ACEIs) can be of considerable help in the diagnosis of human renovascular hypertension (RVH) in three settings. First, a particularly dramatic antihypertensive response or a decline in glomerular filtration rate (GFR), as indexed by a rise in serum creatinine or blood urea nitrogen concentrations, are useful clues to the presence of renovascular hypertension. Second, an exaggerated rise in plasma renin activity (PRA) after short-term captopril administration is a very promising screening test for this condition. Third, ACEI-induced changes in single-kidney hemodynamics (assessed by renography) may be helpful in confirming the diagnosis and offers the prospect of localizing the ischemic kidney.

Cardiac structure and function in renovascular hypertension produced by unilateral and bilateral renal artery stenosis

To evaluate cardiovascular status in human renovascular hypertension, quantitative echocardiographic findings were compared in 42 patients with arteriographically documented renovascular hypertension and 46 age- and sex-matched patients with essential hypertension. Left ventricular (LV) fractional shortening, a measure of systolic performance at rest, was subnormal (less than 26%) in 8 of 42 renovascular hypertensive patients (19%), 0 of 42 essential hypertensive patients (p < 0.005) and 1 of 79 normal subjects (1%) (p < 0.005). Fractional shortening was equally reduced in patients with arteriosclerotic and nonarteriosclerotic causes of renal artery stenosis (32 ± 9% vs 32 ± 6%, both p < 0.025 compared with 36 ± 5% in patients with essential hypertension). The depressed function in renovascular hypertension appeared to be a result of greater LV dilation (p < 0.02) and septal but not LV free wall hypertrophy (p < 0.01) that failed to offset the pressure load, allowing end-systolic stress, a measure of myocardial afterload, to increase to abnormal levels (101 ± 47 × 10 3 dynes/ cm 2, p < 0.001 vs 68 ± 19 in essential hypertension). These data indicate that human renovascular hypertension is associated with more adverse cardiac involvement than essential hypertension of similar severity. In addition, the 14 patients with bilateral renovascular stenosis had a higher cardiac index (3.9 ± 1.1 liters/min/m 2) than the 28 with unilateral stenosis (3.2 ± 1.1. liters/min/m 2, p < 0.05). This result supports the proposition that bilateral renovascular disease is analogous to 1-clip 1-kidney experimental renovascular hypertension, while unilateral renovascular disease resembles the 1-clip 2-kidney model. Volume overload characterizes the former and is absent in the presence of a normal contralateral kidney.

Regulation of renal hemodynamics and glomerular filtration in patients with renovascular hypertension during converting enzyme inhibition with captopril

Changes in regional hemodynamics and function of the kidney during inhibition of angiotensin converting enzyme were studied in 25 patients with renovascular hypertension. A variety of patterns were observed depending upon (1) the activity of the renin-angiotensin system and concomitant administration of diuretics, and (2) the presence of bilateral renal artery stenosis. Increase in blood flow, glomerular filtration rate and sodium excretion during angiotensin blockade, in some instances, indicated tonic renal vasoconstriction before therapy. Release of the kidney from these effects may explain, in part, the sustained effectiveness of converting enzyme inhibition in chronic congestive heart failure. When compared with blood pressure reduction due to nitroprusside administration, initial captopril therapy in patients with unilateral stenosis produced a selective decrease in glomerular filtration, despite well-preserved renal blood flow. These results confirm the importance of efferent arteriolar vasoconstriction due to angiotensin II in man. Experimental studies demonstrate that angiotensin may become critical to sustaining glomerular filtration rate in the presence of stenosis during vasodilation. In patients with bilateral stenosis, this effect produces a syndrome of functional renal insufficiency. Taken together, these data demonstrate an intrarenal action of angiotensin II in human renovascular hypertension and underscore the importance of evaluating the functional impact of changes in regional hemodynamics.