Microvascular dysfunction: a potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension.

The intertwined epidemics of obesity and related disorders such as hypertension, insulin resistance, type 2 diabetes, and subsequent cardiovascular disease pose a major public health challenge. To meet this challenge, we must understand the interplay between adipose tissue and the vasculature. Microvascular dysfunction is important not only in the development of obesity-related target-organ damage but also in the development of cardiovascular risk factors such as hypertension and insulin resistance. The present review examines the role of microvascular dysfunction as an explanation for the associations among obesity, hypertension, and impaired insulin-mediated glucose disposal. We also discuss communicative pathways from adipose tissue to the microcirculation.

Insulin resistance relates to microvascular reactivity 23 years after preeclampsia.

Preeclampsia, an endothelial disorder of pregnancy, is associated with an increased risk on cardiovascular diseases. Cardiovascular risk factors may mediate vascular dysfunction both during pregnancy but also later in life. This study aims to investigate microvascular reactivity, and its relationship with several cardiovascular risk factors, in women with a history of preeclampsia and controls. In this cross-sectional study we compared women with a history of preeclampsia (PE, n=22) with women with uneventful pregnancies only (CON, n=29) 23 years after their first delivery. Participants were matched for BMI, age and date of delivery. We assessed blood concentrations of fasting glucose, HbA1c, insulin, (total, HDL-, LDL-) cholesterol, triglycerides and CRP. Endothelial function was assessed by measurement of skin microcirculatory blood flow by Laser Doppler flowmetry at the dorsal and ventral site of the finger during post-occlusive reactive hyperemia (PORH). PE had higher fasting insulin levels and HOMA-IR compared with CON. The PORH response was similar in both groups. The area under the curve of PORH correlated with insulin and HOMA-IR at both sites, with BMI, triglycerides at the dorsal site and with CRP at the ventral site of the finger in PE and not in CON. In conclusion, 23 years after pregnancy we did not observe a difference in the microvascular hyperemic response between women with a history of preeclampsia and controls. Meanwhile, the results of our study suggest that insulin resistance and other cardiovascular risk factors are related to microvascular reactivity in middle-aged women with a history of preeclampsia.

Renal handling of matrix Gla-protein in humans with moderate to severe hypertension.

Vascular calcifications are common among patients with hypertension. The vitamin K-dependent protein matrix Gla-protein plays an important role in preventing arterial calcification. Since a decrease in renal clearance is a prevalent clinical problem in patients with hypertension, we aimed to study the renal clearance of matrix Gla-protein from the circulation in these patients having a wide range of creatinine clearances. Ninety moderate to severe hypertensive patients who were scheduled for renal angiography were enrolled in the study. In these patients, renal arterial and renal venous blood was sampled prior to the administration of contrast material in order to determine the total renal and single kidney clearance of matrix Gla-protein. The average renal fractional extraction of matrix Gla-protein was 12.8%. There was no significant correlation between creatinine clearance (range 26-154) and renal fractional extraction of matrix Gla-protein in this population. The extraction of matrix Gla-protein was not influenced by the presence of a renal artery stenosis. In conclusion, we demonstrate that the kidney is able to extract matrix Gla-protein from the plasma at a constant level of 12.8%, independent of renal function in hypertensive subjects.

Configuration of the microcirculation in pre-eclampsia: possible role of the venular system.

OBJECTIVE: To test the hypothesis that during pre-eclampsia microvascular function and structure are disturbed, which contributes to raised venular resistance. METHODS: The microcirculation of the skin and bulbar conjunctiva was studied in 11 women with preeclampsia and nine parous controls, both in the third trimester and 3 months postpartum. Using intravital videomicroscopy, arteriolar and venular diameters were determined in the conjunctiva. In addition, skin capillary densities and morphology were determined. RESULTS: Conjunctival venular diameters were 30% smaller in pre-eclampsia compared with controls, both during pregnancy (P < 0.01) and postpartum (P = 0.045). Arteriolar diameters also tended to be smaller; however, this difference was not statistically significant. In women with pre-eclampsia we found a higher percentage of tortuous/dilated skin capillaries (5%) compared with controls (0%; P < 0.05). Three months postpartum, this difference had disappeared. Skin capillary densities did not differ between the groups. CONCLUSION: Women with severe pre-eclampsia have narrow venules, both during manifest disease and postpartum. Possibly, these narrow venules raise venular resistance and with it, hydrostatic pressure in the capillary bed. The latter, in turn, may explain the higher number of tortuous/dilated capillaries in women with preeclampsia. These findings support an important role of the venous system in the pathogenesis of pre-eclampsia.

A novel approach to the study of human microcirculation: Reactivity to locally applied angiotensin II in the conjunctival microvascular bed.

OBJECTIVE: To develop a state-of-the-art, computer-assisted intravital microscopy protocol to evaluate directly the effects of topically applied drugs on conjunctival arteriolar and venular diameters. METHODS: Fifty-one normotensive volunteers were studied. Video-recordings of the bulbar conjunctival microcirculation were made before and following eye drops containing angiotensin II (AngII) (0.001% w/w, or 0.01%) or phenylephrine (0.25%). The computer-assisted analyses of arteriolar and venular diameters were performed off-line. In different protocols the microvascular reactivity to the different eye drops were compared. RESULTS: AngII (0.01%) eye drops, but not AngII (0.001%), induced significant constriction in both arterioles (median, 19%) and venules (13%). Phenylephrine eye drops (pharmacological control) induced similar arteriolar (18%) and venular (12%) constrictions. Repeated AngII challenges with a 30-min interval revealed reproducible vasoconstriction responses (median arteriolar constriction, 11 and 17%, respectively; NS). The vasoconstriction responses following AngII challenges on two consecutive days revealed reproducible responses (median arteriolar constriction, 13 and 11%, respectively; NS). CONCLUSIONS: The present results demonstrate that the proposed model for noninvasive intravital video-microscopy of the conjunctival microcirculation is sensitive for measuring direct arteriolar and venular reactivity following topically applied drugs. We consider this model a valuable tool for sophisticated research on in-vivo microvascular reactivity in humans.

Aldosterone-Renin Ratio and Side-Selective Renal Perfusion in Essential Hypertension.

BACKGROUND: The decrease in kidney perfusion as often observed in hypertensive individuals does not necessarily occur in a symmetrical fashion, thereby potentially introducing left-right differences in response to vasoactive agents. Increased aldosterone levels have been associated with reduced renal perfusion in normotensive and hypertensive individuals, but it is unknown whether both kidneys are equally affected in this respect and how angiotensin II is involved in this relationship. Therefore, our aim was to investigate the association of both aldosterone and the aldosterone-renin ratio with side-selective renal blood flow in essential hypertension. METHODS: We studied 146 essential hypertensive patients with patent renal arteries who had undergone renal angiography for exclusion of renal artery stenosis. Prior to contrast administration, blood samples were drawn for the determination of renin and aldosterone levels, and side-selective renal blood flow was measured using the 133Xenon washout technique. RESULTS: Left mean renal blood flow (MRBF) was significantly lower than right MRBF (227±74 vs. 250±76mL * min-1 * 100g kidney-1, P = 0.01). We could not demonstrate a correlation of ln aldosterone or ln renin with left or right kidney perfusion. Ln aldosterone-renin ratio (ARR), however, was inversely and independently associated with left MRBF (ß = -13.993, P = 0.02; fully adjusted model) but not with right MRBF. CONCLUSIONS: A higher ARR corresponds to reduced perfusion of the left kidney, yet is not associated with right kidney perfusion. Especially under circumstances of diminished right renal blood flow, this may affect blood pressure and kidney function.

Renal hemodynamics and renin-angiotensin system activity in humans with multifocal renal artery fibromuscular dysplasia.

BACKGROUND: Fibromuscular dysplasia (FMD) is the second most common cause of renovascular hypertension. Nonetheless, knowledge on the renal microvasculature and renin-angiotensin system (RAS) activity in kidneys with FMD is scarce. Given the fairly good results of revascularization, we hypothesized that the renal microvasculature and RAS are relatively spared in kidneys with FMD. METHOD: In 58 hypertensive patients with multifocal renal artery FMD (off medication) and 116 matched controls with essential hypertension, we measured renal blood flow (Xenon washout method) per kidney and drew blood samples from the aorta and both renal veins to determine renin secretion and glomerular filtration rate per kidney. RESULTS: We found that renal blood flow and glomerular filtration rate in FMD were comparable to those in controls. Although systemic renin levels were somewhat higher in FMD, renal renin secretion was not elevated. Moreover, in patients with unilateral FMD, no differences between the affected and unaffected kidney were observed with regard to renal blood flow, glomerular filtration rate, or renin secretion. In men, renin levels and renin secretion were higher as compared with women. The renal blood flow response to RAS modulation (by intrarenal infusion of angiotensin II, angiotensin-(1-7), an angiotensin II type 1 receptor blocker, or a nitric oxide synthase blocker) was also comparable between FMD and controls. CONCLUSION: Renal blood flow, glomerular filtration, and the response to vasoactive substances in kidneys with multifocal FMD are comparable to patients with essential hypertension, suggesting that microvascular function is relatively spared. Renin secretion was not increased and the response to RAS modulation was not affected in kidneys with FMD.

Renal contribution to increased clearance of exogenous growth hormone in obese hypertensive patients.

To evaluate the possible role of the kidney in the enhanced metabolic clearance rate (MCR) of GH in obesity, we studied the kinetics of GH and renal fractional extraction of GH (RFEGH) in 12 male hypertensive patients over a wide range of body weights (71.7-129 kg) while undergoing contrast angiography on suspicion of renal artery stenosis. A continuous infusion of recombinant human GH was administered during a continuous infusion of somatostatin to suppress endogenous GH secretion. After 2 h of GH infusion, when plasma GH had reached a steady state at concentrations that were still in the physiological range, blood was sampled from the left and right renal arteries and veins for determination of GH levels. Subsequently, the GH infusion was stopped, and GH kinetics were investigated with noncompartmental analysis. In none of the patients was hemodynamically significant renal artery stenosis present. Whole body MCR of GH averaged 375 +/- 142 ml/min. Average GH levels were significantly higher in arterial plasma than in simultaneously sampled renal venous plasma (P < 0.001). RFEGH was 8.6 +/- 6.8%. The MCRs of both GH and RFEGH correlated significantly with body weight, body fat mass, and endogenous creatinine clearance. Renal uptake of GH per 100 g kidney tissue correlated inversely with MCR. These results suggest that RFEGH rises with increasing adiposity, but per unit of renal mass, the capacity of the kidney to remove GH from the circulation falls at high MCR values.

Microvascular adaptation to changes in dietary sodium is disturbed in patients with essential hypertension.

BACKGROUND: Several studies have shown microvascular changes in patients with hypertension, but the question is still open as to whether these alterations are functional or structural. In particular, it is unknown whether the microcirculation adapts to changes in sodium intake or remains relatively fixed. METHODS: We examined bulbar conjunctival microvascular densities after 1 week of low (55 mmol Na+/24 h) and high (220 mmol Na+/24 h) sodium diet, in untreated patients with essential hypertension and in normotensive control subjects. RESULTS: On a low sodium diet, venular density was lower in essential hypertension (EH) compared with controls [median and interquartile ranges: 4.77 (4.01-5.71) versus 6.43 (6.02-7.20) mm/mm2, P = 0.001], while arteriolar density was higher [3.80 (2.41-4.46) versus 2.06 (1.74-2.23) mm/mm2, P = 0.03]. In the whole group (patients and controls), venular density correlated inversely and arteriolar density correlated positively with mean arterial pressure (MAP). Switching to a high sodium intake resulted in opposite responses in the two groups with respect to venular density (P = 0.0001): a 33% (3-80) increase in EH, but a 28% (-3 to 34) decrease in controls. Changes in venular density with increased sodium intake correlated positively with MAP on a low sodium diet in the whole group. Arteriolar density did not change significantly in either group. Also, capillary density was similar on both diets. CONCLUSION: Functional microvascular density in EH patients differs from that in normotensive subjects in a way that is dependent upon sodium intake.

Neural activity of the cardiac baroreflex decreases with age in normotensive and hypertensive subjects.

OBJECTIVES: Baroreflex control of the heart rate is impaired in hypertensive subjects and decreases with age. The decrease in cardiac baroreflex sensitivity (BRS) is often ascribed to decreased distension of the pressure-sensing arterial wall segments. However, alterations in the sensing and processing of neural signals may be involved as well. DESIGN: Conventionally, both vessel wall stiffness and the sensing and neural processing of the baroreflex are incorporated in the measure of pressure-derived BRS. We introduce stretch-derived BRS, which only considers the sensing and neural components of the baroreflex. METHODS: To determine stretch-derived BRS in a non-invasive manner, we measured the spontaneously occurring low-frequency variations (range, 0.06-0.12 Hz) in the carotid artery diameter and the corresponding R-R interval fluctuations, and determined the associated transfer function. The stretch-derived BRS in a group of age-matched (age range, 25-72 years) normotensive (n = 20) and hypertensive (n = 21) subjects was compared. RESULTS: In both subject groups the stretch-derived BRS decreased significantly with age. Moreover, the stretch-derived BRS of both groups was only different below 50 years of age. CONCLUSIONS: The analysis of low-frequency fluctuations in the carotid artery diameter demonstrates that aging as well as hypertension are associated with impaired neural control of the baroreflex. Beyond 50 years of age the effect of hypertension cannot be distinguished from the effect of aging.

Mechanisms of adenosine-induced renal vasodilatation in hypertensive patients.

BACKGROUND: Adenosine is an endogenous nucleoside with potent vasodilatory capacities, released under ischaemic conditions in particular. Its mechanisms of action, however, remain elusive. OBJECTIVE: To evaluate the role of adenosine, using a non-selective purinergic receptor antagonist, and the possible involvement of nitric oxide in this mechanism. In addition, the production of renin and catecholamines was studied during infusion of adenosine, caffeine, or both. METHODS: Thirty-three hypertensive patients who underwent diagnostic renal angiography received intrarenal infusions of adenosine either alone or in combination with caffeine or the nitric oxide synthase inhibitor, N-monomethyl-L-arginine (L-NMMA). The effects on renal blood flow (RBF) were assessed by the xenon-133 washout technique and both arterial and renal venous blood samples were taken for measurement of renin and catecholamine concentrations. Intra-arterial blood pressure and heart rate were monitored continuously. RESULTS: Adenosine induced a dose-dependent vasodilatation. Caffeine alone did not change RBF, but shifted the dose-response curve of adenosine to the right during concomitant infusion of caffeine. RBF during combined infusion of L-NMMA and adenosine was not different from that during adenosine alone, but the decrease in renal vascular resistance was less pronounced during this combination. Renin secretion did not change during the infusion of either adenosine alone or adenosine in combination with caffeine. Catecholamine concentrations also did not change during any of the experiments. CONCLUSIONS: Adenosine induces vasodilatation in the human hypertensive kidney and this effect is mediated by the adenosine receptor. Nitric oxide plays, at most, a minor part in the adenosine-induced vasodilatation. Furthermore, renin secretion is not affected by adenosine and caffeine.

Vascular and renal actions of brain natriuretic peptide in man: physiology and pharmacology.

During the last decade brain natriuretic peptide (BNP) has received increasing attention as a potential marker of cardiovascular disease. BNP may act as a compensating mechanism in cardiovascular diseases in order to reduce preload. However, the increase in endogenous BNP is often not sufficient to compensate for volume overload in diseases like established hypertension and heart failure. The reported hemodynamic and renal effects of BNP in man differ largely between studies, because of differences in design and doses of BNP employed. In the pharmacological range, BNP has clear blood pressure and afterload lowering effects, and in the kidney blood flow and filtration is increased with concomitant natriuresis and diuresis. While in the physiological range BNP does not affect blood pressure and reduces preload only, and induces natriuresis/diuresis without changes in renal blood flow and filtration. There is increasing evidence from vascular studies that BNP preferentially acts on the venous system resulting in preload reduction, in contrast to atrial natriuretic peptide which acts preferentially on the arterial system to reduce afterload. This review summarizes our current understanding of BNP, and discuss its regulation and mechanisms of action on the vasculature and the kidneys.

Reduced structural and functional skin capillaries in familial combined hyperlipidemia affected men, associated with increased remnant-like lipoprotein cholesterol levels.

We determined whether abnormalities in the number of basal (BC) and post-occlusive (POC) capillaries are present in familial combined hyperlipidemia (FCHL), and investigated the possible relationship of BC and POC with lipids, remnant-like lipoprotein particles (RLP-C), blood pressure, and insulin resistance. Fifty age-matched subjects, 23 (12 men) hyperlipidemic, normotensive FCHL subjects and 27 (14 men) healthy controls participated in this study. Capillary density was measured just above the finger nailfold, before and after 4 min of arterial occlusion. The number of BC and POC were significantly lower in FCHL men compared with healthy men, 113.7+/-15.1 versus 132.0+/-18.0 (P=0.02) and 123+/-19.1 versus 142.3+/-18.3 (P=0.03), respectively. No differences were found between FCHL women and control women. In univariate analyses in FCHL men, BC was inversely correlated with total cholesterol (r=-0.63; P=0.05). POC tended to be inversely correlated with total cholesterol (r=-0.62; P=0.056). No univariate correlations (P>0.3) were observed between BC or POC and blood pressure or insulin resistance. Multivariate analyses revealed that logRLP-C was the only significant independent contributor to BC and POC. This is the first description of a reduction in skin capillaries in FCHL men, which was associated with increased atherogenic lipoprotein levels. Loss of capillary surface may be important in the pathophysiology or can result from adaptation to the hyperlipidemia in FCHL.

Nitric oxide and potassium channels are involved in brain natriuretic peptide induced vasodilatation in man.

OBJECTIVE: Brain natriuretic peptide (BNP) causes vasodilatation but the mechanisms by which this is accomplished are not fully known. The aim of the present study was to determine whether, besides K+Ca2+-channels, nitric oxide (NO) is involved in BNP-induced vasodilatation. METHODS: We studied 10 healthy males twice, in random order, at an interval of 2 weeks. Experiments always started with infusion of BNP (8-16-32-64 pmol/dl per min) into the brachial artery. On the first day this infusion was followed by a second BNP infusion combined with the K+Ca2+-channel-blocker, tetraethylammonium (TEA, 0.1 mg/dl per min), and on the other day by BNP infusion combined with the NO-synthase inhibitor, l-NG-monomethyl arginine (l-NMMA, 0.8 mumol/dl per min). The latter was then followed by a combined infusion of BNP, l-NMMA and TEA. All infusions were separated by a 1 h washout period. Forearm blood flow (FBF) was determined by venous occlusion plethysmography. RESULTS: Mean arterial pressure and heart rate did not change during any of the experiments. BNP alone induced a dose-dependent dilatation, which was similar on both days. TEA, l-NMMA, and their combination all reduced the BNP-induced dilatation (P < 0.05). The combined infusion had a significantly greater effect than TEA alone (P = 0.005). BNP infusions were associated with a significant increase in plasma cyclic guanosine monophosphate (cGMP) and C-type natriuretic peptide (CNP) (P < 0.05). CONCLUSIONS: BNP induces arterial vasodilatation not only by opening K+Ca2+-channels, but also via stimulation of NO production. In addition, BNP stimulates net CNP increase.

Acute intrarenal administration of cortisol has no effect on renal blood flow in hypertensive individuals.

BACKGROUND: Cortisol is known to increase blood pressure. One possible mechanism is the reported increase in renal vascular resistance (RVR). It is unknown whether this is due to a direct effect of cortisol on the kidneys. OBJECTIVE: To study the effect of infusion of cortisol directly into the renal artery on renal blood flow (RBF) and on renal 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-mediated conversion of cortisol to cortisone in patients with primary hypertension. DESIGN AND METHODS: Twenty-seven patients with primary hypertension participated in this study. Fifteen received placebo and 12 received glycyrrhetinic acid (GRA; 500 mg) orally 2.5 h before the study. After a 10 min infusion of 5% glucose, cortisol was infused in stepwise increasing doses (0.625, 1.25 and 2.5 microg/kg per min), for 10 min each dose. At the end of each infusion step, RBF was measured using the xenon-133 washout technique. Plasma samples from the femoral artery and renal vein were taken for measurement of cortisol and cortisone. Urine was collected for measurement of steroid concentrations for 6 h on the day before the infusion and for 6 h after the infusion. RESULTS: After placebo or GRA, cortisol infusion did not change RVR, RBF or blood pressure. RVR values were 0.72 (0.45-0.89) mmHg/ml per min per 100 ml tissue [median (first and third quartiles)] and 0.71 (0.64-0.91) mmHg/ml per min per 100 ml tissue during infusion of 5% glucose and infusion of the highest dose of cortisol, respectively ( P= NS). Cortisol infusion increased the venous-arterial difference in plasma cortisone concentration across the kidney from 76 (40-115) nmol/l to 138 (100-186) nmol/l (P< 0.05) and increased the cortisol : cortisone ratios in the renal vein and in urine (both P< 0.05). As compared with placebo, administration of GRA increased the cortisol : cortisone ratios in peripheral and renal veins and in the urine. CONCLUSION: Acute infusion of cortisol in high doses directly into the renal artery in patients with primary hypertension did not affect RBF or RVR. Infusion of cortisol resulted in increased cortisol-cortisone conversion by renal 11beta-HSD2, but the concurrent increase in renal and urinary cortisol : cortisone ratio suggests a relative insufficiency of renal 11beta-HSD2 activity as a result of enzyme saturation. This may enhance mineralocorticoid receptor stimulation by cortisol.

Hemodynamic and renal effects of low-dose brain natriuretic peptide infusion in humans: a randomized, placebo-controlled crossover study.

Brain natriuretic peptide (BNP) is a cardiac hormone with natriuretic activity. The aim of this study was to investigate the cardiovascular effects of pathophysiological levels of BNP on central hemodynamics, cardiac function, renal hemodynamics and function, and microvascular hemodynamics in healthy subjects. In this double-blind, placebo-controlled crossover study, we intravenously infused BNP (4 pmol. kg-1. min-1) or placebo for 1 h on two separate days in 12 healthy subjects (mean age, 60 +/- 5 yr). Nailfold and conjunctival capillary density, finger-skin (thermoregulatory) microvascular blood flow, and cardiac output were studied before and after infusion using intravital videomicroscopy, laser-Doppler fluxmetry, and echocardiography, respectively. Furthermore, during infusion, we measured the effective renal plasma flow and glomerular filtration rate using p-aminohippurate and inulin clearances. Blood pressure and heart rate were monitored for all measurements. Compared with placebo, BNP significantly decreased stroke volume with a tendency to decrease cardiac output. With subjects in the sitting position, mean arterial pressure decreased and heart rate increased after BNP infusion, whereas with subjects in the supine position, these variables remained unchanged. BNP increased natriuresis, diuresis, glomerular filtration rate, filtration fraction, and filtered load of Na+ compared with placebo, whereas effective renal plasma flow did not change. BNP did not affect the microvascular capillary density of conjunctiva and skin, microvascular blood flow, total skin oxygen capacity, and postocclusive recruitment. These results suggest that BNP has predominantly central and renal hemodynamic effects; however, it does not influence peripheral microcirculation in skin and conjunctiva.

Microvascular abnormalities in chronic heart failure: a cross-sectional analysis.

OBJECTIVES: Similar to what has been found in hypertension, elevated peripheral resistance in chronic heart failure (CHF) might be related to microvascular constriction and rarefaction. Our objective was to evaluate both structural and functional microvascular changes in patients with CHF in relation to left ventricular function and neurohumoral activation. METHODS: In 25 patients with mild and severe CHF (New York Heart Association class I-II [n = 11] and class III-IV [n = 14]) and 10 age-matched healthy subjects, we studied microvascular density, diameters, and morphology of the bulbar conjunctiva and skin nailfold using intravital microscopy. RESULTS: Total conjunctival microvascular density was higher in patients with mild heart failure compared with healthy controls, whereas it was lower in severe heart failure (medians, 6.75, 4.31, and 3.56 mm/mm2, respectively, p < 0.01). In patients with heart failure, venular density was correlated with left ventricular ejection fraction. Nailfold capillary recruitment during postocclusive reactive hyperemia, a measure of functional reserve capacity, was impaired in patients with severe CHF (p < 0.05). Furthermore, in severe CHF, more abnormal capillaries and enlarged diameters were found in the nailfold (p < 0.05). CONCLUSIONS: In heart failure, several microvascular abnormalities occur that differ, depending on the severity of this condition.

Genetic risk of atherosclerotic renal artery disease: the candidate gene approach in a renal angiography cohort.

It is largely unknown to what extent genetic abnormalities contribute to the development of atherosclerotic renal artery disease. Among the potential candidate genes, those of the renin-angiotensin system and the endothelial nitric oxide synthase (eNOS) rank high because of their importance in the atherosclerotic process. We investigated the association of polymorphisms in these genes (the angiotensinogen Met235Thr, the angiotensin-converting enzyme insertion/deletion, the angiotensin II type-1 receptor A1166C, and the eNOS Glu298Asp) with the presence or absence of atherosclerotic renovascular disease in 456 consecutive hypertensive patients referred for renal angiography on the suspicion of renovascular hypertension. Nondiseased normotensive (n=200) and hypertensive (n=154) patients from a family practice served as external controls. Renal artery disease was present in 30% of our angiography group. The Asp allele of the eNOS Glu298Asp polymorphism was associated with atherosclerotic renal artery stenosis with an odds ratio of 1.44 (95% confidence interval 1.00 to 2.09) versus hypertensives with angiographically proven patent arteries, of 1.89 (1.24 to 2.87) versus hypertensive family practice controls, and of 2.09 (1.29 to 3.38) versus normotensive family practice controls. However, this allele also differed significantly between patients with patent renal arteries and normotensive and hypertensive controls. No differences were found with respect to the other genetic polymorphisms. We hypothesize that the Asp allele of the Glu298Asp polymorphism may predispose to the development of atherosclerotic lesions but that renal artery involvement depends on other factors, also.

Nitric oxide dependence of renal blood flow in patients with renal artery stenosis.

In ischemia, nitric oxide (NO) production is increased, possibly to preserve flow. The role of NO was investigated in hypertensive patients with or without renal artery stenosis (RAS). Fifty-five hypertensive patients scheduled to undergo diagnostic renal angiography underwent mean renal blood flow (MRBF) measurements before and after an intrarenal injection of the NO synthase blocker N(g)-monomethyl-L-arginine (L-NMMA) at 0.03 microg/kg, before angiography. A dose-response study indicated that this dose of L-NMMA significantly blocked NO synthesis. MRBF was measured at baseline and 1, 5, 10, and 20 min after L-NMMA treatment. On the basis of the angiographic results, patients were divided into three diagnostic categories, i.e., essential hypertension (n = 26), unilateral RAS (n = 16), or bilateral RAS (n = 8). In essential hypertension, MRBF was decreased by 18 +/- 4% at 20 min. In unilateral RAS, L-NMMA did not affect MRBF in the stenotic kidney but reduced MRBF in the nonstenotic kidney by 40 +/- 9% at 20 min. In bilateral RAS, L-NMMA reduced flow by 32 +/- 14% at 20 min. In the nonstenotic kidney in unilateral RAS, a positive correlation was observed between the effect of NO blockade on MRBF and arterial renin levels (P = 0.009). In the stenotic kidney, in contrast, this correlation was inverse (P = 0.007). In conclusion, MRBF depends on NO in hypertensive patients, except in the stenotic kidney in unilateral RAS. In the nonstenotic kidney in unilateral RAS, NO bioavailability is increased. It is suggested that a compensatory mechanism, regulated by NO and possibly angiotensin II, may preserve renal function.

Asymmetry of renal blood flow in patients with moderate to severe hypertension.

It is generally assumed that renal blood flow is symmetric in the absence of renal artery stenosis. The aim of the present study was to evaluate whether this is really the case. From a group of consecutive hypertensive patients who had undergone renal angiography, we selected those with patent renal arteries. In all of them selective renal blood flow (RBF) measurements (133Xenon washout technique) had been performed with blood sampling from aorta and both renal veins (n=148). Asymmetry of RBF, defined as > or =25% difference in RBF between left and right kidney, was present in 51% of the patients. Subjects with and without asymmetry did not differ in age, body mass index, blood pressure, creatinine clearance, renal volume, or activity of the renin-angiotensin system. The presence of asymmetry coincided with an increased rate of false-positive results on renal scintigraphy. Preliminary data suggest that there may be a relation between asymmetry and renal sympathetic nerve activity. This study demonstrates that asymmetry of RBF is a frequent finding in essential hypertension, which may confound the results of diagnostic tests for renal artery stenosis. Furthermore, the present results underscore the importance of studying the function of both kidneys separately, because it cannot be assumed that they are functionally equal.