Moreno Bardelli

Non-invasive ultrasound assessment of renal artery stenosis by means of the gosling pulsatility index

OBJECTIVE To gauge the effectiveness of a new Doppler test for renal artery stenosis (RAS), based on the pulsatility index of the blood flow velocity spectrum within several interlobar arteries of both kidneys. METHODS Twenty normotensive volunteers and 49 hypertensive patients were investigated with ultrasound. Patients with angiographic signs of RAS underwent bilateral renal vein catheterization for renin measurement. Significant RAS was assumed if lateralization of renal vein renin to the stenotic side was proven. RESULTS The pulsatility index was higher in the hypertensives without RAS than in normal volunteers. Side differences between both kidneys were within methodological variations with the exception of one case, in whom side difference was > 0.12. The pulsatility index was lower in kidneys with significant RAS than in kidneys without RAS. In most patients with significant unilateral RAS the side difference was < 0.12. In the other patients with a low pulsatility index and a side difference < 0.12 RAS was found to be bilateral upon angiography. Doppler signals were absent in all kidneys with renal occlusion. CONCLUSIONS A side difference of > or = 0.12 predicts unilateral RAS, whereas the absence of parenchymal Doppler signals indicate occlusive RAS. A low pulsatility index combined with normal side difference may, in hypertensive patients, indicate bilateral RAS. Renovascular hypertension was correctly diagnosed in 84% of the patients and the presence of RAS in 94%.

Renovascular resistance in primary hypertension: experimental variations detected by means of Doppler ultrasound

Objective To gauge the influence of renovascular resistance changes on blood flow velocity pulsatility in kidneys of hypertensive patients by means of the ultrasonic colour and pulsed-wave Doppler method, since we have previously shown in normotensive subjects that the blood flow velocity pulsatility in renal interlobar arteries varies with changes in renovascular resistance. Methods In six male patients with primary hypertension, renal blood flow velocity profiles were investigated by means of duplex ultrasound. Single-kidney renovascular resistance was assessed by measurements of split renal function (γ-camera renography), renal plasma flow (steady-state para-aminohippurate clearance) and cuff blood pressure. The pulsatility index of the blood flow velocity spectrum in the renal interlobar artery and renovascular resistance were measured either at rest, during infusion of angiotensin II, or after angiotensin converting enzyme inhibition. Results A significant correlation existed between pulsatility index and renovascular resistance (r = 0.50, P< 0.002), which did not improve after correction for the blood pressure pulsatility. Changes of pulsatility index were more closely related (r = 0.64, P< 0.001) to the corresponding changes in renovascular resistance. Conclusions With the two-dimensional image-guided colour and pulsed-wave Doppler method it is possible to assess semiquantitatively small intra-individual changes in renovascular resistance in hypertensive patients by means of pulsatility index measurements. Pharmacologically induced alterations in renovascular haemo-dynamics may therefore be evaluated with this technique.

Stimulation of cardiac apoptosis in ovariectomized hypertensive rats: potential role of the renin-angiotensin system

Objectives The mechanisms underlying the increased cardiovascular risk after menopause are poorly understood. Estrogens modulate the cardiac renin–angiotensin system (RAS) and influence cardiac adaptation to afterload. To investigate whether the loss of the natural inhibition of the RAS by estrogen may be linked to an increase of cardiac apoptosis, we studied 17β-estradiol (E2) and/or angiotensin-converting enzyme (ACE) inhibitor treatment effects on cardiomyocyte survival in ovariectomized spontaneously hypertensive rats (SHRs). Methods Five groups of female SHRs were evaluated for 8 weeks. One group served as nonovariectomized control; the other four groups underwent bilateral ovariectomy and were randomized to receive 60-day-release pellets containing placebo or 0.5 mg of E2, the ACE inhibitor ramipril at the dosage of 2.5 mg/kg per day, or the combination of the two treatments. Results Ovariectomy increased cardiomyocyte apoptosis and induced proapoptotic changes of Bcl-2 and Bax genes and proteins. These modifications were associated with an upregulation of ACE and angiotensin II type 1 (AT1) receptor genes. Ramipril was as effective as E2 in preventing cardiac apoptosis and in restoring cardiac brain natriuretic peptide in association with reduced cardiac ACE and AT1 receptor gene expression. In contrast to the ramipril treatment, the favorable effect of E2 on cardiac apoptosis occurred independently from changes in SBP. No synergistic effect was observed when the two treatments were combined. Conclusion These data show that ovariectomy stimulates myocardium apoptosis by a mechanism involving Bax and Bcl-2 genes. The antiapoptotic effect of E2 and ACE inhibitor treatment was linked to a downregulation of cardiac RAS.

Control of glomerular hyperfiltration and renal hypertrophy by an angiotensin converting enzyme inhibitor prevents the progression of renal damage in hypertensive diabetic rats.

OBJECTIVE Glomerular hyperfiltration and renal hypertrophy are both considered important in the progression of diabetic nephropathy. The aim of this study was to compare the effects of an equivalent reduction in blood pressure produced by the angiotensin-converting enzyme (ACE) inhibitor spirapril (SPI) and an antihypertensive triple drug combination of hydralazine, reserpine and hydrochlorothiazide (HRH) on kidney function, proteinuria and renal structure in hypertensive diabetic rats. DESIGN AND METHODS Four groups of animals were evaluated in short-term and long-term studies. In both studies one group served as a non-diabetic hypertensive control (H). The other three groups were rendered diabetic and were allocated to one of the following groups: the first diabetic group received no specific therapy (HD), the second diabetic group was treated with SPI (HD-SPI) and the third diabetic group was treated with HRH (HD-HRH). In each of the two studies the systolic blood pressure (SBP), 24 h urinary total protein, glomerular filtration rate (GFR), glomerular area, proximal tubular area and glomerular sclerosis were evaluated. RESULTS The blood pressure reduction was equal in rats receiving either SPI or HRH. The GFR, proteinuria, glomerular area and tubular area were significantly increased in the HD group, both in the short-term and the long-term study. In the HD-SPI group the diabetic hyperfiltration and renal hypertrophy responses were prevented. In the HD-HRH group the GFR and proteinuria were slightly reduced in the later phases of diabetes, while the glomerular area and tubular area were not affected. Semiquantitative analysis of renal lesions showed that SPI was more effective than HRH in the prevention of the development of glomerulosclerosis. CONCLUSIONS The results of this study suggest that the control of early adaptive hyperfiltration and renal hypertrophy by SPI may be relevant in the prevention of glomerulosclerosis.

Imaging For Renovascular Disease

Renal artery stenosis is frequently considered in the diagnosis of severe hypertension and renal insufficiency, but the benefits of screening and the choice of imaging modalities is controversial. Sonography, computed tomography angiography (CTA), magnetic resonance angiography (MRA), and conventional angiography are all used and each has advantages and disadvantages. However, performance and interpretation of each requires significant experience and expertise. Since there are no clear data or consensus on the choice of imaging modalities, this should be based on the level of expertise that is available.

Dose and time-dependent apoptotic effects by angiotensin II infusion on left ventricular cardiomyocytes.

Objective To gain insight into the regulation of cardiac apoptosis we studied the dose–response and time-course effects of angiotensin II (Ang II) infusion on ventricular cardiomyocyte apoptosis and on the expression of Bax and Bcl-2 genes and proteins. Study design and methods In the dose–response study, Ang II was infused subcutaneously at doses of 100, 200, 400, 800 and 1200 ng/kg per min for 14 days. In the time-course study, rats infused with Ang II at doses of 200 and 400 ng/kg per min were followed for 7 and 14 days. The cardiomyocyte apoptotic density was assessed by DNA end labelling (terminal deoxynucleotide nick-end labelling; TUNEL). Gene and protein expression of Bcl-2 and Bax were evaluated by reverse transcriptase-polymerase chain reaction and by Western blots. Results Systolic blood pressure and left ventricular mass were increased in a dose-dependent manner in Ang II-infused rats. A statistically significant increase in the rate of cardiac apoptosis and pro-apoptotic changes of Bcl-2 and Bax gene and protein expression was observed when high doses of Ang II (800–1200 ng/kg per min) were infused. A positive correlation of apoptotic density with Bax and a negative correlation with Bcl-2 and Bcl-2/Bax ratio were found. Cardiac apoptosis was greatly influenced by the timing of Ang II infusion. Losartan-treated Ang II-infused rats exhibited normalized systolic blood pressure, left ventricular weight, apoptosis, and Bax and Bcl-2 levels. Conclusions Our results are consistent with the pathophysiological role of Ang II in induction of cardiac apoptosis, and explain the cardioprotective effect of Ang II receptor antagonists.

Peripheral adrenoceptors in hypotension of hemodialyzed uremic patients.

Hypotension is a common problem in patients on hemodialysis. To further investigate this problem, the number of platelet alpha 2-adrenoceptors and the activity of lymphomonocyte beta 2-adrenoceptors were measured in 10 hemodialyzed patients with normal blood pressure and in 10 sex- and age-matched persistently hypotensive hemodialyzed patients. Density of alpha 2-adrenoceptors was assessed by the specific binding of 3H-yohimbine to intact platelets, while the function of beta 2-adrenoceptors was estimated by the production of cAMP after the exposure of lymphomonocytes to isoprenaline. The maximal number of alpha 2-adrenoceptors was increased in the hypotensive compared to the normotensive group (262.13 vs. 77.21 fmol/mg protein; p < 0.01). Plasma norepinephrine was higher in the hypotensive than in the normotensive uremic patients (640 +/- 195 vs. 344 +/- 156 pg/ml; p < 0.01). Plasma epinephrine did not differ in the two groups (90 +/- 30 vs. 94 +/- 24 pg/ml). The amount of cAMP, produced by stimulation of lymphomonocytes, was lower in the hypotensive than that in the normotensive uremic patients (7.7 +/- 2.4 vs. 15.6 +/- 5.4 pmol/10(6) cells; p < 0.002). The increased number of alpha 2-adrenoceptors together with a high level of norepinephrine and reduced activity of adenylate cyclase (coupled with beta 2-adrenoceptors) support the hypothesis that hypotension in the hemodialyzed uremic patients may be related to a defect in adrenoceptor coupling mechanisms.

Modulation of Incipient Glomerular Lesions in Experimental Diabetic Nephropathy by Hypotensive and Subhypotensive Dosages of an ACE Inhibitor

A glomerular permeability defect occurs early in the course of type 1 diabetes and precedes the onset of microalbuminuria and renal morphological changes. Recently, ACE inhibitors have been shown to prevent loss of glomerular membrane permselective function, but the mechanism of this nephroprotective effect is still being debated. The objective of the present study was to evaluate the effects of hypotensive and subhypotensive dosages of the ACE inhibitor quinapril ex vivo and of its active metabolite quinaprilat in vitro on the glomerular albumin permeability (P(alb)) defect in the early phases of experimental diabetes. For the ex vivo study, six groups of male Wistar rats were evaluated for 4 weeks. One group served as a nondiabetic control (C); the other five groups were rendered diabetic and included untreated diabetic rats (D) and diabetic rats receiving quinapril at the dosages of 5 (DQ1), 2.5 (DQ2), 1.25 (DQ3), and 0.625 (DQ4) mg. kg(-1). day(-1). Dosage-dependent effects of quinapril on systolic blood pressure and the glomerular filtration rate were observed. In contrast, control of P(alb) in isolated glomeruli exposed to oncotic gradients, proteinuria, and glomerular and tubular hypertrophy was obtained with subhypotensive dosages (DQ3 and DQ4 groups) of the ACE inhibitor. In the in vitro study, quinaprilat reduced P(alb) significantly in concentration ranges from 10(-6) to 10(-14) mol/l compared with results in control glomeruli. The effect on P(alb) may have occurred by mechanisms different from kidney ACE inhibitor. These study results indicated that ACE inhibitor treatment prevents the early onset of the P(alb) defect in experimental diabetes. This effect seemed to occur independently of systemic or glomerular hemodynamic changes and, at least partially, from kidney ACE inhibition.

Ambulatory Arterial Stiffness Indexes in Acromegaly

OBJECTIVE Acromegaly is associated with increased cardiovascular morbidity and mortality and with specific heart and vascular abnormalities. The aim of our study was to investigate arterial stiffness using the ambulatory arterial stiffness index (AASI) and symmetric AASI (Sym-AASI), two indexes derived from 24-h ambulatory blood pressure monitoring (ABPM), in a group of normotensive and hypertensive patients with active acromegaly, compared with normotensive controls (NOR-CTR) or hypertensive controls (HYP-CTR). SUBJECTS AND METHODS Ninety-six consecutive patients with active acromegaly (46 males, mean age 49±14 years) underwent 24-h ABPM and evaluation of cardiovascular risk factors. Based on ABPM measurement, acromegalic patients were divided into 64 normotensive (normotensive acromegalic patients (NOR-ACRO)) and 32 hypertensive (hypertensive acromegalic patients (HYP-ACRO)) patients, and were compared with 35 normotensive (NOR-CTR) and 34 hypertensive (HYP-CTR) age-, sex,- and ABPM-matched control subjects. RESULTS The AASI and Sym-AASI indexes were significantly higher in acromegalic patients than in controls, either in the normotensive (NOR-ACRO vs NOR-CTR, P<0.0001 for AASI and P=0.005 for Sym-AASI) or in the hypertensive (HYP-ACRO vs HYP-CTR, P=0.01 for AASI and P=0.01 for Sym-AASI) group. Multiple logistic regression analysis showed a significant association of the highest AASI tertile with serum IGF1 (P=0.034) in the whole acromegalic group. CONCLUSION AASIs are increased in acromegaly, independent of blood pressure (BP) elevation, and may have an important role in predicting cardiovascular risk in this disease.

Haemoconcentration, shear-stress increase and carotid artery diameter regulation after furosemide administration in older hypertensives

The aim of the present study was to determine whether changes of carotid wall shear stress induced by changes in blood viscosity after diuretic administration cause carotid arterial dilatation in elderly hypertensives, as reported in the cat. Arterial wall shear rate (ultrasound technique, profilmeter FRP III), the systo-diastolic diameter (echotracking technique) and the mean blood flow velocity and volume of the common carotid artery, the blood viscosity (rotational viscometer) and the finger arterial blood pressure (Finapress Ohmeda) were measured in 12 young volunteers (aged 25+/-2 years) and in 12 elderly hypertensives (aged 80+/-4 years) treated with short-acting calcium antagonists up to 24h before the study, both at baseline and after intravenous furosemide infusion (0.5mg/min), when the haematocrit had increased by at least two percentage points. After furosemide administration the mean arterial blood pressure decreased and blood viscosity and carotid systolic shear stress increased in both groups. However, common carotid artery diameter increased only in the young controls but not in the elderly hypertensives. These data show that an increase in carotid shear stress caused by haemoconcentration induces carotid vasodilatation only in young healthy subjects, and not in elderly hypertensives. This effect may be related to impaired endothelium function and/or arterial wall mechanics.