New intrarenal echo-Doppler velocimetric indices for the diagnosis of renal artery stenosis.

We aimed at comparing the positive and negative predictive values (PPV, NPV) of several intrarenal velocimetric indices for revealing the presence of renal artery stenosis (RAS) among hypertensive patients who underwent a renal angiography for the clinical suspicion of renovascular hypertension. In 106 patients (200 kidneys), the pulsatility index (PI) and resistive index (RI), the acceleration time (AT), and the mean systolic acceleration (ACC(sys)) were evaluated. In addition, the maximal systolic acceleration (ACC(max)), that is, the maximal slope of the acceleration phase, and the maximal acceleration index (AI(max)), that is, the ratio between ACC(max) and the relative peak systolic velocity, were calculated. On angiography, we found that 56 (28%) of the 200 arteries had a greater than 60% RAS. PI and RI had an NPV below 75%, whereas AT, ACC(sys), ACC(max), and AI(max) had an NPV always above 95%. However, ACC(max), and AI(max), at their best cutoff limits, had higher PPV than ACC(sys) and AT (60 and 70% vs 45 and 51%, respectively). Thus, in a cohort of patients with a high prevalence of RAS, PI and RI failed to reach an NPV adequate for a screening test. In contrast, all the acceleration indices we tested had a sufficiently high NPV but AI(max) appears superior to the others because of higher PPV. We propose the evaluation of AI(max) as an additional screening test in patients with hypertension and the clinical suspicion of RAS.

Nimesulide and renal impairment.

OBJECTIVES: To analyse from spontaneous reporting data the renal adverse reactions associated with the use of nimesulide. METHODS: Case reports were obtained from a Northern Italian Regional database (Veneto Pharmacovigilance System), containing all the spontaneous reports filed between 1988 and 1997. The Veneto Region is the principal contributor to the Italian spontaneous reporting system, with an annual report rate of approximately 17 per 100,000 inhabitants. The clinical records of hospitalized patients were also analysed. RESULTS: Of the 120 reports associated with oral nimesulide, 11 referred to suspected renal adverse reactions. The drug was taken by ten patients for a short period. All the patients discontinued the therapy and hospitalization was required in six cases. Other risk factors were identified in six cases. DISCUSSION: Together with the new insights into the possible consequences of renal cyclooxygenase-2 (COX-2) inhibition, the reported cases should draw the attention of doctors and patients to the importance of recognizing any possible signs of renal impairment during nimesulide therapy, although only extensive epidemiological data can define the real impact of its renal toxicity.

Diuretics in hypertension.

Despite the consistent reduction in the incidence of stroke and coronary events demonstrated in numerous clinical trials in young and elderly hypertensive subjects, the use of diuretics has declined as a first-line therapy in hypertension. The metabolic dose-dependent side effects and the increasing availability of new drugs appear the two main reasons for the decline. Although the neutral metabolic effects and the perception of a more physiological approach to hypertension has been advocated with the newer agents, no definite proof has been reported on the long-term effects on cardiovascular end-points. Many of adverse effects of diuretics can be limited by the use of low doses. For this reason, as well as their efficacy, safety, and cost-effectiveness, diuretics should remain a first-line therapy for hypertensive patients.

Influence of glucose load on cardiovascular and humoral responses to a cold pressure test.

To investigate the relationship between insulin and reactivity to the cold pressure test four groups of mildly obese patients (12 per group: normotensive, essential hypertensive, normotensive (N-NIDD) and hypertensive non-insulin-dependent diabetics (H-NIDD)) underwent a standardised oral glucose tolerance test. During the test, BP and heart rate were monitored and venous blood samples were obtained at 0, 60 and 120 minutes to determine serum levels of glucose, insulin (microU/ml), sodium, potassium (mEq/I), renin activity (ng/ml/hour), aldosterone, noradrenaline and adrenaline. The cold pressure tests were performed before glucose ingestion (I-CPT) and again at 60 minute after ingestion (II-CPT). As expected, glucose ingestion caused a significant increase in glycaemia and serum insulin; the latter rose significantly more at 60 minutes in normotensives (85 +/- 6) and essential hypertensives (83 +/- 5) than in N-NIDD (30 +/- 4) and H-NIDD (29 +/- 3). Plasma K significantly decreased in normotensives (4.4 +/- 0.1 vs. 3.6 +/- 0.1, P < 0.05) and essential hypertensives (4.3 +/- 0.1 vs. 3.5 +/- 0.1, P < 0.05) but did not change in either N-NIDD or H-NIDD. PRA significantly increased in normotensives (0.6 +/- 0.1 vs. 1.2 +/- 0.1, P < 0.01) and essential hypertensives (0.8 +/- 0.1 vs. 1.5 +/- 0.2, P < 0.05) but did not change in N-NIDD or H-NIDD. Plasma sodium and catecholamines did not change in any group. I-CPT induced similar reactivity in all the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Ambulatory blood pressure measurement in assessing the antihypertensive effect of benazepril plus hydrochlorothiazide in a fixed combination.

Ambulatory 24-hour blood pressure monitoring was used to assess the antihypertensive efficacy of the angiotensin-converting enzyme (ACE) inhibitor benazepril in combination with the diuretic hydrochlorothiazide (HCTZ) in 17 mildly to moderately hypertensive patients. Compared with placebo, benazepril 10 mg + HCTZ 12.5 mg induced a statistically and clinically significant reduction in the mean, systolic, and diastolic blood pressures. Cumulative percentages of diastolic blood pressure readings < 90 mmHg were also greater with the combination treatment than with placebo. No patient discontinued the treatment because of adverse effects.

Persistent albuminuria in normotensive non-insulin-dependent (type II) diabetic patients: comparative effects of angiotensin-converting enzyme inhibitors and beta-adrenoceptor blockers.

1. Some non-insulin-dependent (type II) diabetic patients show albuminuria without arterial hypertension. In these patients, angiotensin-converting enzyme inhibitors reduce urinary albumin excretion without producing any changes in systemic blood pressure and renal haemodynamics. However, up to now it has not been clear whether these favourable renal effects are specifically related to angiotensin-converting enzyme inhibition or not. 2. Twelve type II diabetic outpatients with persistent macroalbuminuria (greater than 300 mg/daily on at least three consecutive occasions), without any other signs of renal disease and whose blood pressure was persistently below 140/90 mmHg, were studied. 3. In a randomized sequence and in a double-blind fashion, after a 2-month run-in period, patients were allocated to receive 5 mg of enalapril or 50 mg of atenolol daily for the next 6 months. At the end of this first period and after 6 months on placebo in a cross-over fashion, active treatment was replicated. Blood pressure and urinary albumin excretion were measured every 2 months, whereas the other variables studied were determined at the end of each period. 4. Kidney function and blood pressure did not change significantly, whereas albuminuria decreased significantly, after both of the drugs. 5. These data suggest that the inhibition of tissue angiotensin formation and the consequent reduction in glomerular permeability, rather than changes in renal and systemic haemodynamics, are the common mechanisms by which both enalapril and atenolol decreased albuminuria in our patients.

Systemic hemodynamic pattern in primary hyperparathyroidism and its changes after parathyroidectomy.

Twelve patients (7 men and 5 women) with an average age of 53 years (range 37-69) were hospitalized for renal stones and found to have primary hyperparathyroidism. Five were hypertensive and 7 normotensive. The systemic hemodynamics, plasma renin activity and glomerular filtration rate were evaluated before and at least 6 months after removal of a parathyroid adenoma. After surgery the mean intra-arterial blood pressure fell in almost all patients, due to some reduction in the peripheral vascular resistance index with no change in the cardiac index. However, the hemodynamic variations were not uniform in all patients. No change was seen in plasma renin activity and glomerular filtration rate. A positive correlation between the percent change in mean arterial pressure and percent decrease in total serum calcium was found. The results obtained indicate that it is likely that hypercalcemia plays some role both in patients with high and those with normal blood pressure. The systemic hemodynamic changes after parathyroidectomy indicate that the fall in peripheral vascular resistance could have a certain influence.

Comparative effects of enalapril, atenolol and chlorthalidone on blood pressure and kidney function of diabetic patients affected by arterial hypertension and persistent proteinuria.

Arterial hypertension and proteinuric nephropathy are common features in diabetic patients. In streptozotocin-diabetic rats, it has been possible to reduce the blood pressure and proteinuria by converting enzyme inhibitors, and so slowing the decline of kidney function. These results have been confirmed in diabetic patients affected by arterial hypertension and persistent proteinuria. However, up to now it has not been clear if these favorable renal effects are related specifically to converting enzyme inhibition. In the attempt to clarify this last point, from a practical as well as from a speculative point of view, 12 type 2 diabetic outpatients affected by mild to moderate arterial hypertension and persistent macroalbuminuria (greater than 250 mg/daily, at least on three consecutive occasions) without any other signs of renal diseases were studied. In a randomized sequence and in a double blind fashion, after a washout period of 3 weeks, the patients underwent pharmacological treatment which consisted of enalapril 20 mg o.d., chlorthalidone 12.5 mg o.d., atenolol 50 mg o.d. and placebo o.d. Each treatment lasted 45 days. Kidney function, blood pressure and heart rate were checked at the beginning and at the end of each treatment, while urinary albumin excretion was measured at the end of the 4th, 5th, and 6th week of each treatment. Blood pressure significantly decreased in a similar fashion after each active treatment, while kidney function did not change significantly. Urinary albumin excretion rate significantly decreased after enalapril and atenolol, but did not change after chlorthalidone. According to these results we can hypothesize that the inhibition of tissue angiotensin formation and its related change on the glomerular permeability, rather than renal and systemic hemodynamic features, seem to be the common mechanisms by which both enalapril as well as atenolol decrease the albuminuria in our patients.

Cadralazine versus prazosin as second-step treatment in hypertensive patients on beta-blockers: a randomized multicentre study. The Italian Multicentre Study Group.

A randomized multicentre between-patient study comparison has been made of the efficacy and tolerability of cadralazine and prazosin, both administered for 6 weeks to hypertensive patients with a supine diastolic blood pressure (DBP) greater than or equal to 95 mmHg whilst on a beta-adrenoceptor-blocker. The doses of the beta-adrenoceptor-blocker (metoprolol SR 200 mg once daily) and cadralazine (10 mg once daily) were held constant during the study, while prazosin was individually titrated from 0.5 mg to a maximum of 2 mg tds. 108 patients (50 m and 58 f; mean age 54 y) were enrolled in 12 centres. Twelve patients withdrew due to adverse effects or poor efficacy (5 patients on prazosin and 7 on cadralazine). Both treatments induced a similar significant reduction in systolic blood pressure (SBP) and DBP, allowing normalization of BP in 58% of subjects on cadralazine and 55% on prazosin. Heart Rate (hR) increased significantly from 67 to 72 beats.min-1 in those on cadralazine and from 65 to 69 beats.min-1 on prazosin. Body weight was unchanged. Adverse effects were mild and typical of vasodilators, such as headache, flushing and dizziness. Physician evaluation of drug efficacy was not different between drugs, and cadralazine was rated better in terms of tolerability. Thus, in this multicentre study, cadralazine in the fixed dose of 10 mg once daily, as a second-step antihypertensive treatment in patients not satisfactorily controlled by a beta-adrenoceptor-blocker, was as effective and showed a similar side effect profile to prazosin given three times daily.

Effects of ketanserin administration on lipid metabolism and platelet aggregation in hypertensive patients.

Lowering blood pressure is not totally effective in preventing the atherosclerotic complications of systemic hypertension. In hypertensive patients both platelet hyperaggregation and dyslipidemia have been suggested as important risk factors. The effect of 8 weeks' treatment with ketanserin on blood pressure, serum lipid parameters (cholesterol, triglycerides, LDL, HDL-C, apolipoprotein A1 and B) and platelet aggregation, induced by collagen, ADP, arachidonic acid, was evaluated in 10 patients with essential hypertension. Ketanserin was effective in lowering blood pressure in all patients, 6 of whom became normotensive. Both CHOL and TG levels and APO B were significantly reduced, whereas HDL-C and APO A1 were significantly increased after treatment. These results might be attributed to the antagonistic activity of ketanserin on alpha-1 adrenoceptors with a consequent inhibition of phosphodiesterase. Platelet aggregation, after stimulation with collagen and arachidonic acid, was significantly reduced secondary to the inhibition of intraplatelet serotonin synthesis and release. These results suggest that keranserin is effective in reducing blood pressure and in achieving normal serum lipid pattern and platelet aggregation. Therefore, this drug might be helpful in controlling the main risk factors for cardiovascular damage.

Systemic and renal effects of a new angiotensin converting enzyme inhibitor, benazepril, in essential hypertension.

Seventeen essential hypertensive patients with normal renal function were treated with a new non-sulphydryl orally active angiotensin converting enzyme (ACE) inhibitor, benazepril, 10 mg given once or twice daily, according to diastolic blood pressure levels, for 6 weeks. In all patients, changes in blood pressure, systemic and renal hemodynamics, plasma renin activity and urinary aldosterone and albumin excretions were assessed at the end of a 2-week placebo run-in period and at the end of the study. Benazepril monotherapy controlled blood pressure well. No changes in cardiac output, heart rate or stroke volume were observed, while peripheral vascular resistance was significantly decreased (-11%, P less than 0.05). Plasma volume was unaltered. The glomerular filtration rate was stable, but effective renal plasma flow was increased because of the marked reduction in renal vascular resistance (-35%) and, therefore, the filtration fraction was decreased. Urinary albumin excretion remained unchanged. A significant increase in plasma renin activity (P less than 0.001) and a decrease in urinary aldosterone excretion were seen. No side effects were observed during the treatment period. In conclusion, our results suggest that benazepril alone is an effective antihypertensive agent in patients with essential hypertension. The blood pressure lowering effect is due mainly to systemic vasodilation and is observed up to 24 h after administration of the drug. The vasodilation appears to be more consistent in the renal than in the systemic circulation.

Effects of ACE inhibition in normotensive patients with chronic glomerular disease and normal renal function.

A double-blind, placebo-controlled study was carried out to assess the effects of a three-month treatment with a new ACE inhibitor, Benazepril (BNZ), on systemic and renal hemodynamics, and urine protein excretion, in 20 patients with chronic glomerulonephritis, normal blood pressure (130/83 +/- 16/10 mm Hg), and normal renal function (creatine clearance 106 +/- 25 ml/min). Treatments with placebo or BNZ were assigned randomly. A wide range of proteinuria lowering effect was observed in overall population (from 1 to 84%, average 34%). Following the arbitrary level of a 30% reduction, two well-matched subgroups (10 patients for each one) were obtained: "good responders" (average decrease 51%), and "poor responders" (average decrease 17%). The main distinctive feature between the two groups was a higher plasma renin activity level in good than in poor responders. A positive correlation between the fall in proteinuria and blood pressure was found. Although the decrease in blood pressure seems to represent the major factor in determining the reduction in proteinuria, a multiple correlation analysis showed that the most prominent role (71%) was attributable to the combined decrease in blood pressure and filtration fraction, and then also to the efferent arteriole dilatation. Our conclusion is that ACE inhibitors are capable of also reducing proteinuria in patients with renal disease with normal blood pressure, the effect being more pronounced in those exhibiting humoral, systemic and renal hemodynamic patterns, indicating a greater activity of circulating and renal renin angiotensin system.

Renal functional reserve in patients with essential hypertension: effect of inhibition of the renin--angiotensin system.

1. Urinary albumin excretion and the effect of an acute oral protein load (a meat meal) on glomerular filtration rate ('renal functional reserve') were evaluated in 15 essential hypertensive patients with preserved renal function and compared with 12 normal subjects. 2. Seven patients had microalbuminuria (greater than 30 mg/day) that was not correlated with blood pressure values. 3. After an oral protein load, an average increase of 20% in glomerular filtration rate (from 91 +/- 19 to 110 +/- 27 ml min-1 1.73 m-2 was found in the hypertensive patients. This change was not statistically different from that observed in normal controls (from 102 +/- 7 to 124 +/- 9 ml min-1 1.73 m-2). The glomerular response in hypertensive patients was independent of age, duration of hypertension, blood pressure, plasma renin activity, urinary albumin excretion and retinal vascular alterations. 4. All patients were re-evaluated after 6 weeks treatment with a new orally active angiotensin-converting enzyme inhibitor, benazepril. Systolic, diastolic and mean blood pressures were lowered in all the patients, but the drug did not affect the glomerular response to acute protein ingestion or the magnitude of urinary albumin excretion. 5. The findings of a normal 'renal functional reserve' and a lack of change in both urinary albumin excretion and the glomerular response after angiotensin-converting enzyme inhibition cast doubt on the existence of increased intraglomerular pressure in hypertensive patients.

Antihypertensive therapy with ketanserin: effects on central and renal hemodynamics, and microalbuminuria.

Ten patients with essential hypertension and normal renal function were treated with ketanserin (20-40 mg twice a day), administered for 8 weeks. In all patients, the changes in systemic and renal hemodynamics, and in urine albumin excretion, were assessed. Ketanserin monotherapy effectively lowered blood pressure in all patients. No change in cardiac output, pulse rate and stroke volume was observed; peripheral vascular resistance was significantly decreased. Plasma volume was unaltered. Renal plasma flow, glomerular filtration rate and filtration fraction were stable, with a slight but not significant reduction in renal vascular resistance. Urine albumin excretion remained unchanged. No relevant side effects were observed during the treatment period. In conclusion, our results confirm that ketanserin alone is an effective antihypertensive agent in patients with uncomplicated essential hypertension. The blood pressure lowering effect is mainly due to the systemic vasodilatation; renal hemodynamics and function are well preserved.

Hemodynamic, renal, and humoral effects of the calcium entry blocker nicardipine and converting enzyme inhibitor captopril in hypertensive type II diabetic patients with nephropathy.

We compared the effect of nicardipine, a dihydropiridine derivative calcium entry blocker (CEB), with that of captopril (CAP), a converting-enzyme inhibitor (CEI), and that of the two drugs combined, on blood pressure (BP), heart rate (HR), and renal function in 12 hypertensive type II diabetic outpatients with nephropathy (persistent proteinuria greater than 500 mg/24 h) according to a 2 x 2 factorial design. For 4-week treatments, the patients received nicardipine (NIC) 20 mg t.i.d., CAP 50 mg b.i.d., NIC plus CAP, and matched placebo. Each active treatment significantly reduced BP, with an additive effect of NIC and CAP combined versus either drug alone. HR did not change. Effective renal plasma flow (RPF) and glomerular filtration rate (GRF) were unmodified, but renal vascular resistances (RVRs) were significantly reduced by the three active treatments. Filtration fraction (FF) did not change with NIC or with NIC plus CAP and was significantly reduced with CAP. Urinary albumin excretion (UAE) was significantly reduced by each active treatment to a similar extent. Plasma renin activity (PRA) increased significantly with NIC plus CAP only and did not change when the drugs were administered singly. Plasma aldosterone, glucose, potassium, fructosamine, and urinary sodium and volume did not change during the trial. We conclude that the two drugs singly and combined are useful for treatment of hypertensive non-insulin-dependent diabetes (NIDD) patients with persistent proteinuria.

Angiotensin converting enzyme inhibition in normotensive type II diabetics with persistent mild proteinuria.

To evaluate the effect of enalapril on proteinuria, 16 normotensive type II diabetics with persistent proteinuria were studied. At random, the patients were allocated to enalapril (5 mg once a day) or placebo, in a double-blind fashion, for 12 months. Blood pressure, heart rate, urinary albumin excretion, plasma renin activity and aldosterone, blood glucose, serum fructosamine, urine urea and body weight were checked monthly during the run-in period and every 2 months during the treatment period. The kidney function was studied at the beginning of the study and during the sixth and 12th months. Enalapril decreased urinary albumin excretion in our patients in the absence of any effect on blood pressure and kidney function. Our data may be interpreted on the basis of a direct vascular effect of enalapril that is probably related to a tissue mechanism consisting of reduced angiotensin formation, increased kinins, or both, or of other unknown factors.

Systemic and renal effects of chronic angiotensin converting enzyme inhibition with captopril in hypertensive diabetic patients.

Nine outpatients with mild to moderate arterial hypertension, type 2 diabetes mellitus and persistent macroalbuminuria were studied. After 1 month of placebo, the patients were treated with 50 mg captopril twice a day for the following 6 months. Blood pressure and urinary albumin excretion were significantly reduced but no relationship was found between these two variables. No changes were detected in the renal plasma flow, glomerular filtration rate, filtration fraction, renal vascular resistance or metabolic pattern. Captopril significantly reduced blood pressure and albuminuria without any change in the renal function. The decrease in albuminuria may be related to the reduction in blood pressure as well as to a direct effect of captopril on glomerular haemodynamics.

Angiotensin converting enzyme inhibition with a low dose of enalapril in normotensive diabetics with persistent proteinuria.

Angiotensin II is the main regulator of both glomerular haemodynamics and glomerular capillary permeability. An alteration in the function of intrarenal angiotensin II seems to be the cause of diabetic glomerulopathy in animals and humans. In order to investigate the renal effects of the angiotensin converting enzyme (ACE) inhibitor enalapril (5 mg once a day), 24 normotensive diabetic patients with persistent proteinuria, after a 3-month run-in period, were randomly allocated to receive the active drug (12 patients) or the corresponding placebo, for the 6 months. Effective renal plasma flow, glomerular filtration rate, renal vascular resistance and filtration fraction were measured at the end of the run-in and the treatment periods. Blood pressure, heart rate, urinary albumin excretion, plasma renin activity and aldosterone, blood glucose, serum fructosamine and body weight were checked monthly during the run-in and every 2 months during the treatment period. Enalapril decreased urinary albumin excretion in the normotensive diabetic patients without any changes in systemic blood pressure or glomerular haemodynamics. These results indicate that ACE inhibition interferes with the glomerular capillary permeability induced by angiotensin II.