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Obesity is frequently associated with left ventricular hypertrophy (LVH), a condition leading to an increased cardiovascular risk. The objective of this study was to evaluate the prevalence of LVH in a cohort of obese women, with a main focus on the anthropometric and clinical parameters that are associated with an increased left ventricular mass (LVM). The study was performed in 166 obese female patients. LVM was measured by echocardiography. The influence of various parameters on LVM was assessed by multivariate analysis. The prevalence of LVH was drastically different depending on the type of indexed LVM, being 19.9% when the LVM was indexed for body surface area and 72.3% when indexed for height. Age, duration of obesity, weight, waist-to-hip ratio, pulse pressure and hypertension retained an independent direct correlation with the LVM, explaining 39.6% of the overall LVM variability. Among the parameters of the metabolic syndrome, the increase in blood pressure was the main determinant of increased LVM. By using allometric indexation of LVM for height, the results of our study indicate a high prevalence of LVH in a cohort of obese women. Hypertension, pulse pressure, age, duration of obesity, bodyweight and fat distribution, expressed as waist-to-hip ratio, predict 40% of LVM variation.

A 26-year-old man visited the Outpatient Hypertension Unit, Department of Internal Medicine, University of Pisa, Italy, for uncontrolled hypertension under a two-drug antihypertensive treatment. He had been previously diagnosed with essential thrombocythaemia and had been prescribed aspirin (acetylsalicylic acid) 100 mg/day since he was 20 years old, with a stable platelet count of about 700 000–800 000. High blood pressure lasted 3 months and was treated with lisinopril 20 mg/day. One month before the visit he had an acute coronary syndrome, with normal coronary angiogram, and clopidogrel 75 mg/day and amlodipine 5 mg/day were added at discharge. At the Hypertension Unit, a bilateral renal artery stenosis was diagnosed, accompanied by cardiac and renal target organ damage. Moreover, a total occlusion of the right carotid artery was found. The patient underwent bilateral percutaneous renal angioplasty with stent placement. He was discharged with interferon-α-2b, aspirin and warfarin and with no antihypertensive therapy, having blood pressure values of 100/70 mmHg. A few months later he became hypertensive again and lisinopril 20 mg/day was prescribed, while platelet count was reduced to 500 000. Nine months later he died of a sudden death.

BACKGROUND The effect on endothelium-dependent and independent vasodilation of 24-week treatment with a fixed-dose combination of perindopril/indapamide (2/0.625 mg, daily) and atenolol (50 mg, daily), was evaluated in 62 untreated essential hypertensive patients according a double-blind, parallel group, randomized study. METHODS Brachial artery flow-mediated dilation (FMD), response to sublingual glyceril trinitrate (GTN, 25 microg) and to cold pressor test (CPT) were measured at baseline and after treatments at 12 and 24 weeks, as change in diameter from ultrasound scans by a computerized system. RESULTS Blood pressure (BP) was (P < 0.001) reduced in both groups, but to a greater (P < 0.01) extent in the perindopril/indapamide group. After 24 weeks, FMD was significantly increased (P < 0.01) by perindopril/indapamide (from 5.0 +/- 2.1 to 6.0 +/- 1.7%) but not by atenolol (from 5.1 +/- 1.8 to 5.5 +/- 1.8%). Improvement in FMD was not statistically related to BP reduction. Response to GTN was also significantly (P < 0.05) increased by perindopril/indapamide (from 6.2 +/- 1.9 to 6.9 +/- 1.7%), but not by atenolol (from 6.1 +/- 2.8 to 6.6 +/- 2.6%). Improvement in GTN response was significantly (P < 0.05) related to BP reduction. Response to CPT was significantly increased (P < 0.001) by perindopril/indapamide after 12 and 24 weeks, whereas atenolol significantly (P < 0.05) improved it only after 24 weeks. CONCLUSIONS Treatment with perindopril/indapamide improves endothelium-dependent vasodilation in comparison with atenolol. This improvement was observed without significant relations with BP changes, suggesting a pressure-independent effect. Improvement in endothelium-independent and sympathetic-associated vasodilation was also observed. These results suggests that long term therapy with a fixed-dose combination of perindopril/indapamide affords vascular protection in hypertensive patients.

The rapid increasing prevalence of obesity worldwide represents a serious health hazard. Obesity predisposes to increased risk for diabetes, hypertension, renal failure. Direct mechanisms link visceral adiposity and the atherosclerosis process through the action of adipose-derived proinflammatory cytokines. In particular, hypertension can be considered the most important cardiovascular risk factor linking obesity to the development of cardiovascular disease. Obesity among children and adolescents has also reaching epidemic proportions in the industrialized world. Childhood obesity strongly predisposes to cardiovascular adult mortality. Recent reports documented a tracking of blood pressure from childhood to adulthood and obesity occurring in young age plays a crucial pathogenic role. Indeed, fighting overweight and obesity in the pediatric and adolescent age may prevent the occurrence of adults with hypertension and cardiovascular disease. The main strategies for prevention and treatment of overweight and obesity in childhood, which need to involve community, school and family, are the promotion of lifestyle interventions, including as a correct dietary approach, rich in fruit and vegetables and low-fat dairy products, and physical activity.

The relationship between adrenergic stimuli and NO in modulating tissue-type plasminogen activator (t-PA) release from endothelial cells was investigated in normotensive subjects and essential hypertensive patients. Sympathetic activation, a well-known stimulus for endogenous fibrinolysis, is also involved in the determination of cardiovascular risk in essential hypertension. However, the existence of cross-talk between adrenergic stimuli and NO availability in modulating t-PA release is not well established yet. We assessed the release of t-PA in the forearm microcirculation of 58 normotensive subjects (mean age: 47±9 years) and 44 essential hypertensive patients (mean age: 48±11 years) under specific intra-arterial adrenergic stimuli. Intrabrachial infusion of epinephrine (0.1 to 0.3 μg/100 mL per minute) induced greater t-PA release in normotensive subjects as compared with essential hypertensive patients ( P G -monomethyl- l -arginine (100 μg/100 mL per minute) infusion blunted epinephrine-induced t-PA release in normotensive subjects ( P P G -monomethyl- l -arginine ( P G -monomethyl- l -arginine coinfusion. In conclusion, the results of the present study demonstrate that adrenergic-induced t-PA release is mediated by β-adrenoreceptors via a mechanism involving the NO pathway. Our results show an impaired adrenergic-stimulated t-PA release among essential hypertensive patients, probably mediated via a reduced NO availability. This impaired fibrinolytic activity might contribute to the increased cardiovascular risk associated with hypertension.

OBJECTIVE Metabolic syndrome is associated with a high risk of cardiovascular disease in hypertension. We evaluated whether metabolic syndrome is associated with early vascular alterations, such as increased peripheral wave reflections and endothelial dysfunction, in untreated essential hypertensive patients. METHODS Augmentation index and pulse wave velocity were determined with applanation tonometry in 391 untreated hypertensive patients and 166 controls. Endothelium-dependent response was assessed as flow-mediated dilation of the brachial artery. Metabolic syndrome was defined according to the latest National Cholesterol Education Program Adult Treatment panel III. RESULTS Hypertensive patients showed significantly (P < 0.001) increased augmentation index and central pulse wave velocity, as well as reduced flow-mediated dilation, compared with controls. No further impairment in augmentation index or flow-mediated dilation was observed between patients with or without the metabolic syndrome components and with increasing number of metabolic syndrome. Age and systolic blood pressure, but no other single factor of the metabolic syndrome, resulted as significant predictors of augmentation index and flow-mediated dilation. Female gender was associated with increased augmentation index (P < 0.05) in the presence of the metabolic syndrome. Central pulse wave velocity was selectively impaired by metabolic syndrome in both genders. Finally, reactive hyperemia was reduced in patients with the metabolic syndrome and decreased significantly with the increasing number of metabolic syndrome. CONCLUSIONS In untreated hypertensive patients, the presence of metabolic syndrome, which selectively impairs central pulse wave velocity, does not account for a further deterioration of peripheral wave reflection and conduit artery endothelial function. Our results suggest that blood pressure, age and gender are important determinants of peripheral vascular structural and functional parameters in these subjects, irrespective of the metabolic syndrome.

A large body of evidence indicates that patients with essential hypertension, and even more those with complicated hypertension, are characterized by endothelial dysfunction characterized by impaired NO availability secondary to oxidative stress production. A dysfunctioning endothelium is an early marker of the development of atherosclerotic changes and can also contribute to cardiovascular events. Vascular reactivity tests represent the most widely used methods in the clinical assessment of endothelial function. In the last two decades, many studies have evaluated the endothelium in hypertensive patients, using different techniques. Several methodologies were developed to study microcirculation (resistance arteries and arterioles) and macrocirculation (conduit arteries), both in coronary and peripheral vascular districts. This review will centre on the most relevant available techniques in the research on endothelial dysfunction in essential hypertension, their advantages and limitations, focusing on available data on endothelial dysfunction which characterizes patients with complicated hypertension. No available test to assess endothelial function has sufficient sensitivity and specificity to be used in clinical practice. Therefore, the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Only the growing concordant results from different reproducible and reliable methods exploring endothelial function with different stimuli will support and strengthen experimental findings, thus providing conclusive answers in this area of research.

Summary Introduction and aim: Dopamine agonists have been reported to increase the risk of cardiac valve regurgitation in patients with Parkinson’s disease. However, it is unknown whether these drugs might be harmful for patients with hyperprolactinaemia (HyperPRL). The aim of the study was to evaluate whether HyperPRL patients treated with dopamine agonists had a higher prevalence of cardiac valves regurgitation than that of general population. Methods and patients: One hundred consecutive patients (79 women, 21 men, mean age 41 ± 13 years) with HyperPRL during treatment with cabergoline were enrolled in an observational case–control study and compared with 100 matched normal subjects (controls). Valve regurgitation was assessed by echocardiography according to the American Society of Echocardiography recommendations. Results: Seven HyperPRL patients (7%) and six controls (6%) had moderate (grade 3) regurgitation in any valve (p = 0.980). All were asymptomatic and had no signs of cardiac disease. Mean duration of cabergoline treatment was 67 ± 39 months (range: 3–199 months). Mean cumulative dose of cabergoline was 279 ± 301 mg (range: 15–1327 mg). Moderate valve regurgitation was not associated with the duration of treatment (p = 0.359), with cumulative dose of cabergoline (p = 0.173), with age (p = 0.281), with previous treatment with bromocriptine (p = 0.673) or previous adenomectomy (p = 0.497) in patients with HyperPRL. Discussion: In conclusion, treatment with cabergoline was not associated with increased prevalence of cardiac valves regurgitation in patients with HyperPRL. Mean cumulative dose of cabergoline was lower in patients with HyperPRL than that reported to be deleterious for patients with Parkinson’s disease: hence, longer follow-up is necessary, particularly in patients receiving weekly doses > 3 mg.

Omega-3 fatty acids are essential polyunsaturated fatty acids that are crucial components of plasma membrane phospholipids. They influence cell structure and function and have anti-thrombotic and anti-arrhythmic properties, thus potentially exerting a favourable action on primary and secondary prevention of cardiovascular events. However, the supposed beneficial effect of omega-3 fatty acids in the management of cardiovascular risk has been evaluated only in a relatively small number of interventional studies, with results that are not consistent and are only suggestive of a putative beneficial effect of omega-3 supplementation on the prevention of cardiovascular mortality. Benefits have been reported mainly for the prevention of sudden death in patients with recent myocardial infarction and for primary and secondary prevention of nonfatal cardiac events in populations with high fish intake. Therefore, only ongoing trials will provide definitive data to elucidate whether omega-3 fatty acids could represent a new therapeutic approach for cardiovascular disease.

There is a large body of evidence indicating that inflammation plays a crucial role in all steps characterizing the atherosclerotic process. C-Reactive Protein is a circulating marker of inflammation which recently emerged as a powerful independent determinant of cardiovascular events. Hypertension is closely linked to inflammation. Experimental data and results from cross-sectional studies in humans indicate a relationship between CRP levels and blood pressure. In particular, CRP seems to be related with markers of arterial stiffness, thus suggesting a specific interaction between CRP and systolic blood pressure. However, such observational studies cannot provide any direct evidence for a cause-effect relation. Prospective studies are likely candidates to better define the putative causal relationship on this association. Available results from longitudinal studies are scanty, and do not allow to draw definitive conclusions. Moreover, prospective, placebo-controlled intervention trials documenting that reduction of CRP levels by pharmacological treatment might lead to a reduced risk to develop hypertension are not yet available. Without such crucial information, at the present time the causal connection between inflammation and blood pressure, although regarded as an intriguing possibility, remains undiscovered.

PRA was simultaneously measured in both renal veins and in a peripheral vein of patients with essential (6) and renovascular (37) hypertension. In renovascular patients suppression or renin secretion from the contralateral kidney was always observed: otherwise in patients with essential hypertension both kidneys contribute to peripheral PRA. The suppression of renin secretion from the ischemic kidney either by nephrectomy or by revascularization, joins with normalization either of peripheral PRA or of blood pressure. This finding points to the role of the renin-angiotensin system in the genesis of human renovascular hypertension.

L’edema ciclico idiopatico e una sindrome non infiammatoria caratterizzata da un obiettivo incremento ponderale o dalla percezione soggettiva di aumento del peso corporeo per cause non precisate. La sindrome colpisce pressoche esclusivamente il sesso femminile nella vita riproduttiva, e si caratterizza per la sensazione di tensione generalizzata e ritenzione idrica in posizione ortostatica. L’escursione ponderale giornaliera e variabile, ma puo raggiungere anche svariati chilogrammi. Poco si sa sulla genesi della malattia, anche se, verosimilmente, numerosi fattori possono concorrere in varia misura, come una attivazione del sistema renina-angiotensina, disturbi ipotalamici, alterazioni dopaminergiche sistemiche o renali e alterazioni anatomiche della parete vascolare con aumento della permeabilita capillare. Non raramente la malattia si instaura in pazienti con disturbi della condotta alimentare o comunque con alterazione del tono dell’umore e spesso e aggravata dall’uso di farmaci (diuretici, lassativi) che, assunti con lo scopo di perdere peso, aggravano poi la sintomatologia iniziale. La diagnosi di edema idiopatico e da porre dopo avere escluso tutte le altre forme note di edema localizzato o generalizzato. I provvedimenti terapeutici sono concentrati sul controllo del peso corporeo tramite una dieta povera di sodio, limitata nei carboidrati e generosa nei liquidi, il mantenimento giornaliero di posizione clinostatica alternat o a lunghe camminate e talora l’elastocompressione degli arti inferiori. Dal punto di vista farmacologico, e stato proposto l’uso di ACE-inibitori o antialdosteronici, senza peraltro durevoli successi, mentre i diuretici dell’ansa, i farmaci dopaminergici e soprattutto le amine simpaticomimetiche sembrano del tutto inutili e talora ricchi di effetti collaterali.

Objectives We assessed the role of cytochrome P450 2C9 (CYP 2C9)-derived endothelium-derived hyperpolarizing factor (EDHF) in the forearm microcirculation of essential hypertensive patients (EH) by utilizing sulfaphenazole (SUL), a selective CYP 2C9 inhibitor. Background In EH patients, EDHF acts as a compensatory pathway when nitric oxide (NO) availability is reduced. Cytochrome P450 2C9 is a possible source of EDHF. Methods In 36 healthy subjects (normotensive [NT]) and 32 hypertensive patients (HT), we studied forearm blood flow (strain-gauge plethysmography) changes induced by intraarterial acetylcholine (ACH) and bradykinin (BDK), repeated during NG-monomethyl-L-arginine (L-NMMA) (100 μg/100 ml/min) or SUL (0.03 mg/100 ml/min). In HT, the effect of SUL on ACH and BDK was repeated during vitamin C (8 mg/100 ml/min). Sodium nitroprusside (SNP) was utilized as control. Results In NT, vasodilation to ACH and BDK was blunted by L-NMMA and not changed by SUL. In contrast, in HT responses to ACH and BDK, reduced compared with NT, were resistant to L-NMMA. In these patients, SUL blunted vasodilation to ACH and to a greater extent the response to BDK. When retested with vitamin C, SUL was no longer effective on both endothelial agonists. In 2 final groups of normotensive control subjects, vasodilation to ACH or BDK residual to cyclooxygenase and L-NMMA blockade was further inhibited by simultaneous SUL infusion. Response to SNP, similar between NT and HT, was unaffected by SUL. Conclusions Cytochrome P450 epoxygenase-derived EDHF acts as a partial compensatory mechanism to sustain endothelium-dependent vasodilation in HT, particularly the BDK-mediated response, when NO activity is impaired because of oxidative stress.

The influence of catecholamines on vascular remodeling in humans was investigated.The objective was to study the carotid vascular wall in patients with pheochromocytoma (PHEO).An observational study was conducted in a university referral center for blood pressure diseases.Fourteen patients with PHEO, 15 matched high-normal essential hypertensives, 15 mild essential hypertensives, and 15 controls underwent two-dimensional conventional ultrasonography and ultrasonic tissue characterization of the carotid wall.Intimal media thickness (IMT), diameter, and corrected ultrasonic integrated backscatter signal (C-IBS) of carotid arteries were evaluated.IMT in PHEOs (0.844 +/- 0.18 mm, mean +/- sd) was greater than not only controls (0.596 +/- 0.09 mm, P0.0002) but also high-normal (0.710 +/- 0.17 mm, P0.03), and even mild (0.727 +/- 0.20 mm, P = 0.06) hypertensives. IMT in the latter was higher than in controls (P0.03), without difference in comparison with high-normal hypertensives. C-IBS values in PHEOs (-21.71 +/- 2.0 dB, mean +/- sd) were greater than in controls (-26.20 +/- 1.73 dB, P0.0001) but also than in high-normal (-23.84 +/- 1.16 dB, P0.002) and mild (-23.37 +/- 1.99 dB, P0.01) hypertensives. C-IBS values in controls were lower than in high-normal (P0.0005) and mild (P0.0001) hypertensives. Carotid diameter was not significantly different in the four groups. In PHEOs, C-IBS was associated with urinary noradrenaline (r = 0.640, P0.01) and normethanephrine (r = 0.737, P0.009).Carotid IMT of PHEOs is higher than in controls and matched groups of hypertensives with comparable or even higher blood pressure. This vascular rearrangement is characterized by increased IBS values due to collagen deposition and vascular fibrosis. Therefore, our data show that abnormal catecholamine levels take part per se in carotid wall remodeling of patients with PHEO.

Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with atherosclerosis and is therefore held to be an early feature in atherogenesis. However, the mechanisms by which endothelial dysfunction occurs in smoking, dyslipidaemia, hyperhomocysteinaemia, diabetes mellitus, arterial hypertension, cerebrovascular diseases, coronary artery disease and heart failure are complex and heterogeneous. Recent data indicate that endothelial dysfunction is often associated with erectile dysfunction, which can precede and predict cardiovascular disease in men. This paper will provide a concise overview of the mechanisms causing endothelial dysfunction in the different cardiovascular risk factors and disease conditions, and of the impact of the intervention measures and treatments.

An enormous number of studies in the last two decades have been devoted to investigating the role of the endothelium in cardiovascular diseases. Nonetheless, the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Biochemical markers, molecular genetic tests and invasive and non-invasive tools with and without pharmacological and physiological stimuli have been introduced. Furthermore newer pharmacological tools have been proposed. However, the application of these methodologies should fulfil a number of requirements in order to provide conclusive answers in this area of research. Thus, the most relevant methodological issues in the research on endothelial function and dysfunction are summarized in this paper.

OBJECTIVE: To evaluate whether adenomas arising from the adrenal cortex, a tissue of epithelial origin, are associated with high chromogranin A (CgA) levels and whether such tumors may express and release this protein. In addition, to investigate whether high CgA levels imply a neuroendocrine differentiation of the adrenocortical adenomas and, therefore, represent a humoral marker of malignant transformation of these tumors. DESIGN: Plasma CgA of 80 patients with non-functioning, benign adrenocortical adenomas was compared with that of 137 tumor-free subjects. In 15 patients, the masses were surgically removed and CgA was measured 2 months later. The other 65 patients with adrenocortical adenomas underwent clinical and radiological follow-up (range 24-36 months). METHODS: CgA was evaluated by immunoradiometric assay in peripheral blood and by immunohistochemistry in adrenal tissue specimens. RESULTS: An increase in plasma CgA (P

Impaired endothelial function due to reduced nitric oxide availability secondary to an augmented production of oxidative stress has been associated with an increased risk of cardiovascular events in patients with coronary artery disease. Therefore, improvement of endothelial function through antioxidant therapy might be an important therapeutic approach for the prevention of cardiovascular morbidity and mortality. Available evidence indicates that acute high-dose ascorbic acid (vitamin C) improves endothelial function in high-risk patients. In contrast, results from clinical trials on the effect of long-term antioxidant therapy are contradictory. This discrepancy could be due to different experimental designs, vascular areas, diseases, range of doses and concomitant drugs utilised. The possibility that antioxidant vitamins can reduce cardiovascular damage and prevent cardiovascular events has been investigated in several studies. While observational studies suggested an inverse relationship between antioxidant vitamin intake and progression of atherosclerotic lesions, controlled clinical studies showed no effect of antioxidant vitamins on post-percutaneous transluminal coronary angioplasty stenting restenosis, coronary and carotid atherosclerotic lesions. Controlled studies evaluating the effect of antioxidant vitamins, in particular tocopherol (vitamin E), on cardiovascular events showed no beneficial effect in six of eight trials, although data concerning both the presence or absence of benefit in particular patients and the type of cardiovascular events were discordant. Overall, while these data indicated that at this time antioxidant vitamins are not to be recommended for the prevention of cardiovascular events, they did not contradict the hypothesis that antioxidant therapy should still be considered an important tool for prevention-regression of atherosclerosis and prevention of cardiovascular events. However, this potential benefit needs to be confirmed by future controlled clinical studies using new antioxidant substances with optimal pharmacokinetics and pharmacodynamics, in order to achieve high bioavailability and a documented dose-dependent antioxidant effect.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Study, the largest double-blind, randomized trial in hypertensive patients, confirmed and strengthened the clinical relevance of thiazide diuretics in the treatment of hypertension but did not prove the superiority of these drugs. Its claim of the superiority of chlorthalidone was based on some secondary outcomes, principally represented by ( 1 ) an increased incidence of stroke in the doxazosin and lisinopril arms, an effect that might be explained by differences in systolic BP; ( 2 ) greater morbidity but not mortality for congestive heart failure (CHF) in the doxazosin, amlodipine, and lisinopril arms, a finding that might reflect poor accuracy in the diagnosis and/or especially the switching from diuretic treatment in 90% of patients. Moreover, the ALLHAT study has other limitations, and its conclusions are in contrast with data from overall controlled clinical trials indicating that given the same BP reduction, the benefit of different drug classes is similar. As to whether the ALLHAT study will influence ongoing guidelines concerning the choice of antihypertensive drugs, the answer is “yes” if interpretation of its data in favor of diuretics and cost of drugs become the preponderant considerations, as it was in recent JNC VII guidelines. However, the more liberal approach based on the choice of all available drug classes seems still to be valid, as is in the ESH-ESC guidelines, if the preponderant consideration is that the real benefit of antihypertensive therapy is due to efficient BP control and not to a particular benefit of a single drug class.

The present study was designed to evaluate the effect of combination therapy using the angiotensin-converting enzyme-inhibitor lisinopril and the dihydropyridine calcium antagonist nifedipine GITS on the degree and homogeneity of 24-hour blood pressure reduction in essential hypertensive patients. After a 4-week placebo run-in period, 51 patients (mean age, 54.4 +/- 9.4 years) with essential hypertension and clinic diastolic blood pressure between 105 and 115 mm Hg were randomized to 4-week treatment with lisinopril (20 mg), nifedipine GITS (30 mg), or their combination according to a multicenter, randomized, double-blind, crossover study. Trough clinic blood pressure and 24-hour ambulatory blood pressure were measured at the end of the run-in period and after 4 weeks of treatment. In addition to clinic and 24-hour average blood pressure reduction, the trough-to-peak ratio and the smoothness index, a new measure for the homogeneity of blood pressure reduction, were also calculated. Although both lisinopril and nifedipine GITS produced a significant reduction in clinic and 24-hour average blood pressure values, the reduction obtained with the combination was significantly (P < 0.001) greater. Moreover, the combination therapy increased (P < 0.01) the smoothness index as compared with each single drug for both systolic (lisinopril, 1.02; nifedipine GITS, 1.1; combination, 1.76) and diastolic (lisinopril, 0.98; nifedipine GITS, 0.87; combination, 1.54) blood pressure values, whereas trough-to-peak ratio values (expressed as median) for systolic (lisinopril, 0.41; nifedipine GITS, 0.52; combination, 0.55) and diastolic (lisinopril, 0.35; nifedipine GITS, 0.40; combination, 0.49) blood pressure values were not significantly increased by the combination therapy. Thus, antihypertensive treatment with the combination of lisinopril and nifedipine GITS is more effective and balanced over the 24 hours than the combination components administered alone, confirming that the smoothness index is superior to the trough-to-peak ratio in assessing homogeneity of pharmacologic blood pressure reduction.

Essential hypertension is associated with impaired endothelium-dependent vasodilation caused by oxidative stress-induced nitric oxide (NO) breakdown and compensatory production of a hyperpolarizing factor. To test whether calcium antagonist treatment can restore NO availability and prevent hyperpolarization through antioxidant properties, in 15 healthy subjects and 15 patients with essential hypertension, we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial bradykinin (5, 15, 50 ng/100 mL per minute), an endothelium-dependent vasodilator, in basal conditions, during infusion of N G -monomethyl- l -arginine (L-NMMA, 100 μg/100 mL per minute), an NO-synthase inhibitor, and ouabain (0.72 μg/100 mL per minute), an Na + -K + ATPase inhibitor to prevent hyperpolarization. These infusions were repeated in the presence of the antioxidant vitamin C (8 mg/100 mL/min). The response to sodium nitroprusside was also evaluated. In controls, vasodilation to bradykinin was inhibited by L-NMMA and remained unchanged by ouabain or vitamin C. In hypertensive patients, vasodilation to bradykinin was blunted and resistant to L-NMMA but sensitive to ouabain. Vitamin C increased the response to bradykinin and restored the inhibiting effect of L-NMMA while preventing the effect of ouabain. In hypertensive patients, infusions were repeated after 3-month treatment with lercanidipine (10 to 20 mg daily). Lercanidipine decreased plasma lipoperoxides, isoprostanes, and malondialdehyde and increased plasma antioxidant capacity. Moreover, lercanidipine increased the vasodilation to bradykinin and restored the inhibiting effect of L-NMMA on bradykinin-induced vasodilation while preventing the effect of ouabain. Finally, vitamin C no longer exerted its facilitating activity. These results indicate that in essential hypertension, lercanidipine increases endothelium-dependent vasodilation by restoring NO availability and preventing hyperpolarization, an effect probably determined by antioxidant activity.

We sought to investigate whether two polymorphisms located in the promoter (T(-786)C) and exon 7 (Glu298Asp) of the endothelial nitric oxide (NO) synthase (eNOS) gene affected agonists-mediated NO release.Endothelial dysfunction can be genetically determined. Therefore, we investigated whether two polymorphisms located in the eNOS gene affected agonists-mediated NO release.We compared endothelial-dependent and -independent vasodilation of the different eNOS genotypes in a cross-sectional study on 187 subjects, of whom 137 were uncomplicated essential hypertensive patients (PH) (49 +/- 9 years, 151 +/- 11/99 +/- 5 mm Hg) and 50 healthy normotensive subjects (NT) (43 +/- 16 years, 123 +/- 10/78 +/- 7 mm Hg). Endothelial-dependent and -independent vasodilation was assessed as the forearm blood flow response to incrementally increasing doses of acetylcholine (0.15, 0.45, 1.5, 4.5, 15 microg/100 ml/min) and sodium nitroprusside (1, 2, 4 microg/100 ml/min), respectively. Genotyping was performed with melting curve analysis (Lightcycler) of polymerase chain reaction products from acceptor (5' end-labeled with LCRed 640) and donor probes (3' end-labeled with fluorescein) specific for each polymorphism. The genotype distribution of T(-786)C (CC = 21.9%, CT = 48.7%, TT = 29.4%) and Glu298Asp (GG = 39.0%, GT =51.9%, TT = 9.1%) was similar in PH and NT. A repeated measure analysis of variance showed a blunting of endothelium-dependent vasodilation in PH compared with NT (p0.001). A significant effect of the T(-786)C (p = 0.002) but not of the Glu298Asp (p = NS) eNOS polymorphism on endothelial-dependent vasodilation was found. However, we also detected a significant interaction between the T(-786)C and Glu298Asp polymorphism (p0.001). No effect on either polymorphism on endothelial-independent vasodilation was seen.The T(-786)C promoter polymorphism and its interaction with exon 7 Glu298Asp affect endothelium-dependent vasodilation in mild-to-moderate PH patients and NT Caucasian subjects.

OBJECTIVE: To compare clinical and humoral parameters before and after surgery in patients with incidental adrenocortical adenomas. DESIGN: Six patients with subclinical Cushing's syndrome and nine with non-functioning adenomas were investigated before and 12 Months after removal of the mass. METHODS: Anthropometric (body weight, body mass index and waist to hip ratio), haemodynamic (blood pressure and heart rate), metabolic (lipids and oral glucose tolerance test (OGTT)), hormonal (cortisol, plasma renin activity, aldosterone, androgens and catecholamines) and bone metabolism (hydroxyproline, parathyroid hormone, osteocalcin and ostase) parameters were evaluated. RESULTS: In the whole group, a significant decrease in body weight (69.7+/-3.5 vs 70.8+/-3.5 kg, P

A disproportionate accumulation of fibrillar collagen is a characteristic feature of hypertensive heart disease, but the extent of myocardial fibrosis may differ in different models of hypertension. In experimental studies, aldosterone and endothelins emerge as important determinants of myocardial fibrosis. Changes in myocardial extracellular matrix and collagen deposition can be estimated noninvasively by analysis of the ultrasonic backscatter signal, which arises from tissue heterogeneity within the myocardium and describes myocardial texture. This study was designed to investigate the relations between myocardial integrated backscatter and circulating aldosterone and immunoreactive endothelin in human hypertension. The study population consisted of 56 subjects: 14 healthy normotensive volunteers and 42 hypertensive patients (14 with primary aldosteronism, 7 with renovascular hypertension, and 21 with essential hypertension). The patients with essential and secondary hypertension were matched for age, gender, body mass index, and blood pressure. Myocardial integrated backscatter at diastole was 19.8±2.0 and 20.8±2.9 decibels in normotensive control subjects and patients with essential hypertension and significantly higher in patients with primary aldosteronism (27.4±3.8 decibels, P P r =0.73 and 0.71, P r =0.60 and 0.56, P

When planning treatment for patients with hypertension, current guidelines emphasise the importance of risk stratification, based on blood pressure, the presence of end-organ damage and other cardiovascular risk factors. Because the beneficial effect of antihypertensive therapy seems to be linked to the degree of blood pressure reduction, guidelines recommend reducing blood pressure below 140/90mm Hg, with a lower target in patients who are young or who have diabetes mellitus (with or without nephropathy) or non-diabetic nephropathy. Blood pressure reduction can be achieved with several classes of drugs, including diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists and calcium channel antagonists. Calcium channel antagonists have been shown to reduce the risk of stroke and major cardiovascular events. However, it is still controversial whether different treatment regimens based on different drug classes can offer advantages beyond similar degrees of blood pressure control in preventing cardiovascular morbidity and mortality. The International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) was a controlled clinical trial aimed at comparing the efficacy of a long-acting calcium channel antagonist, nifedipine gastrointestinal-transport-system (GITS), versus co-amilozide, a combination of the diuretics hydrochlorothiazide (HCTZ) and amiloride, on morbidity and mortality in high-risk hypertensive patients. Nifedipine GITS and HCTZ/amiloride were equally effective at reducing blood pressure and the risk of primary outcomes (a composite of death from any cardiovascular or cerebrovascular cause, non-fatal stroke, myocardial infarction and heart failure). Results from other studies indicate that there may be greater benefits for stroke and smaller benefits for coronary artery disease with calcium channel antagonist-based regimens than with diuretic or beta-blocker-based regimens. However, there is at present insufficient evidence to recommend a specific drug choice based on patient risk profile. Thus, the choice of antihypertensive drug(s) should be according to efficacy and tolerability. In addition to the reductions in cardiovascular risk, two substudies of INSIGHT showed that nifedipine GITS was able to prevent the progression of intima media thickness in the common carotid artery and slow the progression of coronary calcification. The clinical significance of this effect in the prevention of cardiovascular events still remains to be established.

Endothelium plays a primary role in the local control of vascular function and structure. Thus endothelium-derived nitric oxide (NO) is not only a potent vasodilator but also inhibits platelet aggregation, vascular smooth muscle cell migration and proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall against the development of atherosclerosis and thrombosis. Essential hypertension is associated with endothelial dysfunction, which involves the enhanced production of oxygen free radicals, that can destroy NO and reduce its availability, and the release of endothelium-derived contracting factors, including prostanoids and endothelin-1. Endothelial dysfunction in patients with essential hypertension is, at least in part, genetically determined and shows no correlation with blood pressure load, but is a promoter of atherosclerotic and thrombotic damage, which are typical complications of hypertension. In prospective studies, impaired endothelium-dependent vasodilation is associated with an increased incidence of cardiovascular events. Thus, endothelial dysfunction is often considered a target for cardiovascular treatment. However, endothelial function cannot yet be included among the surrogate endpoints that need to be measured for cardiovascular risk stratification in patients with essential hypertension because of the lack of validated tests. Currently, the tests available for assessing endothelium-dependent vasodilation are invasive or, if not invasive, do not have sufficient sensitivity and specificity for clinical practice. Moreover, despite considerable evidence that impaired endothelium-dependent vasodilation can be improved by the appropriate antihypertensive treatment, further large-scale clinical trials are required to prove conclusively whether reversal of endothelial dysfunction offers a clinical advantage in patients with essential hypertension. Only after a specific and affordable test has been validated, and definite evidence becomes available to demonstrate that endothelial dysfunction must be a target of pharmacological treatment, will the evaluation of endothelium-dependent vasodilation be included in the list of clinical examinations that define cardiovascular risk in patients with essential hypertension.

We evaluated by immunohistochemistry the expression of the Bcl-2 and p53 proteins, as markers of apoptosis control, and of MIB-1, as a marker of cell proliferation, in a series of normal and neoplastic adrenocortical tissues. The specimens were 13 normal adrenals, 13 aldosterone-producing adenomas, 13 non-functioning adenomas and 16 carcinomas. Results were calculated as percentage of immunostained cells by using specific antibodies. No p53 protein was detected in any of the adrenocortical adenomas (functioning and non functioning) or normal adrenals, while p53 was overexpressed in 15 out of 16 carcinomas. In particular, 10 adrenal cancer specimens (62.5%) showed strong staining in a high percentage (range 10–50%) of the malignant cells. The percentage of Bcl-2 positive cells was higher (P

The aim of our study was to evaluate feasibility and accuracy of colour-coded duplex US in the detection of renal artery stenosis before and after stenting. Eighty-four patients (23 women, 61 men; mean age 64 years) with significant renal artery stenosis were studied with Doppler US, before and after stenting. A combined anterior and translumbar approach was used to visualise the renal arteries. Renal artery stenosis and in-stent restenosis were proved by the increase of renal peak systolic velocity (PSV) and reno-aortic ratio (RAR). Laboratory-specific threshold values of PSV and RAR were used to assess sensitivity and specificity of Doppler US. The renal arteries were visualised in all patients (feasibility 100%). A statistically significant difference of PSV and RAR was demonstrated between patent and stenotic renal arteries, before stenting, and between stenotic and stented renal arteries. No difference was demonstrated in cases of in-stent restenosis ( n=21). Before stenting, sensitivity of PSV and RAR was 93%, whereas specificity rates were 92 and 96%, respectively. After stenting sensitivity and specificity rates were, respectively, 90 and 93% for PSV, and 95 and 95% for RAR. Doppler US represents a feasible and reliable technique in the detection of renal artery stenosis and in-stent restenosis, although laboratory-specific threshold values are required to improve its accuracy.

The endothelium can greatly influence vascular tone and structure. The main endothelium-derived factor is nitric oxide (NO), which is not only a potent vasodilator but also inhibits platelet aggregation, smooth muscle cell proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall against the development of atherosclerosis and thrombosis. In human hypertension, endothelial dysfunction has been documented in peripheral and coronary macro- and microcirculation and in renal circulation. The mechanism responsible for endothelial alteration in essential hypertensive patients appears to be the activation of an alternative pathway involving cyclooxygenase, which reduces NO availability through production of oxidative stress. In the presence of impaired NO availability a hyperpolarizing factor seems to act as a compensatory pathway to sustain endothelium-dependent relaxation. This compensatory pathway can be further depressed by the simultaneous presence of essential hypertension and hyperhomocysteinaemia, another cardiovascular risk factor causing endothelial dysfunction. Finally, reduced NO availability can increase the biological activity of endothelin-1 because, while in healthy conditions the vasoconstrictor effect of endothelin-1 is partially blunted by endothelial ETB-receptor mediated NO production, in essential hypertensive patients this protective mechanism is lacking on account of impaired NO availability. This alteration in the NO pathway could be the main mechanism through which a dysfunctional endothelium could be a promoter of atherosclerosis and thrombosis and therefore lead to cardiovascular events in essential hypertensive patients.

Background: Increased expression of the endothelial leukocyte adhesion molecule E-selectin is implicated in vascular disease and may accompany the development of hypertension. We evaluated plasma soluble (s) E-selectin to assess its relationship with endothelium-dependent and endothelium-independent vasodilation in patients with hypertension. Methods: Thirty-one previously untreated and uncomplicated essential hypertensive patients were compared with 16 normotensive controls for changes in forearm blood flow (by strain-gauge plethysmography) in response to brachial artery infusion of the endothelium-dependent vasodilator acetylcholine, and of the endothelium-independent vasodilator sodium nitroprusside. As an index of structural changes, minimal forearm vascular resistances were calculated as the ratio between maximal vasodilation after 13 min of ischemia and mean blood pressure. Results: Responses to acetylcholine were significantly lower and minimal forearm vascular resistances higher in hypertensives versus controls, whereas responses to nitroprusside were comparable. Baseline sE-selectin concentrations were (mean ± SEM) 37.4 ± 1.8 ng/mL in hypertensives and 27.8 ± 0.7 ng/mL in normotensives (P < .001). In essential hypertensive patients, a significant (P < .01) correlation with the response to nitroprusside (r = −0.47) was found, but not with the response to acetylcholine or minimal forearm vascular resistances. sE-selectin was also positively correlated with age and LDL cholesterol. At multivariate analysis, sE-selectin remained significantly correlated with nitroprusside responses and LDL cholesterol. Conclusions: In patients with essential hypertension, plasma levels of sE-selectin are higher than in normotensive controls and mostly related to structural vascular changes.

Essential hypertension is associated with impaired endothelium-dependent vasodilation caused by oxygen free radical–induced nitric oxide (NO) breakdown. Because calcium antagonists can improve endothelial function in patients with essential hypertension, in this study we tested the hypothesis that this beneficial effect could be related to restoration of NO availability by antioxidant properties. In 15 healthy subjects and 15 hypertensive patients, we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (ACh; 0.15, 0.45, 1.5, 4.5, and 15 μg/100 mL per minute), an endothelium-dependent vasodilator in basal conditions, during infusion of N G -monomethyl- l -arginine (L-NMMA, 100 μg/100 mL forearm tissue per minute), an NO-synthase inhibitor, vitamin C (8 mg/100 mL forearm tissue per minute), and finally, simultaneous infusion of L-NMMA and vitamin C. The response to sodium nitroprusside (SNP; 1, 2, and 4 μg/100 mL forearm tissue per minute) was also evaluated. In control subjects, vasodilation to ACh was inhibited by L-NMMA and not changed by vitamin C. In hypertensive patients, vasodilation to ACh was blunted as compared with control subjects and resistant to L-NMMA. Vitamin C, which decreased plasma isoprostanes and increased plasma antioxidant capacity, increased the response to ACh and restored the inhibiting effect of L-NMMA. In hypertensive patients, the study was repeated after 3-month treatment with nifedipine gastrointestinal therapeutic system (30 to 60 mg/daily). Nifedipine treatment decreased circulating plasma lipoperoxides and isoprostanes and increased plasma antioxidant capacity. Moreover, nifedipine increased the vasodilation to ACh but not to SNP and restored the inhibiting effect of L-NMMA on ACh-induced vasodilation, whereas vitamin C no longer exerted its facilitating activity. These results indicate that nifedipine increases endothelium-dependent vasodilation by restoring NO availability, an effect probably determined by antioxidant activity.

Endothelins are potent 21 amino acid vasoconstrictor isopeptides produced in different vascular tissues, including vascular endothelium. Endothelin-1 is the main endothelin generated by the endothelium and probably the most important in the cardiovascular system. Endothelin-1 acts through specific receptors termed ETA, represented only on smooth muscle cells and having the function of growth promotion and mediating contractions, and ETB, located both on smooth muscle cells, where they evoke contractions, and on endothelial cells, inducing relaxation by production of the endothelium-derived relaxing factor nitric oxide. In physiological conditions endothelin-1 administration causes vasodilation and vasoconstriction at low and high concentrations, respectively. However, administration of mixed ETA/B receptor antagonists causes slight or absent vasodilation, indicating that the direct vasoconstrictor effect of the peptide is probably masked by ETB-induced NO-dependent vasodilation. In essential hypertensive patients, the activity of exogenous endothelin-1 is either increased, similar or decreased as compared to normotensive subjects, depending on which vascular district or scheme of administration is considered. But although available evidence does not indicate increased endothelin-1 plasma levels in patients with essential hypertension, simultaneous antagonism of ETA/B receptors causes a greater degree of vasodilation in hypertensives than in normotensive subjects. Moreover administration of a selective ETB receptor antagonist causes vasoconstriction in normotensive subjects and vasodilation in essential hypertensive patients. Finally, the vasodilating effect of a mixed ETA/B receptor antagonist is inversely related to NO availability. Taken together these findings suggest that essential hypertension is characterized by increased endothelin-1 vasoconstrictor tone. This alteration seems to be dependent on decreased endothelial ETB-mediated NO production attributable to impaired NO availability. In such conditions endothelial ETB-induced vasodilation no longer compensates for the direct classical endothelin vasoconstrictor effect mediated by smooth muscle cell ETA and ETB receptors. Therefore endothelin-1 could potentially be involved in the pathogenesis of essential hypertension or of its complications, and blockade of this system is a fascinating new target for therapeutic intervention in this disease.

Background —Aging is associated with increased cardiovascular risk and endothelial dysfunction. Since exercise can improve endothelium-dependent vasodilation, in the present study we tested whether long-term physical activity could prevent aging-related endothelial dysfunction. Methods and Results —In 12 young and elderly (age 26.9±2.3 and 62.9±5.8 years, respectively) healthy sedentary subjects and 11 young and 14 elderly matched athletes (age 27.5±1.9 and 66.4±6.1 years, respectively), we studied (with strain-gauge plethysmography) forearm blood flow modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg/100 mL per minute), an endothelium-dependent vasodilator, at baseline, during infusion of N G -monomethyl- l -arginine (L-NMMA) (100 μg/100 mL forearm tissue per minute), a nitric oxide–synthase inhibitor, vitamin C (8 mg/100 mL forearm tissue per minute), an antioxidant, and finally under simultaneous infusion of L-NMMA and vitamin C. The response to sodium nitroprusside (1, 2, and 4 μg/100 mL forearm tissue per minute) was also evaluated. In young athletes and sedentary subgroups, vasodilation to acetylcholine was inhibited by L-NMMA and was not changed by vitamin C. In elderly subjects, vasodilation to acetylcholine was blunted as compared with young subjects in both control subjects and athletes, whereas the response to sodium nitroprusside was similar. Moreover, in elderly athletes, vitamin C did not change the vasodilation to acetylcholine. In contrast, in elderly sedentary subjects, the response to acetylcholine was resistant to L-NMMA. In this subgroup, vitamin C increased the vasodilation to acetylcholine and restored the inhibiting effect of L-NMMA. Conclusions —These results suggest that regular physical activity can at least in part prevent the age-induced endothelial dysfunction, probably the restoration of nitric oxide availability consequent to prevention of production of oxidative stress.

Background —The goal of this study was to evaluate whether endothelial dysfunction associated with acute estrogen deprivation is caused by an alteration in the l -arginine–nitric oxide (NO) pathway and oxidative stress. Methods and Results —In 26 healthy women (age, 45.7±5.4 years) and 18 fertile women with leiomyoma (age, 44.5±5.1 years), we studied forearm blood flow (strain-gauge plethysmography) changes induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, or 15 μg · 100 mL −1 · min −1 ) or sodium nitroprusside (1, 2, or 4 μg · 100 mL −1 · min −1 ), an endothelium-dependent or -independent vasodilator, respectively. The NO pathway was evaluated by repeating acetylcholine during l -arginine (200 μg · 100 mL −1 · min −1 ; 13 control subjects and 9 patients) or N G -monomethyl- l -arginine (L-NMMA; 100 μg · 100 mL −1 · min −1 ; 13 control subjects and 9 patients); production of cyclooxygenase-derived vasoconstrictors was assessed by repeating acetylcholine during indomethacin (50 μg · 100 mL −1 · min −1 ; 13 control subjects and 9 patients) or vitamin C (8 mg · 100 mL −1 · min −1 ; 13 control subjects and 9 patients). Patients repeated the study within 1 month after ovariectomy and again after 3 months of estrogen replacement therapy (ERT; 17 β-estradiol TTS, 50 μg/d). Basally, vasodilation to acetylcholine was potentiated and inhibited by l -arginine and L-NMMA, respectively ( P l -arginine and L-NMMA disappeared, whereas indomethacin and vitamin C potentiated the response to acetylcholine ( P l -arginine and L-NMMA effects on vasodilation to acetylcholine but prevented the potentiation caused by indomethacin or vitamin C. Response to sodium nitroprusside was unaffected by either ovariectomy or ERT. Conclusions —Endothelial dysfunction secondary to acute endogenous estrogen deprivation is caused by reduced NO availability. Cyclooxygenase-dependent production of oxidative stress could be responsible for this alteration.

Essential hypertension is associated with impaired endothelium-dependent vasodilation and is caused mainly by production of oxygen free radicals that can destroy nitric oxide (NO), impairing its beneficial and protective effects on the vessel wall. Antihypertensive drugs can improve or restore endothelium-dependent vasodilation depending on their ability to counteract the mechanisms that impair endothelial function. Although treatment with atenolol gives negative results in peripheral subcutaneous and muscle microcirculation, acute nebivolol exerts a modest vasodilating effect in the forearm circulation. Whether this compound can activate NO production in essential hypertensive patients is controversial. Calcium entry blockers, particularly the dihydropyridine-like drugs, can reverse impaired endothelium-dependent vasodilation in different vascular districts, including the subcutaneous, epicardial, and peripheral arteries and forearm circulation. In the forearm circulation, nifedipine and lacidipine can improve endothelial dysfunction by restoring NO availability. Angiotensin-converting enzyme (ACE) inhibitors, however, seem to improve endothelial function in subcutaneous, epicardial, and renal circulation, but are ineffective in potentiating the blunted response to acetylcholine in the forearm of patients with essential hypertension. Finally, recent evidence suggests angiotensin II receptor antagonists can restore endothelium-dependent vasodilation to acetylcholine in subcutaneous, but not in the forearm muscle, microcirculation. However, treatment with an angiotensin II receptor antagonist can improve basal NO release and decrease the vasoconstrictor effect of endogenous endothelin-1.

Abstract —Patients with essential hypertension are characterized by impaired basal and agonist-evoked nitric oxide release and increased endogenous endothelin (ET)-1–induced vasoconstriction. To assess whether candesartan, an angiotensin II type 1 receptor blocker, can improve endothelial function, we studied the changes in forearm blood flow (FBF) induced in 15 hypertensive patients and in 15 control subjects by the intrabrachial infusion of N G -monomethyl- l -arginine (L-NMMA), norepinephrine, the ET A/B receptor antagonist TAK 044, sodium nitroprusside, and acetylcholine. In hypertensive patients, the FBF study was repeated 2 and 12 months after the start of treatment with candesartan cilexetil (8 to 16 mg daily). Compared with controls (maximal FBF decrease, −46±11%), hypertensive patients showed a reduced ( P P P P

Endothelium plays a primary role in the local modulation of vascular function and structure by the production and release of several substances including nitric oxide and endothelins (ET). Nitric oxide is a labile substance produced from the catabolism of L-arginine and not only causes vessel relaxation, but also inhibits platelet aggregation, smooth muscle cell proliferation, monocyte adhesion, adhesion molecules expression and endothelin-1 (ET-1) production. Endothelium-derived ET-1 is a potent vasoconstrictor and has inotropic and mitogenic properties. ET-1 acts through smooth muscle ET(A) and ET(B) receptors, which mainly mediate vasoconstriction, and endothelial ET(B) receptors, which oppose ET(A)- and ET(B)-mediated vasoconstriction by stimulating nitric oxide formation. Both nitric oxide and ET-1 play a crucial role in the cardiovascular physiology and an alteration of these systems can be a promoter of or be associated with most cardiovascular diseases. Essential hypertension is a pathological condition characterized by endothelial dysfunction. In hypertensive patients nitric oxide availability is impaired because of the production of cyclooxygenase-derived vasoconstrictor substances. The latter may also mediate the vasoconstrictor response to exogenous ET-1 because in forearm circulation of essential hypertensives, but not of normotensive controls, the ET-1-induced vasoconstriction is significantly blunted by intrabrachial indomethacin. Therefore, in normotensive subjects and essential hypertensives the vasoconstrictor effect of ET-1 seems to be dependent on different mechanisms. Moreover, in the peripheral circulation of normotensive subjects, where tonic nitric oxide production is preserved, unselective ET(A/B), receptor blockade by TAK-044 causes a very modest degree of vasodilation. In contrast in essential hypertensives, where the tonic nitric oxide production is reduced, the vasodilating effect of TAK-044 is more evident, indicating that the predominant vascular effect of endogenous ET-1 is the vasoconstriction. A possible explanation for this finding, in addition to an increased production of the peptide, could be related to a reduced ET(B) receptor-mediated nitric oxide activation. These peculiar aspects of the role of ET-1 in essential hypertension could have physiopathological relevance.

Background —In humans, endothelin (ET)-1 could be implicated in the pathophysiology of several cardiovascular diseases, including essential hypertension. We therefore evaluated the role of ET-1 in control of vascular tone in essential hypertension. Methods and Results —We used strain-gauge venous plethysmography to test changes in forearm blood flow induced by intrabrachial infusion of TAK-044 (10, 30, and 100 μg · 100 mL −1 · min −1 ), an ET A /ET B receptor antagonist, or sodium nitroprusside (1 and 2 μg · 100 mL −1 · min −1 ), a vasodilator that acts on smooth muscle cells, in hypertensive patients and healthy controls (n=10 in each group). The NO pathway was also evaluated by infusion of N G -monomethyl- l -arginine, (L-NMMA; 10, 30, and 100 μg · 100 mL −1 · min −1 ), an NO synthase inhibitor, and norepinephrine (3, 9, and 30 ng · 100 mL −1 · min −1 ) as control. Immunoreactive plasma ET-1 was measured by radioimmunoassay. In hypertensive patients, TAK-044 caused a vasodilation that was significantly ( P P r =−0.56, P Conclusions —These results indicate that TAK-044 caused a greater degree of vasodilation in the forearm vessels of essential hypertensive patients compared with normotensive subjects, an alteration associated with decreased tonic NO release.

OBJECTIVESThe aim of the study was to evaluate whether adenosine infusion can induce production of active renin and angiotensin II in human coronary circulation.BACKGROUNDAdenosine can activate angiotensin production in the forearm vessels of essential hypertensive patients.METHODSIn six normotensive subjects and 12 essential hypertensive patients adenosine was infused into the left anterior descending coronary artery (1, 10, 100 and 1,000 μg/min × 5 min each) while active renin (radioimmunometric assay) and angiotensin II (radioimmunoassay after high performance liquid chromatography purification) were measured in venous (great cardiac vein) and coronary arterial blood samples. In five out of 12 hypertensive patients adenosine infusion and plasma samples were repeated during intracoronary angiotensin-converting enzyme inhibitor benazeprilat (25 μg/min) administration. Finally, in adjunctive hypertensive patients, the same procedure was applied during intracoronary sodium nitroprusside (n = 4) or acetylcholine (n = 4).RESULTSIn hypertensive patients, but not in control subjects, despite a similar increment in coronary blood flow, a significant (p < 0.05) transient increase of venous active renin (from 10.7 ± 1.4 [95% confidence interval 9.4 to 11.8] to a maximum of 13.8 ± 2.1 [12.2 to 15.5] with a consequent drop to 10.9 ± 1.8 [9.7 to 12.1] pg/ml), and angiotensin II (from 14.6 ± 2.0 [12.7 to 16.5] to a maximum of 20.4 ± 2.7 [18.7 to 22.2] with a consequent drop to 16.3 ± 1.8 [13.9 to 18.7] pg/ml) was observed under adenosine infusion, whereas arterial values did not change. Calculated venous–arterial active renin and angiotensin II release showed a strong correlation (r = 0.78 and r = 0.71, respectively; p < 0.001) with circulating active renin. This adenosine-induced venous angiotensin II increase was significantly blunted by benazeprilat. Finally, both sodium nitroprusside and acetylcholine did not affect arterial and venous values of active renin and angiotensin II.CONCLUSIONSThese data indicate that exogenous adenosine stimulates the release of active renin and angiotensin II in the coronary arteries of essential hypertensive patients, and suggest that this phenomenon is probably due to renin release from tissue stores of renally derived renin.