Moderate alcohol use and health: a consensus document.

AIMS: The aim of this consensus paper is to review the available evidence on the association between moderate alcohol use, health and disease and to provide a working document to the scientific and health professional communities. DATA SYNTHESIS: In healthy adults and in the elderly, spontaneous consumption of alcoholic beverages within 30 g ethanol/d for men and 15 g/d for women is to be considered acceptable and do not deserve intervention by the primary care physician or the health professional in charge. Patients with increased risk for specific diseases, for example, women with familiar history of breast cancer, or subjects with familiar history of early cardiovascular disease, or cardiovascular patients should discuss with their physician their drinking habits. No abstainer should be advised to drink for health reasons. Alcohol use must be discouraged in specific physiological or personal situations or in selected age classes (children and adolescents, pregnant and lactating women and recovering alcoholics). Moreover, the possible interactions between alcohol and acute or chronic drug use must be discussed with the primary care physician. CONCLUSIONS: The choice to consume alcohol should be based on individual considerations, taking into account the influence on health and diet, the risk of alcoholism and abuse, the effect on behaviour and other factors that may vary with age and lifestyle. Moderation in drinking and development of an associated lifestyle culture should be fostered.

Prospective appraisal of the prevalence of primary aldosteronism in hypertensive patients presenting with atrial flutter or fibrillation (PAPPHY Study): rationale and study design.

Primary aldosteronism (PA) is the most common endocrine form of hypertension and may carry an increased risk of atrial flutter or fibrillation (AFF). The primary goal of this multicentre cohort study is thus to prospectively establish the prevalence of PA in consecutive hypertensive patients referred for lone (non-valvular), paroxysmal or permanent AFF. Secondary objectives are to determine: (1) the predictors of AFF in patients with PA; (2) the rate of AFF recurrence at follow-up after specific treatment in the patients with PA; (3) the effect of AFF that can increase atrial natriuretic peptide via the atrial stretch and thereby blunt aldosterone secretion, on the aldosterone-to-renin ratio (ARR), and thus the case detection of PA; (4) the diagnostic accuracy of ARR based on plasma renin activity or on the measurement of active renin (DRA) for diagnosing PA in AFF patients. Case detection and subtyping of PA will be performed according to established criteria, including the 'four corners criteria' for diagnosing aldosterone-producing adenoma. Pharmacologic or direct current cardioversion will be undertaken whenever indicated following current guidelines. The hormonal values and ARR will be compared within patient between AFF and sinus rhythm. Organ damage, cardiovascular events and recurrence of AFF will also be assessed during follow-up in patients with PA.

Decreased number of circulating endothelial progenitor cells in patients with Graves' hyperthyroidism.

OBJECTIVE: A relevant biological role of circulating endothelial progenitor cells (EPC) was recently demonstrated. EPC are generated in the bone marrow, and interact with damaged endothelium, restoring the integrity of the monolayer. Therefore, aim of the present study was to evaluate EPC in the blood of patients with untreated Graves' hyperthyroidism (GD), in whom an increased oxidative stress was observed. DESIGN AND METHODS: Twenty-three patients with untreated active GD and 18 matched normal controls (NC) were included in the study. Circulating EPC were isolated from peripheral blood. Mononuclear cells were cultured with endothelial basal medium supplemented with EGM SingleQuots, and were identified by positive double staining after 7 days in culture. Circulating levels of C reactive protein, total antioxidant power, interleukin (IL)-6, IL- 18, monocyte chemoattractant protein-1, tumor necrosis facotr- α, soluble vascular cell adhesion molecule (VCAM) and intracellular adhesion molecule were evaluated by enzymelinked immunosorbent assay kit. EPC number was also evaluated in a subgroup of GD patients after restoration of euthyroidism. RESULTS: Systolic blood pressure resulted increased in GD patients compared with control subjects whereas diastolic blood pressure was not significantly different. Patients with GD showed an increase in circulating levels of IL-18 and VCAM-1 and a reduction of total antioxidant power (p<0.05) compared to NC. Moreover, a reduced number of EPC was observed in patients with GD compared to NC (p<0.05) which turned to NC values after restoring euthyroidism. CONCLUSION: Patients with GD showed a reduction in the physiological protective mechanisms against endothelial damage, probably induced by increased inflammation and oxidative stress.

Small artery remodeling in diabetes mellitus.

AIMS: To briefly review available data regarding changes in the structure of microvessels observed in patients with diabetes mellitus, and possible correction by effective treatment. DATA SYNTHESIS: The development of structural changes in the systemic vasculature is the end result of established hypertension. In essential hypertension, small arteries' smooth muscle cells are restructured around a smaller lumen and there is no net growth of the vascular wall, while in some secondary forms of hypertension, hypertrophic remodeling may be detected. Moreover, in non-insulin-dependent diabetes mellitus hypertrophic remodeling of subcutaneous small arteries is present. Indices of small resistance artery structure, such as the tunica media to internal lumen ratio, may have a strong prognostic significance in hypertensive and diabetic patients, over and above all other known cardiovascular risk factors. Therefore, regression of vascular alterations is an appealing goal of antihypertensive treatment. Different antihypertensive drugs seem to have different effects on vascular structure. In diabetic hypertensive patients, a significant regression of structural alterations to the small resistance arteries with drugs blocking the renin-angiotensin system (ACE inhibitors, angiotensin II receptor blockers) was demonstrated. CONCLUSION: Alterations in the microcirculation represent a common pathological finding, and microangiopathy is one of the most important mechanisms involved in the development of organ damage as well as of clinical events in patients with diabetes mellitus. Renin-angiotensin system blockade seems to be effective in preventing and/or regressing alterations in the microvascular structure.

Macro and microvasculature in hypertension: therapeutic aspects.

Macrovasculature, microvasculature and the heart determine the structure and function of the circulatory system. Due to the viscoelastic properties of large arteries, the pulsatile pressure and flow that result from intermittent ventricular ejection is smoothed out, so that microvasculature mediates the delivery of nutrients and oxygen to tissues steadily. The disruption of this function, which occurs when microvascular structure develops in response to hypertension, leads to end-organ damage. Microvascular structure is not only the site of vascular resistance, but also the origin of most of the wave reflections generating increased central systolic blood pressure (SBP) in the elderly. Nowadays many data of the literature suggest that hypertension-related damage to the micro and macrovascular system may be manageable through pharmacological agents. Among them, beta-blocking agents and diuretics poorly modify microvascular structure, whereas angiotensin and calcium entry blockade has an opposite effect, thereby reducing central wave reflections and, finally, causing a selective SBP reduction.

[Bone density and mineral metabolism in calcitonin-deficiency patients]. / Densità ossea e metabolismo calcico in pazienti calcitonino-privi.

AIM: Calcitonin is a hormone secreted by thyroid C-cells. Its primary effect seems to be a direct inhibition of bone degradation, but the physiological function of calcitonin in humans is still uncertain. The role of this hormone in the development of osteoporosis is unknown, but few authors have shown bone mass reduction in thyroidectomy patients. METHODS: To investigate the influence of calcitonin deficiency on bone turnover, 9 males (age 31 to 66 years) submitted to total thyroidectomy in 1996 for non-toxic goitre have been studied. These patients received thyroxine treatment at individual dose but never with suppressed TSH levels. Moreover 8 sex-, age- and Body Mass Index-matched normal subjects have also been studied as control group. RESULTS: Calcitonin was undetectable in thyroidectomized patients, while the mean value was 7.1+/-3.2 pg/ml in the control group. At bone ultrasonography 50% of patients showed osteopenia, while only 1 subject showed osteopenia in the control group. The mean calcium serum level of patients was significant lower than in the control group (p<0.001). Calcium urinary level was increased in patients than controls. PTH serum levels were statistically decreased (p<0.001) in patients more than in controls. Osteocalcin showed a significantly (p<0.05) lower bone formation in patients than in controls, while the markers of resorption, deoxypyridinoline and N-terminal telopeptide of type I collagen, suggested an increased bone turnover in calcitonin-deficiency patients. CONCLUSION: The results of this study show that the chronic lack of calcitonin in total thyroidectomized patients may play a role in increased bone degradation and osteopenia with a higher risk of bone fracture.

Von Recklinghausen's neurofibromatosis associated with duodenal somatostatinoma. A case report and review of the literature.

Somatostatin producing duodenal carcinoids are rare, comprising a mere 2% of small bowel carcinoids and 5-10% of all duodenal tumors. Since the 1st case described by Kaneko in 1979 more than 50 cases have been reported in the world literature. From these reports, it is gradually emerging that duodenal somatostatinomas may show a strong association with von Recklinhausen's neurofibromatosis (VRNF) as a distinct neuroendocrine syndrome. A case of a patient affected by VRNF associated with duodenal somatostatinoma with consequent obstructive jaundice is reported. The authors discuss the characteristics of these tumors and review the literature. A total of 27 patients with Von Recklinghausen's disease associated with immunohistologically proved duodenal somatostatinoma have been identified and compared with 29 duodenal somatostatinoma not associated with VRNF, and with 32 cases of pancreatic somatostatinomas.

Circulating adhesion molecules and carotid artery structural changes in patients with noninsulin-dependent diabetes mellitus.

Hypertension and non insulin-dependent diabetes mellitus (NIDDM) are well-known risk factors for atherosclerotic disease. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) may exert a relevant role in the pathogenesis of atherosclerosis; their prognostic relevance has been recently demonstrated. The aim of the study was to investigate possible inter-relation between circulating adhesion molecule levels, carotid artery structure and endothelial function in 15 patients with NIDDM, as well as in 15 patients with both NIDDM and essential hypertension (NIDDM+EH) compared with 15 normal subjects (NS) and 15 euglycaemic patients with EH, matched for age, sex and body weight. All subjects were submitted to a biopsy of the gluteal subcutaneous fat. Small arteries were dissected and mounted on a micromyograph, and the media-to-lumen (M/L) ratio was then calculated. Carotid artery structure was investigated by Doppler ultrasound. Endothelial function was evaluated by investigation of the flow-mediated dilatation (FMD) of the brachial artery. ICAM-1 and VCAM-1 plasma levels were measured by ELISA. ICAM-1 and VCAM-1 plasma levels were significantly greater and FMD smaller in EH, NIDDM and NIDDM+EH than in NS, but no difference was observed among the three pathological groups. Carotid artery structural changes were more pronounced in NIDDM+EH. No significant difference was observed among NIDDM, EH and NS. The M/L ratio of subcutaneous small resistance arteries was significantly greater in NIDDM+EH than in NIDDM or EH. NS had a smaller M/L ratio than the other groups. Significant correlations were observed between ICAM-1 plasma levels and indices of carotid artery structure in diabetic patients. However, the relations were close only in NIDDM+EH. In conclusion, our data suggest that NIDDM+EH may present more pronounced vascular structural alterations than NIDDM, and that adhesion molecules plasma levels are closely inter-related with carotid artery structural alterations, at least in NIDDM+EH, but not with M/L ratio of small resistance arteries.

Evaluation of the efficacy and tolerability of the combination delapril plus indapamide in the treatment of mild to moderate essential hypertension: a randomised, multicentre, controlled study.

The aim of the study was to evaluate efficacy and tolerability of two different fixed combinations of an angiotensin-converting enzyme inhibitor and a diuretic: delapril+indapamide (D+I) and captopril+hydrochlorothiazide (C+H) administered for 6 months to patients with mild to moderate essential hypertension. In all, 96 centres participated in this randomised, parallel groups, controlled study. A total of 829 patients with uncomplicated mild to moderate hypertension were randomised, and 790 were eligible for the analysis of efficacy (intention to treat). Patients of both sexes, aged 18-75 years, newly diagnosed or untreated during the last month were included in the study if their diastolic blood pressure (DBP) was > or =95 and < or =114 mmHg. The starting doses of the drugs were delapril 30 mg+indapamide 1.25 mg tablets o.d. or captopril 50 mg+hydrolchlorothiazide 15 mg tablets o.d. After a 1-month treatment period, nonresponders (DBP >90 mmHg, or decrease in DBP <10 mmHg) had the daily dose increased to either delapril 30 mg+indapamide 2.5 mg or captopril 50 mg+hydrochlorothiazide 25 mg tablets for a further 5 months. The primary assessment of antihypertensive efficacy was the percentage of patients who responded after a 6-month drug treatment. The responder rates were 72.6% with D+I and 62.9% with C+H (P=0.004 between treatments) after 60 days of treatment, and 92.6% in the D+I and 85.2% in the C+H (P<0.001 between treatments) at the end of the treatment period. The final value of systolic blood pressure was 134.5+/-13.1 mmHg with D+I and 138.3+/-14.0 mmHg with C+H (P<0.001 between treatments). At the final visit, DBP was 84.57+/-7.0 mmHg in the D+I group and 85.57+/-8.0 mmHg in the control group (P=0.017 between treatments). In all, 11 patients in the D+I group and 19 patients in the C+H group were withdrawn from the study because of adverse events. In all, 30 patients (7.6%) with D+I and 32 patients (8.1%) with C+H experienced adverse events. In conclusion, D+I was more effective than C+H in terms of overall reduction in blood pressure and response rate. Greater efficacy was obtained without any increase in adverse effects, since both treatments were equally well tolerated.

Endothelial dysfunction in small resistance arteries of patients with non-insulin-dependent diabetes mellitus.

OBJECTIVE: Arterial hypertension is frequently associated with the presence of endothelial dysfunction in human subcutaneous small resistance arteries, as evaluated by responses to acetylcholine or bradykinin; however it is not known whether patients with diabetes mellitus show similar alterations. Therefore, we have investigated endothelial function in subcutaneous arteries of normotensive subjects (NT), of patients with essential hypertension (EH), of patients with non-insulin-dependent diabetes mellitus (NIDDM), as well as of patients with both essential hypertension and non-insulin-dependent diabetes mellitus (NIDDM+EH). PATIENTS AND METHODS: All subjects were submitted to a biopsy of the subcutaneous fat Small arteries were dissected and mounted on a micromyograph. The media to lumen ratio (M/L) was calculated. A concentration-response curve to acetylcholine, to bradykinin as well as to the endothelium-independent vasodilator sodium nitroprusside were performed. We also evaluated the contractile response to endothelin-1. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) plasma levels were also measured. RESULTS: The vasodilatation to acetylcholine and bradykinin (but not to sodium nitroprusside) was significantly and similarly reduced in EH, in NIDDM, and in NIDDM+EH compared with NT. The contractile response to endothelin-1 was similarly reduced in EH, in NIDDM and in NIDDM+EH. Plasma ICAM-1 and VCAM-1 concentrations were higher in EH, NIDDM and NIDDM+EH than in NT. CONCLUSIONS: An evident endothelial dysfunction was detected in patients with NIDDM, and the simultaneous presence of EH did not seem to exert an additive effect. The contractile responses to endothelin-1 were reduced possibly as a consequence of ET(A) receptor down-regulation.

Flow-mediated dilatation of the brachial artery and left ventricular geometry in hypertensive patients.

OBJECTIVES: In arterial hypertension, the spectrum of geometric patterns in the left ventricle may parallel the structural alterations detected in the carotid arteries and in subcutaneous small arteries. It has been also reported that hypertensive left ventricular hypertrophy (LVH) may be associated with endothelial dysfunction, as evaluated by the response of coronary or forearm vasculature to acetylcholine infusion. The aim of this study was to evaluate the flow-mediated vasodilatation (FMD) of the brachial artery, non-invasive estimate of endothelium-dependent vasodilatation according to left ventricular geometric adaptations in hypertensive patients. METHODS AND RESULTS: In 16 normotensive (nine males, seven females, aged 40-68 years) and in 78 hypertensive subjects (50 males, 28 females, aged 42-67 years), we performed an echocardiographic study for the measurement of left ventricular mass index (LVMI) and relative wall thickness (RWT); we measured to a high resolution the brachial artery diameter at rest, during reactive hyperaemia (5 min of brachial artery occlusion) and after sublingual glyceril trinitrate (GTN); brachial artery flow velocity was measured by pulsed Doppler. Twenty-six hypertensive patients had a normal LVMI (LVMI < 51 g/ m2.7) and geometry (RWT < 0.44), five had concentric remodelling (RWT > or = 0.44), and concentric and eccentric LVH were observed in 19 and 28 patients, respectively. FMD was reduced in hypertensive patients as compared with normotensive subjects (P< 0.01). No correlation was found between FMD and LVMI (r= -0.078) or RWT (r = 0.049); in addition, no difference in FMD was found among the left ventricular geometric patterns in hypertensive patients. CONCLUSIONS: In hypertensives, the presence of endothelial dysfunction is not associated with the LVH or with different left ventricular geometric patterns, suggesting that different and independent mechanisms may be responsible for the presence of LVH and of endothelial dysfunction.

The smoothness index, but not the trough-to-peak ratio predicts changes in carotid artery wall thickness during antihypertensive treatment.

BACKGROUND: It has recently been demonstrated that the smoothness index (SI) (the ratio between the average of the blood pressure changes computed for each hour of the recording and its standard deviation), a new and reproducible measure of the homogeneity of blood pressure reduction by antihypertensive treatment, has evident advantages over trough-to-peak ratio (T/P) in the prediction of the regression of left ventricular hypertrophy. Therefore we considered it to be worthwhile to compare the ability of SI and T/P to predict changes of the carotid artery intima-media thickness (IMT) during pharmacological treatment in patients with essential hypertension. METHODS: In 100 patients with essential hypertension, 24 h ambulatory blood pressure and carotid artery IMT were measured after 3 weeks of therapeutic wash-out and after 12 months of antihypertensive treatment (calcium antagonists, diuretics, angiotensin converting enzyme (ACE) inhibitors or beta-blockers). The homogeneity of the effect of treatment over blood pressure was evaluated by computing T/P and SI. RESULTS: Twenty-four hour blood pressure was significantly reduced by therapy, while, on average, a small but significant increase in indices of carotid artery wall thickness was observed. However, IMT was clearly reduced in patients with high SI. Statistically significant correlations were observed between changes in indices of carotid artery IMT during therapy and SI. No significant correlation was observed between indices of carotid artery morphology and T/P, basal 24 h blood pressure or changes in blood pressure during therapy. CONCLUSIONS: SI, but not T/P is the predictor of changes in carotid artery wall thickness. The information provided by SI is independent from basal blood pressure values. For carotid artery morphology, the smoothness of blood pressure reduction is even more important than its absolute change.

Structural alterations in subcutaneous small arteries of normotensive and hypertensive patients with non-insulin-dependent diabetes mellitus.

BACKGROUND: It is not presently known whether non-insulin-dependent diabetes mellitus (NIDDM) is associated with the presence of structural alterations in small arteries or whether the combination of hypertension and NIDDM may have an additive effect on endothelial dysfunction. Therefore, we investigated subcutaneous small arteries in 12 normotensive subjects (NT group), 18 patients with essential hypertension (EH group), 13 patients with NIDDM, and 11 patients with NIDDM and EH (NIDDM+EH group). METHODS AND RESULTS: Subcutaneous small arteries were evaluated by a micromyographic technique. The internal diameter, the media-to-lumen ratio, remodeling and growth indices, and the collagen-to-elastin ratio were calculated. Concentration-response curves to acetylcholine, bradykinin, the endothelium-independent vasodilator sodium nitroprusside, and endothelin-1 were performed. The media-to-lumen ratio was higher in the EH, NIDDM, and NIDDM+EH groups compared with the NT group. EH patients showed the presence of eutrophic remodeling, whereas NIDDM and NIDDM+EH patients showed 40% to 46% cell growth. The collagen-to-elastin ratio was significantly increased in the EH and NIDDM+EH groups compared with the NT group. The vasodilatation to acetylcholine and bradykinin was similarly reduced in EH, NIDDM, and NIDDM+EH groups compared with the NT group. The contractile responses to endothelin-1 were similarly reduced in EH, NIDDM, and NIDDM+EH patients. CONCLUSIONS: Our data suggest that the effects of NIDDM and EH on small artery morphology are quantitatively similar but qualitatively different and that the presence of hypertension in diabetic patients has little additive effect on small artery morphology and none on endothelial dysfunction.

Endothelial factors and microvascular hypertensive disease.

This paper discusses the role of endothelial dysfunction in human hypertension, especially in relation to small resistance artery structure, as well as the effects of anti-hypertensive drugs on endothelial function of small arteries in human and experimental hypertension. A significant impairment of endothelial function was observed in human essential hypertension as well as in secondary forms of hypertension. No correlation was observed with vascular structure. In animal models of genetic hypertension there is substantial evidence for a beneficial effect of anti-hypertensive treatment with angiotensin converting enzyme (ACE) inhibitors, calcium entry blockers and angiotensin II receptor blockers on endothelial function in small resistance arteries. A significant improvement in endothelial dysfunction may be observed in hypertensive patients after prolonged treatment with ACE inhibitors (cilazapril, lisinopril), calcium entry blockers (nifedipine), and angiotensin II receptor blockers (losartan), while atenolol and hydrochlorotiazide proved to be ineffective in this regard despite similar blood pressure reductions. We conclude that: (i) the development of hypertension is usually associated with the presence of endothelial dysfunction in small resistance arteries of essential hypertensive patients; (ii) vascular structure does not seem to be the major determinant of endothelial function, at least in subcutaneous small resistance arteries; (iii) anti-hypertensive therapy with ACE inhibitors, angiotensin II receptor blockers and calcium entry blockers may improve endothelial function; (iv) a decrease in blood pressure seems to be necessary but not sufficient to obtain a beneficial effect on the endothelium in humans.

Night time blood pressure and cardiovascular structure in a middle-aged general population in northern Italy: the Vobarno Study.

The aim was to determine, in a cross-sectional study, the relation between structural alterations in the heart and carotid arteries, and blood pressure (BP) changes from day to night time, measured by ambulatory BP (ABP). In 225 untreated subjects (107 F, 118 M, age range 48-64 years) and 59 treated subjects (24 M, 35 F, age range 50-64), living in a small town of northern Italy (Vobarno, Brescia) carotid intima media thickness as well as the occurrence of plaque, were evaluated by ultrasound. Echocardiographic left ventricular (LV) mass was measured according to the Penn Convention. BP was determined by clinic measurement and by 24-h non-invasive ABP monitoring. Subjects were divided in two groups, according to the decrease of night time systolic BP (SBP) "dippers" (SBP decreased by at least 10% during night time) and "non-dippers" (decrease of night time SBP <10%). The intima-media thickness in the common carotid, in the carotid bifurcation, in the internal carotid artery and average intima-media thickness were significantly greater in untreated non-dippers as compared with dipper subjects (ANOVA P < 0.05). A significantly higher prevalence of plaque was observed in untreated non-dippers as compared with dippers (P = 0.002). After adjusting for age, sex, 24-h SBP, and smoking, IMT in the carotid bifurcation and average intima-media thickness remained significantly greater in non-dipper subjects (P < 0.05 for all comparisons). No significant differences in LV mass were observed between dippers and non-dipper subjects. In conclusion, in a general population of unselected middle-aged subjects, night time BP values, among other risk factors, seem to represent an important determinant of carotid wall structure.

Changes in midwall systolic performance and cardiac hypertrophy reduction in hypertensive patients.

OBJECTIVE: To investigate changes in left ventricular (LV) performance, as evaluated by measurement of midwall LV fractional shortening (FS), after reduction of cardiac hypertrophy. DESIGN AND METHODS: Echocardiographic evaluation of LV anatomy and function was performed by M-mode echocardiography at baseline, after long-term antihypertensive therapy, and after treatment withdrawal in 68 asymptomatic hypertensive patients (50 males, 18 females, age range 22-62 years). Patients were divided according to the presence of LV hypertrophy (LVH) at baseline (LV mass index, LVMI, > or = 51 g/m(2.7)). RESULTS: At baseline patients with concentric (relative wall thickness > 0.44) LV hypertrophy (n = 38) or remodelling (n = 7) had reduced midwall shortening with respect to patients with normal LV geometry (n = 4) or eccentric LVH (n = 19); no differences were observed for endocardial FS. After long-term treatment (average 15 months), in 11 patients LV mass remained within normal limits, in 45 patients LVH reduction was obtained, while in 12 patients LV mass remained persistently elevated. Midwall FS was significantly increased in patients with reduction of LVH both during treatment and after withdrawal of treatment, while it remained significantly lower in patients with persistently elevated LV mass. Changes in midwall fractional shortening were independently associated with modifications in relative wall thickness (P < 0.00001), with changes in end-diastolic dimensions (P < 0.0001) and those of LVMI (P< 0.02) as shown by multivariate analysis. CONCLUSION: LV midwall systolic performance significantly improved after reduction of LVH, even in the presence of high blood pressure values. Modifications in relative wall thickness are more independently associated with changes, in LV diastolic dimensions and mass, to midwall improvement

Time course of apoptosis in small resistance arteries of spontaneously hypertensive rats.

OBJECTIVE: The time course of programmed cell death (apoptosis) in the vasculature of spontaneously hypertensive rats (SHRs) is still unclear. Moreover, no data are presently available about the possible inter-relationships between apoptosis and vascular remodelling. The aim of this study was to investigate the mesenteric small resistance arteries and large arteries (aortas) of SHRs and normotensive Wistar-Kyoto (WKY) rats at different ages, before and after the development of overt hypertension. METHODS: Twenty-four SHRs (4, 8 or 12 weeks old) and 24 age-matched WKY rats were included in the study. Blood pressure was measured non-invasively. Rats were killed by decapitation and segments of aortas and small mesenteric arteries were dissected free from the surrounding tissue. Mesenteric arteries were mounted on a micromyograph and structural characteristics were measured (media thickness, media:lumen ratio, etc.). Apoptotic cells in the tunica media of large and small vessels were then stained using modified TdT-mediated dUTP Nick-End Labeling (TUNEL). RESULTS: At 4 weeks of age no difference in the blood pressure and percentage of apoptosis in mesenteric arteries between SHRs and WKY rats was detected; however, the media:lumen ratio of mesenteric small resistance arteries was significantly greater in SHRs. At 8 and 12 weeks of age systolic blood pressure, media:lumen ratio and apoptosis rate in mesenteric small arteries was significantly higher in SHRs. The rate of apoptosis in the aortas was similar in the two strains at all three ages. CONCLUSIONS: An increased prevalence of apoptosis was observed in mesenteric small arteries of 8- and 12-week-old SHRs. It is possible that apoptosis may exert a role in small resistance artery remodelling during the development and establishment of hypertension.

Enhanced vascular reactivity in the sympathectomized rat: studies in vivo and in small isolated resistance arteries.

OBJECTIVE: In the conscious rat, sympathectomy (6-hydroxydopamine pretreatment, 100 mg/kg intraperitoneally, twice in the previous 5-6 days) induces, among various homeostatic modifications, the frequent occurrence of sudden and wide oscillations of blood pressure. Since one of the mechanisms underlying this, as yet unexplained, phenomenon may be an enhanced vascular reactivity, we tested the hypothesis that sympathectomized rats exhibit such a hyper-reactivity. We examined the response to a variety of vasoactive agents both in vivo (chronically instrumented conscious animals) and in vitro (small isolated resistance arteries). DESIGN AND METHODS: Wistar-Kyoto sympathectomized rats (6-hydroxydopamine pretreatment, n = 19) and control rats (vehicle pretreatment, n = 23) were studied. In conscious animals, concentration-blood pressure response curves to intra-venous bolus injections of vasopressin, phenylephrine and angiotensin II were obtained. In isolated vessels, concentration-wall tension response curves were obtained for norepinephrine, phenylephrine, vasopressin, serotonin and potassium. Vasodilator responses to acetylcholine (with or without L-NAME), bradykinin and sodium nitroprusside were also evaluated after precontraction with norepinephrine (mesenteric arteries) or vasopressin (cerebral arteries). RESULTS: In sympathectomized rats in vivo the pressor responses to vasopressin, phenylephrine and angiotensin II were significantly larger than in control rats, the difference amounting to 46.5, 40.2 and 57.1%, respectively (all P < 0.05). In vitro, the vascular reactivity of isolated cerebral arteries was similar in sympathectomized and control rats. In contrast, the mesenteric arteries showed significantly increased contractions in sympathectomized compared to control rats in response to norepinephrine, phenylephrine and vasopressin but not to serotonin and potassium, whereas the vasodilator responses to acetylcholine and sodium nitroprusside (but not to bradykinin and acetylcholine+L-NAME) were reduced. CONCLUSIONS: In conclusion, we showed that sympathectomy produces complex alterations of vascular reactivity both in vivo and in isolated vessels, which shift the balance of the sensitivity of the vessel between vasoconstrictor and vasodilating agents towards an increased constriction. These results are unlikely to simply reflect denervation supersensitivity; their underlying receptor, post-receptor and/or contractile mechanisms are yet to be identified.

Cellular hypertrophy in subcutaneous small arteries of patients with renovascular hypertension.

Structural alterations of small arteries in patients with essential hypertension are characterized by inward eutrophic remodeling. However, small arteries in patients with secondary hypertension, as well as in experimental models of hypertension with high circulating renin, are characterized by inward hypertrophic remodeling, which is characterized by smooth muscle cell hypertrophy in animal models. The aim of our study was to determine whether remodeling of subcutaneous small arteries in patients with secondary forms of hypertension is associated with smooth muscle cell hypertrophy and/or alterations in the elastic modulus of the vessel wall. Fifteen patients with renovascular hypertension, 9 with primary aldosteronism, and 13 with essential hypertension and 9 normotensive subjects were included in the study. A biopsy of subcutaneous fat was taken from all subjects. Small arteries were dissected, and morphology was determined on a micromyograph. Unbiased estimates of cell volume and number were made in fixed material. From the resting tension-internal circumference relation of the small arteries, the incremental elastic modulus was calculated and plotted as a function of wall stress. Blood pressure was greater in patients with essential hypertension, renovascular hypertension, or primary aldosteronism than in normotensive subjects, but no significant difference was observed among the 3 groups of hypertensive patients. The media/lumen ratio, the medial cross-sectional area, and the smooth muscle cell volume were significantly greater in patients with renovascular hypertension than in normotensive subjects and patients with essential hypertension. No difference in cell number or in the elastic properties was observed among the 4 groups of subjects. In conclusion, our data demonstrate for the first time that a pronounced activation of the renin-angiotensin-aldosterone system is associated with vascular smooth muscle cell hypertrophy in human hypertension in a manner similar to that found in animal models.