Hyperuricemia and Risk of Cardiovascular Outcomes: The Experience of the URRAH (Uric Acid Right for Heart Health) Project.

The latest European Guidelines of Arterial Hypertension have officially introduced uric acid evaluation among the cardiovascular risk factors that should be evaluated in order to stratify patient's risk. In fact, it has been extensively evaluated and demonstrated to be an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infraction, stroke and heart failure. Despite the large number of studies on this topic, an important open question that still need to be answered is the identification of a cardiovascular uric acid cut-off value. The actual hyperuricemia cut-off (> 6 mg/dL in women and 7 mg/dL in men) is principally based on the saturation point of uric acid but previous evidence suggests that the negative impact of cardiovascular system could occur also at lower levels. In this context, the Working Group on uric acid and CV risk of the Italian Society of Hypertension has designed the Uric acid Right for heArt Health project. The primary objective of this project is to define the level of uricemia above which the independent risk of CV disease may increase in a significantly manner. In this review we will summarize the first results obtained and describe the further planned analysis.

Blood pressure levels and control in Italy: comprehensive analysis of clinical data from 2000-2005 and 2005-2011 hypertension surveys.

This analysis is aimed to determine blood pressure (BP) levels and BP control rates in a large population of hypertensive patients in Italy. Data were taken from two large and inclusive cross-sectional surveys, which covered two distinct and subsequent time periods (2000-2005 and 2005-2011, respectively). Observational clinical studies and surveys, which reported average systolic/diastolic clinic BP levels, proportions of treated/untreated and controlled/uncontrolled patients, and prevalence of cardiovascular risk factors in hypertensive patients followed in either outpatient clinics, hypertension centres or general practice, were considered for the analyses. The overall sample included 211 591 hypertensive patients (119 997 (56.7%) women, age 57.0±10.0 years, body mass index 26.9±4.0 kg m(-2), BP levels 146.9±16.7/88.7±9.6 mm Hg). BP levels were 148.2±15.4/87.5±9.3 mm Hg in patients followed by general practitioners (n=168 313, 79.5%), 148.1±17.3/90.1±9.7 mm Hg in those followed by hypertension centres (n=28 180, 13.3%), and 142.4±17.6/86.6±9.8 mm Hg in those followed by outpatient clinics and hospital divisions (n=15 098, 7.1%). Among treated hypertensive patients (n=128 079; 60.5%), 43 008 (33.6%) were reported to have controlled BP levels. Over one decade of observation, we reported that ~60% of hypertensive patients were treated and among these only 33% achieved effective BP control. These findings highlight the need for more effective interventions to improve management of hypertension in Italy.

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.

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.

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.

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.

High-dose, not low-dose insulin increases the vasoconstrictor effect of norepinephrine in spontaneously hypertensive rats: effects of antihypertensive treatment.

The effect of insulin on the vasoconstriction induced by norepinephrine is presently controversial. Therefore, the aims of our study were: (1) to evaluate the effect of low- and high-dose insulin on the concentration-response curve to norepinephrine in small resistance arteries of spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) before and after the development of hypertension, and (2) to evaluate the effects of antihypertensive treatment on vascular response to insulin and norepinephrine. Fifty-six rats were included in the study. Six SHR were treated with enalapril and 6 with candesartan cilexetil from the 4th to the 12th week of age, while 10 WKY and 14 SHR were kept untreated. Two additional groups of 10 untreated SHR and 10 WKY were killed at 4 weeks of age, in a prehypertensive phase. Mesenteric small arteries were dissected and mounted on a micromyograph. A dose-response curve to norepinephrine was performed at cumulative concentrations in the presence or absence of low- and high-dose insulin. We found that only high-dose insulin increased the vascular response to norepinephrine in 12-week-old SHR, but not in 4-week-old SHR or in age-matched WKY. The increased responsiveness to norepinephrine disappeared after preincubation of the vessels with a selective inhibitor of endothelin-1 type A receptors. After antihypertensive treatment with enalapril or candesartan cilexetil, the potentiation of the vasoconstrictor response to norepinephrine was abolished. In conclusion, insulin at high, nonphysiological doses seems to induce an increase in the reactivity to norepinephrine in mesenteric small arteries of SHR, possibly mediated by a local production of endothelin-1. Antihypertensive treatment with an ACE inhibitor or an angiotensin II receptor blocker may normalize this altered response. This mechanism may be relevant in the development of hypertension in SHR.

The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness.

BACKGROUND: It is unclear whether the carotid intima-media thickness can be influenced by antihypertensive treatment and whether some antihypertensive agents, such as calcium antagonists, may have a greater effect on this parameter than others, such as diuretics. The present paper reports the principal results of the ultrasound substudy of the randomized, prospective, controlled, Verapamil in Hypertension and Atherosclerosis Study (VHAS). DESIGN AND METHODS: In 498 hypertensive patients in eight Italian centres, randomized to either verapamil (240 mg once a day) or chlorthalidone (25 mg once a day), a B-mode ultrasound scan was performed according to a standardized procedure at baseline and after 3, 12, 24, 36 and 48 months of treatment. The maximum intima-media thicknesses of the far walls of common, bifurcation and internal carotid arteries were measured bilaterally, and the following indices calculated: the mean thickness at the six measured sites, the mean thickness at the common and bifurcation sites and the single maximum thickness. The primary endpoint for treatment efficacy was the slope of the change over 4 years (rate of change, mm/year), corrected by using the initial mean over the six sites (baseline + 3 months) as a covariate (mm/year per mm). The patients were also classified into three strata according to their baseline single maximum thickness: those with normal carotid arteries (single maximum ( 1 mm), those with thickened carotid arteries (single maximum > 1 and < or = 1.5 mm and those with carotid plaques (single maximum > 1.5 mm). RESULTS: Among the 456 patients with satisfactory baseline ultrasound readings, 33% were classified with normal carotid arteries, 27% with thickened carotid arteries and 40% with plaques. In the intention-to-treat population (377 patients with ultrasound measurements taken on at least three different occasions over a period of at least 2 years), the rate of change in the mean thickness at the six sites measured was rather small (0.015 mm/year), but significantly (P < 0.05) smaller in patients with plaques (0.003 mm/year) than in patients with thickened or with normal carotids (0.023 and 0.025 mm/year, respectively). When related to initial values, the rate of change in the mean thickness at the six sites had a negative slope (-0.059 mm/year per mm, P < 0.01). Although rates of change in the carotid intima-media thickness in unstratified patients were not different in those treated with verapamil or with chlorthalidone, when changes in the mean thickness of six sites were related to the initial value, the slope of this relationship was significantly different in the two treatment groups (verapamil -0.082 versus chlorthalidone -0.037 mm/year per mm, P < 0.02). The blood pressure-lowering effect of the two randomized treatments was similar. Taking fatal and nonfatal, major and minor cardiovascular events together, there were 19 events in the verapamil group and 35 in the chlorthalidone group, with a significantly (P < 0.01) greater incidence in patients with plaques, and among patients with plaques in those who were randomized to chlorthalidone (P < 0.05). CONCLUSIONS: In accord with evidence from animal models of atherosclerosis, the calcium antagonist verapamil was more effective than the diuretic chlorthalidone in promoting regression of thicker carotid lesions. Changes in the carotid intima-media thickness were small in both groups, and the differences between the changes under the two treatments were consequently small, but the observation that these small differences in carotid wall changes were paralleled by differences in the incidence of cardiovascular events (better intima-media thickness regression with verapamil paralleled by a lower cardiovascular event rate) suggests that even small effects on carotid plaques may have clinical and prognostic relevance.

Effects of candesartan cilexetil and enalapril on structural alterations and endothelial function in small resistance arteries of spontaneously hypertensive rats.

It was previously observed that a significant regression of structural alterations and endothelial dysfunction in mesenteric small arteries of spontaneously hypertensive rats (SHRs) may be obtained after therapy with angiotensin-converting enzyme (ACE) inhibitors. It is not clear whether angiotensin II-type 1 receptor blockers may share this properties. We evaluated the effects of the ACE inhibitor enalapril and of the angiotensin II-receptor blocker candesartan cilexetil on structural alterations of mesenteric small resistance arteries, on cardiac mass, and on endothelial function in SHRs. Seventy-three rats were included in the study. Sixteen SHRs were treated with enalapril and 21 with candesartan cilexetil, whereas 18 Wistar-Kyoto (WKY) and 18 SHRs were untreated. Enalapril and candesartan cilexetil were administered in the drinking water from weeks 4 to 12 of age. Blood pressure was measured noninvasively every week. The rats were killed at the end of the treatment period, after 3 or 4 days of therapeutic washout. Heart weight/body weight ratio (HW/BW) was measured. Mesenteric arterioles were dissected and mounted on a micromyograph (Mulvany's technique). Then the media-to-lumen ratio (M/L) was evaluated. In addition, endothelium-dependent and endothelium-independent relaxation was evaluated by dose-response curves to acetylcholine (in the presence or absence of a bradykinin-receptor blocker and of indomethacin) and sodium nitroprusside. Systolic blood pressure was significantly reduced by both drugs, compared with untreated SHRs, although the hypotensive effect was greater with enalapril than with candesartan cilexetil. A significant reduction of M/L of mesenteric small arteries and of HW/BW was observed in SHRs treated with candesartan cilexetil or enalapril. A significant improvement of endothelial function, as evaluated by a dose-response to acetylcholine, was observed. The acetylcholine-induced vasodilatation was similar after addition to the organ bath of a selective blocker of bradykinin receptors, thus suggesting a minor role (if any) of the increased local availability of bradykinin, as a consequence of inhibition of ACE, in the improvement of endothelial function observed after enalapril treatment. In addition to a satisfactory antihypertensive effect observed with both drugs, candesartan cilexetil and enalapril were proven to be equally effective in reducing structural alterations in mesenteric small resistance arteries, in normalizing cardiac mass, and in improving endothelial function. The inhibition of bradykinin breakdown does not seem to be involved in the improvement of endothelial dysfunction observed with ACE inhibitors.

Effects of hypotensive and non-hypotensive doses of manidipine on structure, responses to endothelin-1 and ICAM-1 production in mesenteric small resistance arteries of spontaneously hypertensive rats.

OBJECTIVE: We have evaluated the effects of a new calcium channel blocker, manidipine, given at both high, hypotensive and low, non-hypotensive doses, on vascular morphology, response to endothelin-1 and ICAM-1 production in mesenteric small resistance arteries of spontaneously hypertensive rats (SHR). METHODS: Ten SHR were treated with manidipine 3 mg/kg per day (high dose) and 10 with manidipine 0.3 mg/kg/per day (low dose). The drug was administered by gavage from the 4th to 12th weeks of age. Eighteen Wistar-Kyoto (WKY) rats and 18 SHR were kept untreated as controls. Rats were killed at 13 weeks. Mesenteric small arteries were dissected and mounted on a micromyograph for determination of indexes of vascular structure (media thickness, wall thickness, media/lumen ratio). RESULTS: Systolic blood pressure was significantly reduced by the high dose of the drug, while no effect was observed with low-dose manidipine. A reduction in the media/lumen ratio was observed only in SHR treated with high-dose manidipine. The response to endothelin-1 in untreated SHR was significantly lower in comparison with WKY; a significant reduction was observed in SHR treated with high-dose manidipine. ICAM-1 vascular concentrations were higher in untreated SHR than in WKY controls. Both high- and low-dose manidipine reduced ICAM-1 concentrations toward normalization. CONCLUSIONS: Manidipine at high, hypotensive, but not at low, non-hypotensive doses has been proven to reduce structural alterations in mesenteric small resistance arteries, and to normalize vascular responses to endothelin-1. In addition, manidipine, at both low and high doses, may reduce ICAM-1 vascular production, thus suggesting a possible anti-atherogenic effect.

Clinical results of the Verapamil inHypertension and Atherosclerosis Study. VHAS Investigators.

OBJECTIVE: The Verapamil in Hypertension and Atherosclerosis Study (VHAS) is a prospective randomized study the objective of which was to compare the long-term effects of verapamil and chlorthalidone on the blood pressure, clinical safety, and the progression/regression of carotid wall lesions in members of a large population of hypertensive patients. DESIGN: After a 3-week placebo run-in period, 1414 hypertensive patients [692 men and 722 women, aged 53.2 +/- 7 years, blood pressure 168.9 +/- 10.5/ 102.2 +/- 5.0 mmHg (means +/- SD)] were assigned randomly to be administered either 240 mg sustained-release verapamil (n = 707) or 25 mg chlorthalidone (n = 707) once a day for 2 years. The study design was double blind for the first 6 months and open thereafter. 25-50 mg/day captopril were added to the treatment of non-responding patients; subsequently, patients not responding to combined therapy were switched to any therapy chosen by the treating doctors (free therapy). The blood pressure of the sitting subject, heart rate, and a standard clinical safety profile (electrocardiogram, laboratory tests, adverse events, cardiovascular events, and deaths) were assessed regularly throughout the study. RESULTS: After 2 years the systolic and diastolic blood pressures were reduced significantly in members of both treatment groups (by 16.3/16.6% with verapamil and by 16.9/16.2% with chlorthalidone, both by analysis of variance, P < 0.0001). The patients for whom we added captopril treatment constituted 22.6% of the verapamil and 26.2% of the chlorthalidone group; while 11.6 and 12.2% of patients in these groups, respectively, were administered free therapy. Normalization of the diastolic blood pressure (to < or = 90 mmHg or to < or = 95 mmHg with a > or = 10% decrease) was achieved for 69.3% of the verapamil and 66.9% of the chlorthalidone group. A decrease in heart rate (by 5.8%) occurred in members of the verapamil group only. A decrease in total serum cholesterol (from 223.6 to 216.9 mg/dl, P < 0.01) and in the total cholesterol: high-density lipoprotein cholesterol ratio (from 4.9 to 4.5, P < 0.01) was noted for the verapamil group only, whereas significantly greater rates of hyperuricemia (plasma urate > 7.0 mg/dl; 10.8 versus 3.9%) and hypokalemia (serum K < 3.5 mmol/l; 24.6 versus 4.4%) were observed for the chlorthalidone group (P < 0.01, versus verapamil for both). Adverse events were reported by 32.5% of patients treated with verapamil and by 33.4% of those treated with chlorthalidone. The most frequent adverse events were constipation in members of the verapamil group (13.7%) and asthenia in members of the chlorthalidone group (8.5%). In total 315 dropped out (153 from the verapamil and 162 from the chlorthalidone group). The occurrence of cardiovascular events was similar for both treatments (42 events for verapamil and 43 for chlorthalidone, NS). CONCLUSION: Similar antihypertensive efficacies, tolerabilities and cardiovascular event rates were observed with verapamil and with chlorthalidone. However, treatment with chlorthalidone was associated with significantly higher incidences of hyperuricemia and hypokalemia than was treatment with verapamil.

Prolonged effects of short-term fosinopril on blood pressure and vascular morphology and function in rats.

The aim of this study was to evaluate the delayed effects of an angiotensin converting enzyme (ACE) inhibitor on blood pressure and on structural and functional alterations in mesenteric small resistance arteries of spontaneously hypertensive rats (SHR). The ACE inhibitor fosinopril (25 mg/kg/day) was administered according to three different schedules: in one group of SHR from 4 to 8 weeks of age (n = 12), in a second group from 8 to 12 weeks of age (n = 15), and in a third group from 4 to 12 weeks of age (n = 12). Eighteen untreated SHR and 18 untreated Wistar-Kyoto rats served as controls. About half the animals in each group were killed at 13 weeks of age, and the remaining were killed at 38 weeks of age. After death, relative left ventricular mass (left ventricular weight/body weight) was calculated. Vascular morphology (media:lumen ratio) and function (responses to norepinephrine and acetylcholine) in mesenteric small resistance arteries were then assessed using a micromyographic technique. Short-term fosinopril, given either before or after the development of hypertension, persistently reduced (but did not normalize) systolic blood pressure, vascular structural alterations, and reactivity to norepinephrine in mesenteric resistance arteries in SHR. These favorable effects were maintained at least for 26 to 30 weeks after treatment withdrawal. The endothelium-dependent vasodilator response to acetylcholine was improved at 13 but not at 38 weeks of age, in treated SHR. Therefore, the vascular response to norepinephrine seems to be dependent mainly on the structure of the vessels, whereas endothelial function is probably more linked to the hemodynamic load.

Structural changes of small resistance arteries in spontaneously hypertensive rats after treatment with various doses of lacidipine.

OBJECTIVE: To evaluate the modifications of the morphology of mesenteric small resistance vessels in spontaneously hypertensive rats (SHR) induced by lacidipine treatment. METHODS: Lacidipine was administered at three different dosages, 20, 10, and 0.3 mg/kg per day. Fifty rats were studied. Nine SHR and 11 Wistar-Kyoto (WKY) rats were not treated. Each lacidipine dose was administered to 10 SHR. The drug and the placebo were administered by gavage from age 4 to age 12 weeks. The blood pressure was measured noninvasively every week. The animals were killed when they were aged 13 weeks, and the relative left ventricular mass (left ventricular weight plus septum weight/body weight) was calculated. Small mesenteric resistance vessels were dissected and mounted on a micromyograph (Mulvany's technique), and morphological parameters of the vessels were studied (media thickness and media: lumen ratio). RESULTS: The systolic blood pressure of SHR administered 20 and 10 mg/kg lacidipine per day was reduced significantly during the treatment period, whereas that of rats treated with 0.3 mg/kg lacidipine per day did not change. A significant reduction in media: lumen ratio was observed for all three groups of treated rats, including those to which 0.3 mg/kg lacidipine per day had been administered, and no reduction in systolic blood pressure could be detected. The relative left ventricular mass was reduced significantly only in rats to which 20 and 10 mg/kg lacidipine per day had been administered. CONCLUSION: A significant reduction in magnitude of vascular structural alternations was observed even in SHR treated with a low, nonhypotensive dose of lacidipine.

Chronic ACE-inhibitor treatment and adrenergic mechanisms in spontaneously hypertensive rats.

We investigated the effects of chronic treatment with the angiotensin-converting enzyme (ACE) inhibitor fosinopril on cardiac and vascular noradrenergic neurotransmission as related to cardiovascular hypertrophy in spontaneously hypertensive rats (SHRs). SHRs were treated with fosinopril at "high dose" (SHR-HD, 25 mg/kg/day) or "low dose" (SHR-LD, 1 mg/kg/day) from the 6th to the 12th week of age, and compared to age-matched untreated SHRs (SHR-C) and Wistar-Kyoto controls (WKY). Blood pressure was significantly reduced in SHR-HD but not in SHR-LD when compared to SHR-C. The antihypertensive dose of fosinopril reduced both cardiac and vascular hypertrophy, whereas the low dose was effective only in reducing vascular hypertrophy. Several differences in presynaptic and postsynaptic cardiovascular noradrenergic neurotransmission were observed between SHR-C and WKY rats (increased cardiac norepinephrine concentration, down-regulation of cardiac beta-adrenoceptors, reduced alpha-adrenergic receptor-mediated vasoconstrictor response of small mesenteric arteries to exogenous norepinephrine). All these differences were abolished by ACE inhibitor treatment, both at antihypertensive or at subantihypertensive doses. The results of this study are consistent with the hypothesis that chronic ACE inhibition may exert an inhibitory modulation on the peripheral adrenergic transmission, which is not related to blood pressure reduction. This modulation does not appear to be a determinant in preventing the development of cardiac hypertrophy but may play a role in the regression of vascular structural alterations in spontaneously hypertensive rats.

Effects of low and high doses of fosinopril on the structure and function of resistance arteries.

It has been suggested that angiotensin-converting enzyme inhibitors may induce a significant regression of cardiovascular hypertrophy not only through blood pressure reduction but also as a possible consequence of growth factor inhibition. The aim of this study was to evaluate the effects of the angiotensin-converting enzyme inhibitor fosinopril, given either at a hypotensive high dose or a nonhypotensive low dose, on structural and functional alterations of mesenteric resistance arteries and on cardiac mass in spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats. Fosinopril was administered in the drinking water from 6 to 12 weeks of age. Rats were killed at 12 weeks, and the ratio of heart weight to body weight was measured. Mesenteric arterioles were dissected and mounted on a micromyograph (Mulvany's technique). Vascular morphology (media-lumen ratio, media thickness) and endothelial function (response to acetylcholine) were then assessed. During the 6 weeks of treatment, systolic pressure in SHR treated with high-dose fosinopril was significantly lower compared with that in untreated SHR, whereas no difference was observed with low-dose fosinopril. In SHR treated with both high-dose and low-dose fosinopril, a statistically significant reduction of vascular structural alterations, in terms of both media-lumen ratio and media thickness, was observed. The ratio of heart weight to body weight was reduced only in SHR treated with high-dose fosinopril. An improvement in the endothelium-dependent relaxation to acetylcholine was observed in SHR treated with high-dose fosinopril compared with untreated SHR, whereas in SHR treated with low-dose fosinopril no improvement in endothelial function was detected.(ABSTRACT TRUNCATED AT 250 WORDS)