Combination therapy with lercanidipine and enalapril reduced central blood pressure augmentation in hypertensive patients with metabolic syndrome.

Arterial stiffness and blood pressure (BP) augmentation are independent predictors of cardiovascular events. In a randomized, open, parallel group study we compared the effect on these parameters of combination therapy with an ACE-inhibitor plus calcium channel blocker or thiazide diuretic in 76 hypertensive patients with metabolic syndrome uncontrolled by ACE-inhibitor monotherapy. After 4weeks run-in with enalapril (ENA, 20mg), patients were randomized to a combination therapy with lercanidipine (LER, 10-20mg) or hydrochlorothiazide (HCT, 12.5-25mg) for 24weeks. Aortic stiffness (carotid to femoral pulse wave velocity, PWV), central BP values and augmentation (augmentation index, AIx) were measured by applanation tonometry. The two groups showed similar office and central BP after run-in. Office (ENA/LER: from 149.1±4.9/94.5±1.5 to 131.7±8.1/82.2±5.3; ENA/HCT: from 150.3±4.7/94.7±2.1 to 133.1±7.1/82.8±5.3mmHg) and central BP (ENA/LER 127.4±17.1/85.2±12.1 to 120.5±13.5/80.0±9.5mmHg; ENA/HCT 121.6±13.4/79.3±9.5mmHg) were similarly reduced after 24weeks. PWV was comparable after run-in and not differently reduced by the two treatments (ENA/LER from 8.6±1.5 to 8.1±1.3m/s, p<0.05; ENA/HCT from 8.5±1.2 to 8.2±1.0m/s, p<0.05). Finally, both combinations reduced AIx, but its reduction was significantly greater (p<0.05) in ENA/LER (from 26.8±10.9 to 20.6±9.1%) than in ENA/HCT arm (from 28.2±9.0 to 24.7±8.7%). In conclusion, the combination with LER caused a similar PWV reduction as compared to HCT, but a greater reduction in AIx in hypertensive patients with metabolic syndrome not controlled by ENA alone. These results indicate a positive effect of the combination of ENA/LER on central BP augmentation, suggesting a potential additive role for cardiovascular protection.

Blood pressure control and treatment adherence in hypertensive patients with metabolic syndrome: protocol of a randomized controlled study based on home blood pressure telemonitoring vs. conventional management and assessment of psychological determinants of adherence (TELEBPMET Study).

BACKGROUND: Inadequate blood pressure control and poor adherence to treatment remain among the major limitations in the management of hypertensive patients, particularly of those at high risk of cardiovascular events. Preliminary evidence suggests that home blood pressure telemonitoring (HBPT) might help increasing the chance of achieving blood pressure targets and improve patient's therapeutic adherence. However, all these potential advantages of HBPT have not yet been fully investigated. METHODS/DESIGN: The purpose of this open label, parallel group, randomized, controlled study is to assess whether, in patients with high cardiovascular risk (treated or untreated essential arterial hypertension--both in the office and in ambulatory conditions over 24 h--and metabolic syndrome), long-term (48 weeks) blood pressure control is more effective when based on HBPT and on the feedback to patients by their doctor between visits, or when based exclusively on blood pressure determination during quarterly office visits (conventional management (CM)). A total of 252 patients will be enrolled and randomized to usual care (n = 84) or HBPT (n = 168). The primary study endpoint will be the rate of subjects achieving normal daytime ambulatory blood pressure targets (< 135/85 mmHg) 24 weeks and 48 weeks after randomization. In addition, the study will assess the psychological determinants of adherence and persistence to drug therapy, through specific psychological tests administered during the course of the study. Other secondary study endpoints will be related to the impact of HBPT on additional clinical and economic outcomes (number of additional medical visits, direct costs of patient management, number of antihypertensive drugs prescribed, level of cardiovascular risk, degree of target organ damage and rate of cardiovascular events, regression of the metabolic syndrome). DISCUSSION: The TELEBPMET Study will show whether HBPT is effective in improving blood pressure control and related medical and economic outcomes in hypertensive patients with metabolic syndrome. It will also provide a comprehensive understanding of the psychological determinants of medication adherence and blood pressure control of these patients. TRIAL REGISTRATION: Clinical Trials.gov: NCT01541566.

An observational, prospective, open-label, multicentre evaluation of aliskiren in treated, uncontrolled patients: a real-life, long-term, follow-up, clinical practice in Italy.

INTRODUCTION: The addition of the direct renin inhibitor aliskiren is demonstrated to improve blood pressure (BP) control rate and reduce progression of organ damage in treated hypertensive patients in clinical trials with a relatively short follow-up period. AIM: The objective of this study was to assess the effectiveness, safety and tolerability of aliskiren as an add-on antihypertensive therapy in high-risk, treated, hypertensive patients, who were not controlled with concomitant treatment with at least two antihypertensive drugs under 'real-life' conditions, during a planned observation and treatment period of at least 12 months in Italy. METHODS: Clinical data were derived from medical databases of treated, uncontrolled, hypertensive patients followed by specialized physicians operating in different clinical settings (hospital divisions or outpatient clinics) in Italy. Aliskiren was added to stable antihypertensive treatment, including at least two drug classes (independently of class or dosage) and unable to achieve BP control. Follow-up visits for measuring clinic BP levels and collecting data on drug safety and tolerability were planned at time intervals of 1, 6 and 12 months. At each predefined follow-up visit, aliskiren could be up-titrated from 150 to 300 mg daily if BP control was not achieved. RESULTS: From May 2009 to June 2011, a total of 1186 treated, uncontrolled, hypertensive patients (46.3% female, aged 65.2 ± 11.7 years, mean duration of hypertension 13.2 ± 9.3 years, mean clinic BP levels 156.5 ± 15.9/90.3 ± 9.5 mmHg) were enrolled. Systolic and diastolic BP levels were 141.1/82.4, 134.9/79.8 and 133.6/78.9 mmHg at 1-, 6- and 12-month follow-up visits, respectively (p < 0.0001 vs baseline for all comparisons). These effects were consistent in all predefined subgroups, including those with left ventricular hypertrophy, renal disease, diabetes mellitus, coronary artery disease or cerebrovascular disease. Reduced levels of microalbuminuria were also reported, without affecting other renal and electrolyte parameters. Overall, compliance to study medication was high (93.0%), with a very low proportion of patients experiencing adverse events leading to drug discontinuation (3.6%). CONCLUSIONS: In this observational, prospective, open-label, multicentre study, we reported the 12-month clinical effectiveness, safety and tolerability of adding aliskiren to treated, uncontrolled, hypertensive patients in a 'real-life' setting in Italy. This strategy leads to a significantly improved BP control rate and low incidence of drug-related side effects or discontinuations.

Local carotid stiffness and intima-media thickness assessment by a novel ultrasound-based system in essential hypertension.

OBJECTIVE: To evaluate local carotid stiffness (CS) and intima-medial thickness (C-IMT) in hypertensive patients with different cardiovascular risk profile, using a new user-friendly ultrasound-based system, previously validated vs. RF-based echotracking device. METHODS: We investigated a population with different cardiovascular risk: 45 healthy normotensives (NT), 90 non-diabetic hypertensives (HT), and 48 patients with hypertension and type-2 diabetes (DM). Framingham risk factor score (FRS) was calculated. PWV was assessed by applanation tonometry. The relative stroke change in diameter (ΔD) and C-IMT were measured on carotid scans. Distensibility coefficient (DC) was calculated as ΔA/(A*ΔP), where A = diastolic lumen area, ΔA = stroke change in lumen area, and ΔP = carotid pulse pressure. CS (m/s) was calculated as (ρ*DC) - 1/2 (ρ = blood density). RESULTS: CS, C-IMT, PWV were significantly increased in HT and DM vs. NT. C-IMT and PWV were significantly higher in DM than HT. ΔD and DC were significantly lower in HT and DM vs. NT. FRS ≥10% group showed increased carotid diameter, C-IMT and CS than the FRS <10%. FRS was (p < 0.001) correlated with CS (r = 0.35); ΔD (r = -0.36), DC (r = 0.35), C-IMT (r = 0.48), PWV (r = 0.38). CS correlated (p < 0.05) with PWV in the entire population (r = 0.37), in the NT (r = 0.35), in the HT and DM (r = 0.20). PWV (r = 0.50) and CS (r = 0.33) were correlated with age. Determinants of aortic and carotid stiffness were identified by multivariate stepwise analysis. CONCLUSIONS: The proposed B-mode ultrasound-based system is a reliable and user-friendly method that could serve to investigate the predictive value of CS for cardiovascular events in future large clinical studies.

Investigation of skin vasoreactivity and blood flow oscillations in hypertensive patients: effect of short-term antihypertensive treatment.

BACKGROUND AND METHOD: In order to evaluate whether arterial hypertension (AH) affects skin microcirculation, 46 newly diagnosed, never-treated, hypertensive patients and 20 healthy normotensive controls underwent a forearm skin postocclusive reactive hyperaemia (PORH) test, using laser-Doppler flowmetry (LDF). Their resting skin blood flow oscillations (SBFOs) were also investigated using wavelet spectral analyses of skin LDF tracings within six frequency subintervals in the 0.005-2 Hz spectral range. To evaluate whether antihypertensive treatment affects skin microcirculation, the same measurements were repeated in 22 of the recruited hypertensive patients after 8 ±â€Š2 weeks of antihypertensive treatment. RESULTS: Significantly reduced PORH, together with significantly higher spectral amplitudes within the majority of the investigated SBFO subintervals, was found in untreated hypertensive patients compared with controls. In the 22 hypertensive patients who completed the follow-up, there was a significant increase in PORH after antihypertensive treatment compared with before (357 ±â€Š178 vs. 284 ±â€Š214%, respectively, P < 0.05). Following antihypertensive treatment, the same 22 hypertensive patients did not differ significantly from controls either in PORH or in the majority of the investigated SBFO frequency subintervals. CONCLUSION: This study showed reduced skin vasoreactivity in the hypertensive patients, confirming that antihypertensive treatment negatively affects skin microcirculation. The short period of efficacious antihypertensive treatment resulted in normalization of skin vasoreactivity in hypertensive patients who completed the follow-up, suggesting that antihypertensive treatment affects positively skin microcirculation in AH. The SBFO increase in untreated hypertensive patients, and its almost complete normalization in treated hypertensive patients, suggests that SBFO enhancement in untreated hypertensive patients could be an adaptive reversible response to AH.

Effect of sulfaphenazole on tissue plasminogen activator release in normotensive subjects and hypertensive patients.

BACKGROUND: A nitric oxide-independent response, possibly mediated by hyperpolarization, regulates vascular tone, acting as a compensatory mechanism in the presence of impaired nitric oxide availability. Cytochrome P450 2C9 (CYP 2C9) is a source of endothelium-derived hyperpolarizing factors and modulates tissue-type plasminogen activator (tPA) release from endothelial cells; however, no effect of hyperpolarization on fibrinolysis has been documented in humans. We aimed to assess the effect of sulfaphenazole, a specific CYP 2C9 inhibitor, on tPA release in normotensive subjects and patients with essential hypertension. METHODS AND RESULTS: tPA release was measured in the forearm microcirculation of 56 normotensivesubjects and 57 patients with essential hypertension after bradykinin (0.015 microg x 100 mL(-1) x min(-1)) and acetylcholine (1.5 microg x 100 mL(-1) x min(-1)) infusions, with or without sulfaphenazole (0.03 microg x 100 mL(-1) x min(-1)). Bradykinin and acetylcholine infusions were repeated with N(G)-monomethyl-l-arginine (L-NMMA; 100 microg x 100 mL(-1) x min(-1)) and/or sulfaphenazole. tPA release by bradykinin and acetylcholine was higher in normotensive subjects than in patients with essential hypertension (P<0.01). Sulfaphenazole (P<0.01) blunted bradykinin-induced but not acetylcholine-induced tPA release in both groups. In normotensive subjects, L-NMMA infusion reduced tPA release (P<0.01). When L-NMMA was coinfused with sulfaphenazole, tPA release induced by bradykinin, but not by acetylcholine, was further reduced (P<0.01). In patients with essential hypertension, tPA release by both agonists was unaffected by L-NMMA, but only bradykinin-induced tPA release was blunted by sulfaphenazole, alone or with L-NMMA (P<001). CONCLUSIONS: Sulfaphenazole inhibits bradykinin-induced tPA release, which suggests a modulatory role of CYP 2C9-derived endothelium-derived hyperpolarizing factors in tPA release in humans. In patients with essential hypertension, tPA release depends exclusively on endothelium-derived hyperpolarizing factor, which is an ineffective compensatory mechanism in the presence of impaired nitric oxide availability.

Fixed dose combination of perindopril and indapamide improves peripheral vascular function in essential hypertensive patients.

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.

Skin vasodilator effect of exogenous urotensin-II in hypertensives not exposed to antihypertensive medication.

To investigate the effect of urotensin-II (U-II) on skin vascular tone in normotensive subjects and in patients with essential arterial hypertension (EHT), forearm skin blood flux and skin blood flowmotion (SBF) response to U-II cathodal iontophoresis was investigated using laser Doppler flowmetry (LDF) and spectral Fourier analysis in 10 young normotensive subjects, before and after intra-dermal injection of the nitric oxide synthetase inhibitor N(G)-monometil-l-arginine (L-NMMA). Forearm skin blood flux response to U-II cathodal iontophoresis was also investigated using LDF in 15 newly diagnosed EHT patients, in 15 long-standing EHT patients and in 15 age- and sex-matched normotensive subjects. Intra-dermal injection of L-NMMA significantly blunted the increase in skin blood flux (from 342.5+/-153.0% to 193.5+/-78.9%, p<0.05) and completely inhibited the increase in spectral amplitude of 0.009-1.6 Hz total-spectrum SBF, as well as of the 0.009-0.02 Hz component, related to endothelial activity, which occurred following U-II iontophoresis in normotensive subjects. A significant increase in skin blood flux compared with baseline was also induced by U-II iontophoresis in newly diagnosed (354+/-195% change from baseline) and long-standing patient (324+/-180% change from baseline), without significant difference with normotensive subjects (400+/-251% change from baseline). These findings demonstrate that: (i) U-II exerts a skin vasodilator effect in normotensive subjects, which is partly endothelial-dependent; (ii) U-II skin vasodilator effect is preserved in newly diagnosed and in long-standing EHT patients.

Tissue-type plasminogen activator release in healthy subjects and hypertensive patients: relationship with beta-adrenergic receptors and the nitric oxide pathway.

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 microg/100 mL per minute) induced greater t-PA release in normotensive subjects as compared with essential hypertensive patients (P<0.05). However, inhibition of NO synthase with N(G)-monomethyl-L-arginine (100 microg/100 mL per minute) infusion blunted epinephrine-induced t-PA release in normotensive subjects (P<0.05) but not in essential hypertensive patients. In normotensive subjects, t-PA release by epinephrine was not affected by phentolamine (8 microg/100 mL per minute) coinfusion and was abolished in the presence of propanolol (10 microg/100 mL per minute). Intrabrachial isoproterenol (0.03 microg/100 mL per minute) induced a significant increase in t-PA release (P<0.01), an effect blunted by N(G)-monomethyl-L-arginine (P<0.05). In essential hypertensive patients, the response to isoproterenol was impaired as compared with normotensive subjects and was unaffected by N(G)-monomethyl-L-arginine coinfusion. In conclusion, the results of the present study demonstrate that adrenergic-induced t-PA release is mediated by beta-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.

Peripheral wave reflection and endothelial function in untreated essential hypertensive patients with and without the metabolic syndrome.

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.

Supplementation with vitamins C and E improves arterial stiffness and endothelial function in essential hypertensive patients.

BACKGROUND: Essential hypertension is characterized by endothelial dysfunction, arterial stiffness, and increased oxidative stress. We evaluated the effect of short-term combined treatment with the antioxidants vitamins C and E on endothelial function, arterial stiffness, and oxidative stress in untreated essential hypertensive patients. METHODS: A randomized, double-blind, placebo-controlled, crossover study design was used to assign 30 male essential hypertensive patients to either vitamin C (1 g) and vitamin E (400 IU) or placebo for 8 weeks. Endothelium-dependent response was assessed as flow-mediated dilation (FMD) of the brachial artery. Arterial stiffness was assessed as central pulse wave velocity (PWV) and augmentation index (AIx). Plasma markers of oxidative stress and antioxidant status were measured. RESULTS: After vitamin supplementation, FMD was significantly improved. Central PWV was significantly reduced, while AIx tended to decrease. Plasma vitamin levels and antioxidant capacity increased significantly. Levels of oxidative stress decreased. Changes in central PWV were related to changes in levels of oxidative stress. CONCLUSIONS: Combined treatment with vitamins C and E has beneficial effects on endothelium-dependent vasodilation and arterial stiffness in untreated, essential hypertensive patients. This effect is associated with changes in plasma markers of oxidative stress.

Nitric oxide modulates tissue plasminogen activator release in normotensive subjects and hypertensive patients.

We evaluated the possible role of NO in modulating tissue plasminogen activator (t-PA) release in the forearm microcirculation of normotensive subjects and hypertensive patients. Essential hypertensive patients are characterized by endothelial dysfunction because of a reduced NO availability and also show an impaired t-PA release. In healthy volunteers and essential hypertensive patients, we studied local t-PA release and forearm blood flow changes (strain-gauge plethysmography) induced by intrabrachial administration of acetylcholine (0.45 and 1.5 microg/100 mL/min) and of sodium nitroprusside (0.5 and 1.0 microg/100 mL/min), an endothelium-dependent and -independent agonist, respectively. Acetylcholine was also repeated in the presence of intra-arterial infusion of the NO synthase inhibitor N(G)-monomethyl-l-arginine (100 microg/100 mL/min). In normotensive subjects, vasodilation to acetylcholine was blunted by N(G)-monomethyl-l-arginine. In these subjects, acetylcholine infusion induced a significant, dose-dependent increase in net forearm t-PA release. N(G)-monomethyl-l-arginine significantly reduced basal t-PA release, as well as acetylcholine-induced t-PA release. In essential hypertensive patients, vasodilation to acetylcholine was reduced as compared with controls and resistant to N(G)-monomethyl-l-arginine. In contrast to what was observed in healthy control subjects, in hypertensive patients, acetylcholine had no effect on t-PA release. Similarly, N(G)-monomethyl-l-arginine failed to modify either the tonic or the agonist-induced t-PA release. Both tonic and agonist-induced release of NO are directly involved in t-PA release by endothelial cells. Essential hypertension, characterized by a reduction in tonic and stimulated NO availability, is also associated with impaired capacity of t-PA release, suggesting a major role of impaired NO availability in worsening both vasodilation and t-PA release.

Ramipril dose-dependently increases nitric oxide availability in the radial artery of essential hypertension patients.

DESIGN AND PARTICIPANTS: A double-blind, crossover, randomized study was designed to evaluate the effect of 3-month treatment with a lower versus a higher antihypertensive dosage of ramipril (5 or 10 mg/day) on nitric oxide (NO)-dependent vasodilation in 46 untreated patients with essential hypertension. Radial artery flow-mediated dilation (FMD), before and after the intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA), to block NO synthase, and the response to sublingual glyceril trinitrate (GTN, 25 microg) were measured at baseline and after the two treatment periods as a change in artery diameter (computerized system from ultrasound scans). Plasma angiotensin II and oxidative stress markers were also assessed. RESULTS: FMD was significantly (P < 0.01) lower in hypertensive patients (4.6 +/- 1.8%) than in normotensive subjects (7.1 +/- 2.6%), whereas the response to GTN was similar. L-NMMA significantly (P < 0.001) inhibited FMD in normotensive but not in hypertensive subjects. Mean 24-h ambulatory blood pressure, plasma angiotensin II and oxidative stress marker levels were similarly reduced at the end of the two treatment periods. Both dosages of ramipril significantly (P < 0.001) increased FMD (5 mg: 5.9 +/- 2.1%; 10 mg: 6.3 +/- 2.4%) without modifying the response to GTN. However, compared with baseline (11 +/- 19%), the inhibiting effect of L-NMMA on FMD (NO-dependent FMD) was significantly (P < 0.01) greater with ramipril 10 mg (49 +/- 12%) than 5 mg per day (38 +/- 15%). The improvement in FMD and NO-dependent FMD was not related to changes in plasma levels of angiotensin II or markers of oxidative stress. CONCLUSION: Treatment with ramipril at a higher dosage induced a greater improvement in NO-dependent vasodilation compared with the lower antihypertensive dosage in hypertensive patients.

Identification of a cytochrome P450 2C9-derived endothelium-derived hyperpolarizing factor in essential hypertensive patients.

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 N(G)-monomethyl-L-arginine (L-NMMA) (100 mug/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.

Reduced left ventricular functional reserve in hypertensive patients with preserved function at rest.

In many hypertensive patients, left ventricular pump function is normal at rest but abnormal during exercise. Myocardial dysfunction or altered left ventricular loading may be responsible for this finding. To verify the hypothesis of impaired myocardial functional reserve in the hypertensive heart, we assessed the response of stress-adjusted midwall shortening to graded, low-dose dobutamine infusion in hypertensive subjects with normal midwall shortening at rest. Sixty-five subjects (45 never treated hypertensive subjects and 20 normotensive volunteers comparable for age) received dobutamine at 1, 2, 3, 4, and 5 microg x kg(-1) x min(-1) for 5-minute steps; within this range of infusion rates, heart rate and systemic blood pressure were stable. Two-dimensional, M-mode, and Doppler echocardiography were performed at baseline and at the end of each step. In normotensive controls, midwall shortening increased from baseline during 2 microg x kg(-1) x min(-1) dobutamine by an average of 16+/-4.5% (P<0.01); a value of 2 standard deviations below this mean response was taken as the lower limit of normal. In the hypertensive subjects, 24 had a normal midwall shortening response to dobutamine at this dose (group I) and 21 had a subnormal response (group II). Whereas blood pressure and left ventricular mass were similar in group II and group I, the former had greater relative wall thickness (P<0.01) than the latter. beta-adrenergic stimulation by very-low-dose dobutamine unmasks subtle impairment of myocardial functional reserve in hypertensive subjects with normal myocardial performance at rest. This alteration seems to be related mainly to increase in left ventricular relative wall thickness.

Different effect of antihypertensive drugs on conduit artery endothelial function.

To compare the effect of antihypertensive drugs on endothelium-dependent vasodilation in the peripheral conduit arteries of patients with essential hypertension, in a prospective, randomized, parallel group study, endothelial function was assessed in 168 hypertensive patients before and after 6-month treatment with randomly assigned nifedipine GITS (30 to 60 mg, n=28), amlodipine (5 to 10 mg, n=28), atenolol (50 to 100 mg, n=29), nebivolol (5 to 10 mg, n=28), telmisartan (80 to 160 mg, n=29), and perindopril (2 to 4 mg, n=28). If necessary, hydrochlorothiazide (25 mg) was added to each compound. We evaluated brachial artery flow-mediated, endothelium-dependent dilation (high-resolution ultrasound) compared with endothelium-independent response to glyceryl trinitrate (25 microg/s). Brachial artery diameter was measured by automatic computerized analysis. Forty healthy subjects were evaluated as a control group. Oxidative stress production was evaluated by measuring plasma malondialdehyde and plasma lipoperoxides; plasma antioxidant capacity was assessed as ferric-reducing antioxidant power. Hypertensive patients showed a significantly (P<0.01) lower flow-mediated dilation (5.2+/-1.9%) as compared with healthy control subjects (7.1+/-2.6%). Response to glyceryl trinitrate was similar in control subjects and patients. At baseline, blood pressure, diameter, flow-mediated dilation, and response to glyceryl trinitrate were similar in the different treatment groups. All treatments similarly reduced blood pressure, but only perindopril increased flow mediated dilation (from 5.1+/-2 to 6.4+/-2.4%; P<0.01) without modifying the response to glyceryl trinitrate. Perindopril but also telmisartan nifedipine and amlodipine reduced oxidative stress and increased plasma antioxidant capacity. In patients with essential hypertension, ACE inhibitors appear to be the only compounds able to improve conduit artery endothelium-dependent vasodilation.

Calcium antagonist treatment by lercanidipine prevents hyperpolarization in essential hypertension.

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 NG-monomethyl-l-arginine (L-NMMA, 100 microg/100 mL per minute), an NO-synthase inhibitor, and ouabain (0.72 microg/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.

Ventricular repolarization is prolonged in nondipper hypertensive patients: role of left ventricular hypertrophy and autonomic dysfunction.

OBJECTIVE: The aim of this study was to investigate the influence of circadian behavior of blood pressure, left ventricular hypertrophy, and autonomic function on QTc interval duration in untreated hypertensive patients. DESIGN: Hypertensive patients underwent simultaneous blood pressure and ECG 24-h ambulatory monitoring. Patients were classified into two groups on the basis of a lack of nocturnal fall in blood pressure, as dippers and nondippers. A group of normotensive healthy subjects was studied as controls. METHODS: QT and QTc intervals were automatically computed and spectral analysis was applied to RR interval time series from the same electrocardiogram (ECG) recordings. Left ventricular mass index (LVMI) was computed by echocardiogram. RESULTS: No difference among the three groups was found concerning mean values and circadian pattern of heart rate; by contrast, QTc was significantly longer in nondippers compared to dippers or to normotensive subjects, particularly at night-time, whereas all groups exhibited similar circadian variations in heart rate. Compared to dippers, nondippers showed significantly higher LVMI, which positively correlated with QTc, and parasympathetic withdrawal, which negatively correlated with QTc. CONCLUSIONS: Nondippers show a prolonged ventricular repolarization throughout the 24-h period, absent either in dippers or normotensives. The association of left ventricular hypertrophy and vagal deactivation may lead to prolongation of QTc, potentially facilitating ventricular arrhythmias in nondipper hypertensive patients.