Heart rate recovery is useful for evaluating the recovery of exercise tolerance in patients with heart failure and atrial fibrillation.

This study aimed to examine the factors that contribute to improvement of exercise tolerance in patients with heart failure (HF) and atrial fibrillation (AF) following cardiac rehabilitation. Our hypothesis is that parasympathetic values are important for recovering exercise tolerance in those patients. We included 84 consecutive patients with HF and AF (mean age: 69 ± 15 years, 80% men). All of the patients underwent a cardiopulmonary exercise test and had pre and post 5 month cardiac rehabilitation assessed. After 155 ± 11 days and 44 ± 8 sessions, 73 patients (86%) showed an increase in peak oxygen uptake (VO2) and VO2 at the anaerobic threshold. In univariate linear regression analysis, the % change in heart rate recovery, plasma B-type natriuretic peptide levels, resting heart rate, and the minute ventilation /carbon dioxide output slope were significantly related to that of peak VO2 (p < 0.01, p = 0.03, p = 0.02, p < 0.01, respectively). Stepwise multivariate linear regression analysis showed that the % change in heart rate recovery was independently related to that of peak VO2 (p < 0.05). Our results suggest that heart rate recovery is closely associated with recovery of exercise tolerance in patients with HF and AF after CR.

Acute Deterioration of Pulmonary Arterial Hypertension (PAH) in a Patient with Neurofibromatosis Type 1 (NF1).

A 56-year-old woman was diagnosed as having chronic obstructive pulmonary disease with heavy smoking. Mild pulmonary hypertension (mean pulmonary arterial pressure: 31 mmHg) was detected at the first visit. She was diagnosed with pulmonary hypertension due to pulmonary disease and medicated only with bronchodilators. Simultaneous, multiple freckling in the trunk of her body and café au lait macules in her back with some cutaneous neurofibromas were also detected. A plastic surgeon removed one of the neurofibromas and pathologically diagnosed it as neurofibromatosis type 1 (NF1). We finally rediagnosed her with pulmonary hypertension with unclear and/or multifactorial factors when she deteriorated 1 year after being treated only with bronchodilators. We then administrated upfront combination therapy with macitentan and tadalafil. Mean pulmonary arterial pressure rapidly improved. Learning Objective. Pulmonary arterial hypertension (PAH) in neurofibromatosis type 1 (NF1) can occur due to lung disease or due to certain involvement of pulmonary arteries, or a combination of both. Increased awareness of PAH in NF1 is very important for patients survival. The current therapeutic strategy is almost identical to that of idiopathic PAH; however, there is no clinical evidence. Insights gained from clinical experiences should help identify promising novel therapeutic approaches in NF1-PAH.

Heart failure with preserved vs reduced ejection fraction following cardiac rehabilitation: impact of endothelial function.

There is no proven therapy for heart failure with preserved ejection fraction (HFpEF). Research has shown beneficial responses to cardiac rehabilitation (CR) among HF patients. To date, there are no reports comparing those responses between patients with HFpEF and those with reduced ejection fraction (HFrEF). The purpose of this study was to compare responses to CR in patients with HFpEF versus those with HFrEF. We included 78 consecutive patients (mean age 69 ± 15 years; 80% male) with HF in our CR unit who underwent cardiopulmonary exercise testing and brachial artery flow-mediated dilation (FMD) testing pre- and 5 months post-CR. Patients were judged as HFpEF (n = 40) or HFrEF (n = 38) using a left ventricular ejection fraction (LVEF) cut-off of 50%, and endothelial dysfunction was defined as FMD ≤ 5.0%. Following 155 ± 11 days and 44 ± 8 sessions, peak oxygen uptake ([Formula: see text]) and plasma B-type natriuretic peptide concentrations improved significantly in both groups. The percentage change in peak [Formula: see text] of HFrEF patients was significantly greater than compared with the HFpEF patients (P < 0.01). To further investigate whether a combination of LVEF and FMD values predicts the effect of CR, we divided patients into four groups according to LVEF of 50% and FMD of 50%. Post hoc analysis showed a significant difference between HFrEF patients without endothelial dysfunction and HFpEF patients with endothelial dysfunction (P = 0.01). In conclusion, although CR improves prognosis in HF patients, a larger effect can be expected in HFrEF patients than in HFpEF patients, and endothelial function may enhance the effect.

Efficacy and Safety of Alirocumab in Japanese Patients With Heterozygous Familial Hypercholesterolemia or at High Cardiovascular Risk With Hypercholesterolemia Not Adequately Controlled With Statins　- ODYSSEY JAPAN Randomized Controlled Trial.

BACKGROUND: The ODYSSEY Japan study was designed to demonstrate the reduction in low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on to existing lipid-lowering therapy in Japanese patients with heterozygous familial hypercholesterolemia (heFH) or non-FH at high cardiovascular risk who require additional pharmacological management to achieve their LDL-C treatment goal (<2.6 or <3.1 mmol/L, depending on risk category). METHODS AND RESULTS: This randomized, double-blind, parallel-group, 52-week study was conducted in Japan. Patients (n=216) with heFH, non-FH at high cardiovascular risk with coronary disease, or classified as category III were enrolled. The prespecified safety analysis was done after the last patient completed 52 weeks. Patients were randomized (2:1, alirocumab:placebo) with stratification for heFH to s.c. alirocumab (75 mg every 2 weeks [Q2 W] with increase to 150 mg if week 8 LDL-C ≥2.6/3.1 mmol/L) or placebo for 52 weeks plus stable statin therapy. At week 24, mean±SE change in LDL-C from baseline was -62.5±1.3% in the alirocumab group and 1.6±1.8% in the placebo group (difference, -64.1±2.2%; P<0.0001); the reduction was sustained to week 52 (alirocumab, -62.5±1.4%; placebo, -3.6±1.9%). No patterns were evident between treatment groups for adverse events at 52 weeks. CONCLUSIONS: In high-risk Japanese patients with hypercholesterolemia on stable statin therapy, alirocumab markedly reduced LDL-C vs. placebo and was well tolerated over 52 weeks. (Circ J 2016; 80: 1980-1987).

Spontaneous development of left ventricular hypertrophy and diastolic dysfunction in mice lacking all nitric oxide synthases.

BACKGROUND: The role of the nitric oxide synthase (NOS) system in cardiac architecture and function remains unknown. This point was addressed in mice that lack all 3 NOS genes. METHODS AND RESULTS: Morphological, echocardiographic, and hemodynamic analyses were performed in wild-type (WT), singly nNOS(-/-), iNOS(-/-), eNOS(-/-), and triply n/i/eNOS(-/-) mice. At 5 months of age, but not at 2 months of age, significant left ventricular (LV) hypertrophy was noted in n/i/eNOS(-/-) mice and to a lesser extent in eNOS(-/-) mice, but not in nNOS(-/-) or iNOS(-/-) mice, compared with WT mice. Importantly, significant LV diastolic dysfunction (as evaluated by echocardiographic E/A wave ratio and hemodynamic -dP/dt and Tau), with preserved LV systolic function (as assessed by echocardiographic fractional shortening and hemodynamic +dP/dt), was noted only in n/i/eNOS(-/-) mice, and this was associated with enhanced LV end-diastolic pressure and increased lung wet weight, all of which are characteristics consistent with diastolic heart failure in humans. Finally, long-term oral treatment with an angiotensin II type 1 (AT(1)) receptor blocker, olmesartan, significantly prevented all these abnormalities of n/i/eNOS(-/-) mice. CONCLUSIONS: These results provide the first direct evidence that the complete disruption of all NOSs results in LV hypertrophy and diastolic dysfunction in mice in vivo through the AT(1) receptor pathway, demonstrating a pivotal role of the endogenous NOS system in maintaining cardiac homeostasis.

Severe dyslipidaemia, atherosclerosis, and sudden cardiac death in mice lacking all NO synthases fed a high-fat diet.

AIMS: The precise role of the nitric oxide synthase (NOS) system in lipid metabolism remains to be elucidated. We addressed this point in mice that we have recently developed and that lack all three NOS isoforms. METHODS AND RESULTS: Wild-type (WT), singly, doubly, and triply NOS(-/-) mice were fed either a regular or high-cholesterol diet for 3-5 months. The high-cholesterol diet significantly increased serum low-density lipoprotein (LDL) cholesterol levels in all the genotypes when compared with the regular diet. Importantly, when compared with the WT genotype, the serum LDL cholesterol levels in the high-cholesterol diet were significantly and markedly elevated only in the triply NOS(-/-) genotype, but not in any singly or doubly NOS(-/-) genotypes, and this was associated with remarkable atherosclerosis and sudden cardiac death, which occurred mainly in the 4-5 months after the high-cholesterol diet. Finally, hepatic LDL receptor expression was markedly reduced only in the triply NOS(-/-) genotype, accounting for the diet-induced dyslipidaemia in the genotype. CONCLUSION: These results provide the first direct evidence that complete disruption of all NOS genes causes severe dyslipidaemia, atherosclerosis, and sudden cardiac death in response to a high-fat diet in mice in vivo through the down-regulation of the hepatic LDL receptor, demonstrating the critical role of the whole endogenous NOS system in maintaining lipid homeostasis.

Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 correlates with oxidative stress markers in stable coronary artery disease.

BACKGROUND: Although serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) is reported to be associated with acute coronary syndrome (ACS), its correlation with oxidative stress markers has not been elucidated. We therefore investigated the association of serum sLOX-1 with the severity of CAD, and serum biomarkers for oxidative stress and inflammation, as well as extracellular superoxide dismutase (EC-SOD), which is protective against oxidative stress in the vascular wall. METHODS AND RESULTS: Ninety-four patients with stable CAD were enrolled in this study. Serum sLOX-1, serum high-sensitivity C-reactive protein (hs-CRP), urinary 8-isoprostane, plasma BNP and serum lipid levels were measured. We also measured EC-SOD at baseline and post-heparin injection. Heparin-released EC-SOD (DeltaEC-SOD) was calculated as the difference between these two values. No significant correlation was found between log (sLOX-1) and log (basal EC-SOD) (p=0.096), log (hs-CRP) (p=0.108), or log (BNP) (p=0.908) levels, log (sLOX-1) had a significant correlation with DeltaEC-SOD (r=-0.325, p=0.0014) levels and urinary 8-isoprostane levels (r=0.243, p=0.020). In the multivariable analysis, DeltaEC-SOD (p=0.0177) and 8-isoprostane (p=0.0318) were independent predictors for log (sLOX-1). CONCLUSION: Serum sLOX-1 levels were positively correlated with urinary 8-isoprostane levels and inversely correlated with EC-SOD levels. These results thus suggest that increased serum sLOX-1 levels may reflect enhanced oxidative stress in vascular walls.

Mycobacterium avium pleuritis in a non-immunocompromised patient.

Nontuberculous mycobacterium infection is rarely accompanied by pleural involvement. We describe a very rare occurrence of Mycobacterium (M) avium pleuritis with pleural effusion in a non-compromised 73-year-old woman patient who had been treated for sick sinus syndrome. She was admitted to our hospital with general malaise and left pleural effusion. To establish a definitive diagnosis, a biopsy specimen was obtained from the left parietal pleura by video-assisted thoracoscopic surgery. The pleural biopsy specimen revealed only diffuse lymphoid cell infiltration and neoplastic or granulomatous lesions were absent. Culture of the pleural biopsy specimen revealed M. avium, indicating that the pleuritis was caused by this organism. A course of anti-tubercular agents (rifampin, ethambutol and streptomycin sulfate) and clarithromycin gradually resolved the pleural effusion.

Derivatives of reactive oxygen metabolites correlates with high-sensitivity C-reactive protein.

AIM: High-sensitivity C-reactive protein (hsCRP) is a predictor of cardiovascular events. Although oxidative stress may also be related to cardiovascular disease, there are few studies comparing the two. We therefore examined the association of hsCRP, serum lipids, and derivatives of reactive oxygen metabolites (D-ROMs) in coronary artery disease. METHODS: We measured the levels of serum lipids, hsCRP, plasma brain natriuretic peptides (BNP) and D-ROMs in 131 consecutive patients undergoing cardiac catheterization. We divided these subjects into three groups according to their levels of hsCRP. RESULTS: In group C (hsCRP>3.0 mg/L), mean levels of serum D-ROMs were significantly higher than in groups A (hsCRP<1.0 mg/L) and B (hsCRP 1.0 to 3.0 mg/L). Serum levels of D-ROMs and log (hsCRP) correlated in the total population (r=0.479, p<0.0001), and D-ROMs, HDL-C, LDL-C and log-transformed plasma BNP were independent predictors of hsCRP (p<0.0001). CONCLUSION: We concluded that oxidative stress increases in patients at high risk for cardiovascular events based on their hsCRP.

Intracoronary administration of isosorbide dinitrate induced severely slow flow and transient ST-segment elevation.

Nitroglycerin is one of the most widely used drugs in the treatment of angina. However, nitroglycerin fails to relieve angina in patients with syndrome X who have microvessel dysfunction. Microvessel function is impaired in several diseases. In this article, the authors report that despite normal coronary angiograms at control, intracoronary administration of isosorbide dinitrate induced severe coronary slow flow and transient ST-segment elevation with mild chest pain in a patient with congestive heart failure. The authors speculated that functional stenosis and a delay in the dilatation of microvessels less than 100 microm in diameter because of their dysfunction resulted in a severely slow flow after intracoronary administration of isosorbide dinitrate.

Spontaneous myocardial infarction in mice lacking all nitric oxide synthase isoforms.

BACKGROUND: The roles of nitric oxide (NO) in the cardiovascular system have been investigated extensively in pharmacological studies with NO synthase (NOS) inhibitors and in studies with NOS isoform-deficient mice. However, because of the nonspecificity of the NOS inhibitors and the compensatory interactions among NOS isoforms (nNOS, iNOS, and eNOS), the ultimate roles of endogenous NO derived from the entire NOS system are still poorly understood. In this study, we examined this point in mice deficient in all 3 NOS isoforms (triply n/i/eNOS(-/-) mice) that we have recently developed. METHODS AND RESULTS: The triply n/i/eNOS(-/-) mice, but not singly eNOS(-/-) mice, exhibited markedly reduced survival, possibly due to spontaneous myocardial infarction accompanied by severe coronary arteriosclerotic lesions. Furthermore, the triply n/i/eNOS(-/-) mice manifested phenotypes that resembled metabolic syndrome in humans, including visceral obesity, hypertension, hypertriglyceridemia, and impaired glucose tolerance. Importantly, activation of the renin-angiotensin system was noted in the triply n/i/eNOS(-/-) mice, and long-term oral treatment with an angiotensin II type 1 receptor blocker significantly suppressed coronary arteriosclerotic lesion formation and the occurrence of spontaneous myocardial infarction and improved the prognosis of those mice, along with ameliorating the metabolic abnormalities. CONCLUSIONS: These results provide the first direct evidence that genetic disruption of the whole NOS system causes spontaneous myocardial infarction associated with multiple cardiovascular risk factors of metabolic origin in mice in vivo through the angiotensin II type 1 receptor pathway, demonstrating the critical role of the endogenous NOS system in maintaining cardiovascular and metabolic homeostasis.

Gene transfer of extracellular superoxide dismutase ameliorates pulmonary hypertension in rats.

RATIONALE: Pulmonary hypertension (PH) is a life-threatening disease, characterized by vascular remodeling and vasoconstriction. Evidence suggests that oxidative stress may contribute to the pathogenesis and/or development of PH. OBJECTIVES: In the present study, we examined whether intratracheal gene transfer of human extracellular superoxide dismutase (EC-SOD) could ameliorate monocrotaline (MCT)-induced PH in rats. METHODS: MCT-injected rats were intratracheally administered vehicle (MCT group) or an adenovirus encoding beta-galactosidase (Adbetagal group) or human EC-SOD (AdEC-SOD group). MEASUREMENTS AND MAIN RESULTS: After intratracheal gene transfer, EC-SOD was successfully expressed in lung tissue, bronchoalveolar lavage fluid, and plasma. Twenty-eight days after MCT injection, right ventricular systolic pressure and the weight ratio of the right ventricle to the left ventricle plus septum were significantly lower in the AdEC-SOD group (42.50 +/- 1.46 mm Hg and 0.453 +/- 0.029, respectively) than in the MCT group (59.89 +/- 1.61 mm Hg and 0.636 +/- 0.022, respectively) or the Adbetagal group (61.50 +/- 2.61 mm Hg and 0.653 +/- 0.038, respectively). Moreover, vascular remodeling and proliferation of vascular smooth muscle cells in pulmonary arteries were markedly suppressed in the AdEC-SOD group. Importantly, 8-isoprostane in lung tissue was also significantly reduced in the AdEC-SOD group. CONCLUSIONS: EC-SOD overexpression to the lung ameliorated MCT-induced PH in rats. We suggest that EC-SOD may act as an antioxidant in PH and that increased oxidative stress may be important in the pathogenesis of MCT-induced PH.

Angiotensin receptor blocker improves coronary flow velocity reserve in hypertensive patients: comparison with calcium channel blocker.

Large-scale clinical studies have indicated that angiotensin receptor blockers (ARBs) have beneficial effects against cardiovascular diseases. We designed this study to compare the effects of an ARB and a calcium channel blocker (CCB) on coronary flow velocity reserve (CFVR), a predictor of cardiovascular events, as estimated using transthoracic Doppler echocardiography. Sixteen hypertensive patients (63.1+/-9.6 years old; 10 males) were randomly allocated in a double-blind fashion to valsartan (n=8, 40-80 mg/day) or nifedipine (n=8, 20-40 mg/day) groups. Age- and gender-matched subjects without hypertension were enrolled as a control group (n=12). CFVR was calculated by dividing the adenosine triphosphate-induced hyperemic flow velocity by the basal flow velocity in the left anterior descending coronary artery. Baseline characteristics and reduction in systolic and diastolic blood pressure after 6 months were similar in both groups. CFVR in the valsartan group increased from 2.34+/-0.38 to 3.10+/-0.84 at 2 months (p<0.05), and to 3.04+/-1.09 at 6 months (p<0.01). Both values became comparable to that in the control group (2.81+/-0.60). CFVR in the valsartan group was significantly higher (p<0.001) than that in the nifedipine group, which was little changed at 6 months. This discrepancy was derived from the significant increase of hyperemic velocity in the valsartan group, from 36.6+/-17.3 cm/s to 41.1+/-12.7 cm/s at 2 months, and to 48.1+/-20.2 cm/s at 6 months. We concluded that the ARB valsartan not only reduced high blood pressure but improved CFVR in hypertensive patients. However, these effects were not seen with the CCB nifedipine.

PTEN reduces cuff-induced neointima formation and proinflammatory cytokines.

An inflammatory response followed by vascular injury plays an important role in neointima formation and development of atherosclerotic lesions, which are in part mediated by proinflammatory cytokines. Using a cuff injury model, we examined the effects of adenovirus-mediated overexpression of phosphatase and tensin homology deleted on chromosome 10 (PTEN) on neointima formation and the proinflammatory response. A cuff was placed around the femoral artery, and adenovirus expressing human PTEN type 1 (AdPTEN) or Escherichia coli beta-galactosidase (AdLacZ) was injected between the cuff and the adventitia. After 14 days, the arteries were examined histopathologically and by Western blotting. The significant reduction of neointima formation by AdPTEN compared with AdLacZ was accompanied by reduced cell proliferation and increased adventitial cell apoptosis. AdPTEN also reduced expression of phosphorylated I kappa B-alpha, but not nonphosphorylated I kappa B-alpha. Western blotting revealed that AdPTEN reduced the cuff injury-induced expression levels of monocyte chemoattractant protein-1, TNF-alpha, and IL-1 beta and their expression in all layers of the arterial wall. In contrast, cuff-induced macrophage invasion, which was also inhibited by AdPTEN, was detected only at the intimal surface and in the adventitia. In cultured vascular smooth muscle cells, PTEN directly inhibited ANG II-induced monocyte chemoattractant protein-1 expression as quantified by real-time PCR and Western blotting. Our results suggest that overexpression of PTEN reduces neointima formation, possibly in part through inhibition of the inflammatory response by macrophage invasion and proinflammatory cytokine expression.

Decreased plasma extracellular superoxide dismutase level in patients with vasospastic angina.

OBJECTIVE: Extracellular superoxide dismutase (EC-SOD) is the major extracellular scavenger of superoxides, and one of the main regulators of nitric oxide bioactivity in vessel walls. Here, we examined whether plasma EC-SOD level was associated with vasospastic angina (VSA), and if it was a risk factor for VSA. METHODS AND RESULTS: We assigned 105 patients with normal or mildly stenotic coronary arteries into either a VSA (n=58) or chest pain syndrome (CPS) (n=47) groups. Plasma EC-SOD and other biochemical variables were measured, and major coronary risk factors were assessed. Results showed that apart from smoking status there were no significant differences in patient characteristics and biochemical variables between the two groups. In the VSA group, prevalence of smoking was significantly higher (53% versus 26%, p=0.0055), and plasma EC-SOD level was significantly lower (68.9+/-18.5 ng/ml versus 83.8+/-25.9 ng/ml; p=0.0009). Not only smoking (OR 2.742, 95% CI 1.032-7.287, p=0.0431) but also plasma EC-SOD (OR 0.971, 95% CI 0.949-0.993, p=0.0102) was an independent risk factor for VSA. CONCLUSIONS: In patients with VSA, plasma EC-SOD level was substantially reduced. Furthermore, plasma EC-SOD level followed by cigarette smoking was the most predictive risk factor for coronary spasms.

Statin treatment upregulates vascular neuronal nitric oxide synthase through Akt/NF-kappaB pathway.

OBJECTIVE: Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are known to enhance vascular expression of endothelial (eNOS) and inducible nitric oxide synthase (iNOS). In this study, we examined whether statins also upregulate vascular expression of neuronal NOS (nNOS). METHODS AND RESULTS: In cultured rat aortic smooth muscle cells, treatment with atorvastatin significantly increased nNOS expression, associated with activation of Akt and NF-kappaB. Inhibition of Akt by dominant-negative Akt suppressed atorvastatin-induced nNOS expression as well as Akt and NF-kappaB activation. Inhibition of NF-kappaB by dominant-negative IkappaB also attenuated atorvastatin-induced nNOS expression and NF-kappaB activation, but not Akt activation. We further examined whether atorvastatin also enhances nNOS expression in isolated mouse aorta, and if so, how much nNOS-derived NO accounts for atorvastatin-induced NOx production. In isolated aortas of wild-type mice, atorvastatin significantly increased all three NOS isoform expression and NOx production. In isolated aortas of doubly i/eNOS(-/-), n/eNOS(-/-), and n/iNOS(-/-) mice, which express only nNOS, iNOS, and eNOS, respectively, atorvastatin-induced NOx production was approximately 25%, 25%, and 50% to that of wild-type mice, respectively, suggesting that nNOS accounts for 25% of the atorvastatin-mediated NOx production. CONCLUSIONS: These results indicate that atorvastatin upregulates vascular nNOS through Akt/NF-kappaB pathway, demonstrating a novel nNOS-mediated vascular effect of the statin.

Detection of patency of internal mammary artery grafts to the left anterior descending artery by transthoracic Doppler echocardiography.

BACKGROUND: To determine whether a coronary artery bypass graft (CABG) is patent, we examined the flow of the left internal mammary artery (LIMA) to the left anterior descending artery (LAD) by transthoracic Doppler echocardiography (TTDE). PATIENTS AND METHODS: Eighty-seven patients with CABG (LIMA to distal LAD) were enrolled in the study. The flows from each subject were analyzed by three criteria: mosaic flow at the anastomosis site, distal anterograde flow (ante flow), and proximal retrograde flow (retro flow). RESULTS: On angiography, 79 grafts were patent and eight were not. TTDE study of 79 patent grafts demonstrated mosaic, ante, and retro flow in 63 (79.7%), 74 (93.7%), and 35 grafts (49.4%), respectively. The averaged diastolic peak velocity of ante flow was 26.3 +/- 11.0 cm/sec, significantly higher than that (4.8 +/- 7.1 cm/sec, P < or = 0.0001) in eight patients without patent grafts. These eight patients had no mosaic or retro flow and only three had ante flow. The accuracies to predict patency were 81.6%, 90.8%, and 49.4% for mosaic, ante, and retro flows, respectively. CONCLUSIONS: The existence of mosaic, retro, or sufficient ante flows strongly indicated the patency of LIMA to the LAD. When symptoms are possible to be derived from the occlusion of CABG to LAD, TTDE is a promising method to examine whether a LIMA to LAD bypass is patent.

Long-term treatment with imidapril but not with nifedipine enhances plasma NOx concentration in patients with essential hypertension.

We investigated whether long-term treatment with the angiotensin-converting enzyme (ACE) inhibitor imidapril or the calcium channel antagonist nifedipine increases systemic nitric oxide (NO) production in patients with essential hypertension. Twenty-nine patients with essential hypertension were randomly divided into two groups, and they were treated with either imidapril or nifedipine once daily p.o. for 4 weeks. Long-term treatment with imidapril significantly decreased blood pressure and increased plasma NOx concentration. Long-term treatment with nifedipine also caused a comparable extent of significant decrease in blood pressure, but failed to alter plasma NOx levels. The imidapril treatment significantly inhibited serum ACE activity and increased plasma bradykinin concentration. Furthermore, the extent of inhibition of serum ACE activity and the extent of increase in plasma bradykinin concentration in response to the imidapril treatment were both significantly correlated with the extent of increase in plasma NOx concentration. In contrast, no such changes were noted after the nifedipine treatment. These results provide the first evidence that long-term treatment with imidapril enhances plasma NOx concentration in patients with essential hypertension. This effect does not seem to be due to the decrease in blood pressure. The increase in bradykinin concentration may be involved in the enhancing effect of the ACE inhibitor on NOx production in vivo.