Effects of monocrotaline on endothelial nitric oxide synthase expression and sulfhydryl levels in rat lungs

The nitric oxide-cyclic guanosine monophosphate signal-transduction mechanism plays a key role in the regulation of vascular tone and structure. Monocrotaline-induced pulmonary hypertension is associated with low bioavailability of nitric oxide. To characterize the mechanism(s) involved in this dysfunction, rats received a single subcutaneous injection of monocrotaline, normal saline (control), or monocrotaline plus daily L-arginine, a precursor of nitric oxide, in drinking water. Pulmonary artery pressure and right ventricular hypertrophy were assessed 2 weeks later. In addition, the authors evaluated the expression of endothelial nitric oxide synthase messenger RNA, endothelial nitric oxide synthase protein, cyclic guanosine monophosphate, and sulfhydryl levels in the lungs. Sulfhydryls are needed for the dynamic modulation of soluble guanylate cyclase by nitric oxide, which results in cyclic guanosine monophosphate formation. L-arginine treatment did not attenuate monocrotaline-induced pulmonary hypertension or right ventricular hypertrophy. Monocrotaline did not alter the expression of endothelial nitric oxide synthase messenger RNA or endothelial nitric oxide synthase protein in the lungs. Protein-bound sulfhydryls (28 +/- 5 vs. 75 +/- 16 pmol/microg protein) and cyclic guanosine monophosphate (0.63 +/- 0.05 vs. 1.06 +/- 0.017 pmol/microg protein) levels in the monocrotaline group were significantly low compared with controls. The low sulfhydryl levels, an indicator of oxidant stress, may account for the impaired availability of bioactive nitric oxide and low cyclic guanosine monophosphate levels. These results suggest that oxidative stress may, in part, contribute to the pathogenesis of pulmonary hypertension in the monocrotaline model.     

L-arginine partially reverses established adrenocorticotrophin-induced hypertension and nitric oxide deficiency in the rat

BACKGROUND: L-arginine treatment prevents adrenocorticotrophin (ACTH) induced hypertension in the rat. This study examined whether L-arginine treatment could reverse established ACTH hypertension and its effects on markers of decreased NO activity. METHODS: Sixty-four male Sprague-Dawley rats were randomly divided into 6 groups given 12 days of treatment: (1) sham (0.9% NaCl, 0.5 ml/kg, subcutaneously, sc, n = 16); (2) ACTH (0.5 mg/kg/day, sc, n = 16); (3) sham + L-arginine (0.6% in food, from treatment day 8 onwards, n = 10); (4) ACTH + L-arginine (n = 10); (5) sham + D-arginine (0.6% in food, from T 8 onwards) (n = 6); and (6) ACTH + D-arginine (n = 6). Systolic blood pressure, water intake, urine volume, and body weight were measured every second day. At the end of the experiments, plasma and urinary nitrate/nitrite (NOx), plasma amino acid concentrations (in groups 1-4), and urinary cyclic guanosine monophosphate (cGMP) concentrations were measured. RESULTS: Sham, sham + L-arginine, and sham + D-arginine treatments did not affect blood pressure. ACTH increased systolic blood pressure (from 121 +/- 1 to 147 +/- 2 mmHg, p < 0.001, pooled control vs treatment day 12, mean +/- sem), and this was partially reversed by L-arginine (group 4: from 141 +/- 2 on day 8 to 133 +/- 1 mmHg on day 12, n = 10, p < 0.001). In contrast, D-arginine did not affect blood pressure in ACTH-treated rats (group 6). ACTH increased water intake and urine volume and decreased body weight, and L-arginine administration did not alter these parameters. ACTH decreased plasma citrulline (group 1 vs 2: 115 +/- 7 vs 67 +/- 6 micro M/L, n = 16, p < 0.001) and NOx concentrations (group 1 vs 2: 8.3 +/- 0.8 vs 4.5 +/- 0.6 microM/L, n= 10, p < 0.001) and these decreases were reversed by L-arginine treatment (group 4: citrulline 98 +/- 9 micro M/L, NOx 9.1 +/- 1.6 micro M/L, group 2 vs 4, both p < 0.05). ACTH produced marked increases in urinary cGMP excretion (group 1 vs 2: 0.5 +/- 0.1 vs 1.9 +/- 0.4 nmol/24 h, p < 0.01). CONCLUSION: Supplementation with L-arginine partly reversed established ACTH-induced hypertension and restored plasma NOx and citrulline concentrations to levels seen in sham-treated rats. These data are consistent with previous studies suggesting that functional NO deficiency has a role in ACTH-induced hypertension in rats.     

Effects of atrial natriuretic factor on natriuresis and cGMP in patients with essential hypertension

Human atrial natriuretic factor (h-ANF) or its vehicle only, were infused at rates of 0.8, 1.6 and 3.2 micrograms/min over three successive 30-min periods, into five patients with mild essential hypertension and seven normotensive controls. Baseline (mean +/- s.e.m.) plasma ANF levels were 13 +/- 2 in patients and 8 +/- 1 pg/ml in controls. During the first period, plasma ANF and cyclic guanosine monophosphate (cGMP) levels increased in both groups without significant alteration of blood pressure, heart rate, diuresis, natriuresis or cGMP excretion rate. During the second period of infusion, plasma ANF levels increased up to 179 +/- 39 and 177 +/- 30 pg/ml in patients and controls and plasma cGMP concentrations increased X 5.0 and X 4.9, respectively; natriuresis increased X 2.4 in patients and X 3.1 in controls while urinary cGMP increased X 10.9 in patients and X 10.5 in controls. During the last period, three controls became hypotensive while blood pressure remained stable in the other controls and in the patients with essential hypertension. During this period, the increases in plasma ANF concentration, diuresis, natriuresis and urinary cGMP excretion were similar in both groups. However, the mean plasma cGMP concentration after 90 min infusion was significantly higher in hypertensive patients than in control subjects (30.7 +/- 3.3 versus 15.6 +/- 3.4 pmol/ml, P less than 0.05). The half-life and clearance of plasma ANF, upon discontinuation of the infusion, were similar in both groups. Our data suggest that patients with mild essential hypertension have enhanced increases in plasma cGMP but normal increases in diuresis, natriuresis and cGMP excretion following infusion of h-ANF at pharmacological rates.     

Effects of cyclooxygenase inhibition on endothelial function in hypertensive patients treated with angiotensin-converting enzyme inhibitors

BACKGROUND: Cyclooxygenase inhibition restores endothelium-dependent vasodilatation in hypertension, but it is unknown whether it restores endothelial function in hypertensive patients treated with angiotensin-converting enzyme (ACE) inhibitors. HYPOTHESIS: The purpose of the present study was to evaluate the effects of cyclooxygenase inhibition on endothelial function in hypertensive patients treated with ACE inhibitors. METHODS: Endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent glyceryl trinitrate-induced dilatation were investigated in 10 patients treated with enalapril (ACE group), 11 patients treated with manidipine and metoprolol (non-ACE group), and 12 normotensive control subjects. After administration of 1000 mg of aspirin, FMD was investigated once again. Plasma cyclic guanosine monophosphate (cGMP) and eicosanoids were also measured during reactive hyperemia before and after aspirin administration. RESULTS: Flow-mediated dilatation was more impaired in the non-ACE group than in the ACE group (8.3 +/- 3.8%, 5.7 +/- 1.7%, respectively, p<0.04). Glyceryl trinitrate-induced dilatation was similar in the ACE group, the non-ACE group, and in the control subjects. In the ACE group, FMD was reduced after administration of aspirin (5.3 +/- 4.2%, p<0.05). The percent change in FMD after administration of aspirin correlated significantly with percent change in cGMP (r=0.77, p<0.03; y-intercept, -62.1%, p<0.01). After aspirin administration, levels of thromboxane B2 and 6-keto-prostaglandin(1alpha) were significantly decreased compared with those before aspirin administration in all groups. CONCLUSIONS: Cyclooxygenase inhibition may reduce the beneficial effect on endothelium-dependent vasodilatation induced by ACE inhibitors. The results suggested that prostacyclin in addition to nitric oxide plays a significant role in the restoration of endothelial function in hypertensive patients treated with ACE inhibitors.     

Effect of oral L-arginine on blood pressure and symptoms and endothelial function in patients with systemic hypertension, positive exercise tests, and normal coronary arteries

Thirteen hypertensive patients with microvascular angina were studied before and after receiving oral L-arginine (4 weeks, 2 g, 3 times daily). L-arginine significantly improved angina class, systolic blood pressure at rest, and quality of life. Maximal forearm blood flow, plasma L-arginine, L-arginine:asymmetric dimethyl arginine ratio, and cyclic guanylate monophosphate increased significantly after treatment. In medically treated hypertensive patients with micro-vascular angina, oral L-arginine may represent a useful therapeutic option.     

Oral L-arginine improves endothelial dysfunction in patients with essential hypertension

BACKGROUND: L-Arginine is a nitric oxide precursor, which augments endothelium-dependent vasodilatation in hypercholesterolemic humans and animals. Endothelium-dependent vasodilation is attenuated in patients with hypertension; however the effects of oral L-arginine on endothelial function of the conduit arteries in patients with essential hypertension have not previously been investigated. METHODS: In a prospective randomized double blind trial, 35 patients with essential hypertension received either 6 g L-arginine (18 subjects) or placebo (17 subjects). Patients were examined for flow-mediated endothelium-dependent dilatation of the brachial artery before and 1.5 h after administration of L-arginine or placebo. At the end of the protocol the nitrate-induced, endothelium-independent vasodilatation was evaluated. RESULTS: Two groups of L-arginine and placebo were similar regarding age, sex, blood lipids, smoking, diabetes, coronary artery disease, body mass index, intima-media thickness of the common carotid artery, clinics blood pressure and baseline brachial artery parameters. Administration of L-arginine or placebo did not change significantly heart rate, blood pressure, baseline diameter, blood flow or reactive hyperemia. L-Arginine resulted in a significant improvement of flow-mediated dilatation (1.7+/-3.4 vs. 5.9+/-5.4%, P=0.008) while placebo did not significantly change this parameter (3.0+/-2.7 vs. 3.1+/-2.2%, P=ns). The effect of L-arginine on flow-mediated dilatation was significantly different from the effect of placebo (P=0.05). L-Arginine did not significantly influence nitrate-induced dilatation (16+/-6.9 vs. 17.7+/-6.7%, P=ns). CONCLUSIONS: Oral administration of L-arginine acutely improves endothelium-dependent, flow-mediated dilatation of the brachial artery in patients with essential hypertension. The long-term effects of L-arginine in these patients require further investigation.     

GTP环化水解酶I/四氢生物蝶呤通路对高血压内皮祖细胞体外活性和体内再内皮化能力的调节

目的研究GTP环化水解酶Ⅰ/四氢生物蝶呤信号通路对高血压患者循环内皮祖细胞功能的调节。方法分别纳入高血压患者和健康志愿者各19例,采集外周血进行内皮祖细胞分离、培养及鉴定,评估其迁移、增殖、黏附活性;建立裸鼠动脉损伤模型并移植高血压患者和健康志愿者内皮祖细胞,评估内皮祖细胞修复损伤血管内皮功能,并检测内皮祖细胞GTP环化水解酶Ⅰ/四氢生物蝶呤通路及一氧化氮、环磷酸鸟苷、凝血酶敏感蛋白1的mRNA表达水平。通过基因干扰、基因转染或药物阻滞干预,进一步证实该信号通路对内皮祖细胞功能的调节作用。结果高血压患者内皮祖细胞体外活性及体内再内皮化功能降低,且内皮祖细胞GTP环化水解酶Ⅰ/四氢生物蝶呤通路及其下游信号分子一氧化氮、环磷酸鸟苷的mRNA表达水平亦下降,而凝血酶敏感蛋白1 mRNA表达水平则升高。抑制该信号通路的表达可削弱内皮祖细胞的体外活性及再内皮化功能。结论研究证实GTP环化水解酶I/四氢生物蝶呤通路可通过凝血酶敏感蛋白1及可溶性鸟苷酸环化酶/环磷酸鸟苷系统调节高血压患者内皮祖细胞的体外及体内功能。     

Insulin receptor number is reduced in healthy offspring of patients with essential hypertension

BACKGROUND: Epidemiologic studies have shown that healthy offspring of hypertensive patients exhibit many features of the metabolic syndrome, such as hyperinsulinemia, insulin resistance, and lipid disorders. Patients with essential hypertension have reduced numbers of insulin receptors. The aim of this study was to examine whether the number of insulin receptors is reduced in the erythrocytes of healthy offspring of hypertensive patients in comparison to the offspring of healthy normotensive subjects. METHODS: The study population consisted of 25 healthy offspring of patients with essential hypertension (group A) and 28 healthy offspring of healthy normotensive individuals (group B). The two groups were matched for sex, age, and body mass index. Systolic blood pressure (SBP) and diastolic blood pressure (DBP), resting heart rate (HR), plasma insulin levels, and human insulin receptor (hINR) number in erythrocytes were determined in each participant. RESULTS: Mean SBP, DBP, and resting HR were significantly higher in group A than in group B (121 +/- 13 v 110 +/- 10 mm Hg, 78 +/- 6 v 73 +/- 8 mm Hg, and 76 +/- 4 v 72 +/- 6 beats/min; P < .01, P < .05, and P < .01, respectively). Plasma insulin levels were significantly higher, whereas hINR density was significantly lower, in group A than in group B (21 +/- 7 v 15 +/- 6 pIU/mL, P < .01, and 5.6 +/- 1.4 v 6.8 +/- 1.3 receptors x 10(3)/red cell, P < .01, respectively). CONCLUSIONS: Our findings suggest that increased SBP, DBP, HR, plasma insulin levels, and decreased erythrocyte hINR density preexist in healthy offspring of patients with essential hypertension.     

Biochemical endothelial markers and cardiovascular remodeling in refractory arterial hypertension

BACKGROUND: Hypertension is the most important and well established risk factor for atherosclerosis. The vascular and cardiac remodeling present in refractory hypertensive patients are related to endothelial dysfunction, a key factor in early atherogenesis and cardiovascular disease. However the mechanistic relationship among biochemical endothelial function markers, cardiovascular remodeling, and refractory hypertension is unknown. METHODS: We evaluated the left ventricular mass and function, carotid thickness, and plasma nitrate/nitrite (NO2/NO3), cyclic 3'-5'-guanosine monophosphate (cGMP), and thromboxane B2 (TXB2) levels in refractory hypertensive (RH; n = 20) and healthy (CONTROL; n = 20) subjects 22-65 years old. Carotid thickness, left ventricular mass index (LVMI), and left ventricular fraction ejection (LVFE) were estimated by duplex scan ultrasound. Nitrates/nitrites were assayed using the Griess reaction, and plasma cGMP and thromboxane B2 were determined by enzymatic immunoassay (EIA). RESULTS: Left ventricular mass index was higher in the RH group (138 +/- 20 vs. 108 +/-17 g/m2, p < 0.001) but there was no significant difference in the ejection fraction (67 +/- 5% vs. 69 +/- 4%). Pulse pressure (61 +/- 9 mmHg vs. 46 +/- 10 mmHg) and carotid thickness (1.59 +/- 0.22m vs. 1.04 +/- 0.14mm) were significantly higher (p < 0.001) in RH patients whereas NO2/NO3, cGMP, and thromboxane B2 plasma concentrations were similar in bot groups. CONCLUSION: There was no association between cardiovascular remodeling and the particular biochemical markers of endothelial function we assessed in refractory hypertensive patients.     

Venous abnormality in normotensive young men with a family history of hypertension

Maximal vasodilator capacity of resistance vessels has been shown to be reduced in normotensive young men with a family history of hypertension. The present study attempted to examine whether venous distensibility is decreased in normotensive men with hypertensive relatives. The venous pressure-volume relationship was determined in the forearm with a water-filled plethysmograph in 17 normotensive young men with hypertensive relatives (mean blood pressure, 85 +/- 2 [SE] mm Hg; age, 22 +/- 1 years) and 18 young men with no family history of hypertension (mean blood pressure, 81 +/- 2 mm Hg; age, 22 +/- 1 years). The venous pressure-volume curve in men with hypertensive relatives as compared to that in men with no family history of hypertension was shifted toward the pressure axis (p less than 0.001). This findings suggests that venous distensibility is decreased in normotensive young men with hypertensive relatives. Administration of phentolamine, 1 mg/min i.v. for 5 minutes, did not alter venous distensibility, and venous distensibility after phentolamine administration was less in men with hypertensive relatives than in men with no family history (p less than 0.001), which suggests that decreased venous distensibility found in normotensive young men with hypertensive relatives was unlikely to be related to alpha-adrenergic mechanisms. These results suggest that normotensive young men with a family history of hypertension have vascular abnormalities that involve veins as well as arteries.     

Prolonged Low Dose Infusion of Atrial Natriuretic Factor in Essential Hypertension

The C-terminal fragment of atrial natriuretic factor (ANF) was infused intravenously at 0.5 pmol/kg/min during 12 hours in 6 patients with mild to moderate essential hypertension, and in 6 normotensive volunteers, all recumbent and well hydrated, under a daily intake of 200 and 120 mmoles of sodium and potassium, respectively. Plasma C-terminal ANF tended to increase during ANF and to decrease during vehicle infusions. Plasma concentrations of the N-terminal fragment of ANF decreased by 20 to 40% (p < 0.05) during ANF and remained unchanged following vehicle infusion, suggesting that exogenous ANF reduces endogenous ANF secretion. ANF increased significantly plasma cyclic guanosine monophosphate (p < 0.01) from 3.1 ± 0.4 to 4.3 ± 0.8 and from 2.8 ± 0.4 to 5.1 ± 0.5 nmol/L in controls and patients respectively. ANF reduced systolic diastolic blood pressure during the last 8 hours of the infusion, by about 5% (p = 0.055) in patients, but did not alter blood pressure in controls. Sodium excretion during ANF increased 42% vs vehicle (p < 0.05), in the patients group and remained unchanged in controls. Hematocrit levels increased significantly in both groups with ANF infusion. We conclude that a prolonged infusion of ANF at a physiological rate causes a modest increase in plasma cyclic guanosine monophosphate, hemoconcentration, and reduces endogenous ANF secretion. It also stimulates diuresis and natriuresis and slightly reduces systolic blood pressure in patients with essential hypertension.     

Nifedipine and arotinolol in combination for accelerated-malignant hypertension: results of one year follow-up.

The effects of a combined therapy with a calcium channel antagonist and alphabeta-blocker in patients with accelerated-malignant hypertension on blood pressure and renal function were examined. Thirteen patients presented with the clinical features of malignant hypertension (diastolic blood pressure >130 mmHg, retinal damage and progressive renal failure) at our hospital, over the 3 yr period from 1995 to 1997. These patients were treated with both a calcium antagonist, 60-80 mg/d dose of long acting nifedipine, and an alphabeta-blocker, 20 mg/d dose of arotinolol, for over 12 mo. At admission, the average blood pressure of the patients was 233+/-8/144+/-3 mmHg. The level of serum creatinine in these patients was 6.2+/-1.0 mg/dl. Intermittent hemodialysis therapy was introduced in 7 patients. Three days after treatment, blood pressure decreased to 162+/-4/102+/-4 mmHg. A month later, blood pressure decreased to 148+/-3/89+/-2 mmHg and serum creatinine levels were 3.6+/-0.4 mg/dl. Renal function in these patients improved, and they completely recovered from renal dysfunction, allowing withdrawal of haemodialysis therapy. One year later, the blood pressure in all of these patients was well controlled and no further renal deterioration was observed, except in one patient. Despite the reduction in blood pressure, one patient was on hemodialysis three times a week after 8 mo of treatment. From these finding, it is concluded that combination therapy with a calcium antagonist and alphabeta-blocker is effective in both the reduction of highly elevated blood pressure and protection of the kidneys, resulting in amelioration of accelerated-malignant hypertension.     

Hemodynamic studies in long- and short-term portal hypertensive rats: the relation to systemic glucagon levels

It is not known whether the hyperdynamic state which has been observed in several experimental models and in patients with portal hypertension reflects a temporary phase during the evolution of the portal hypertensive syndrome or is an expression of a permanent steady state. A hemodynamic study was performed in a group of rats with long-standing portal hypertension induced by portal vein constriction performed 6.2 +/- 0.1 months earlier. A group of rats matched by age and weight with short-term (20.7 +/- 0.9 days) portal hypertension and a group of long-term (6.2 +/- 0.1 months) sham-operated rats were used as controls. Cardiac output and regional blood flows were measured using a radioactive microsphere technique. Arterial blood levels of glucagon, a known vasodilator that was implicated in the etiology of the hyperdynamic circulation, were also measured. Portal pressure in long- and short-term portal hypertensive groups (12.3 +/- 0.4 and 13.7 +/- 0.4 mm Hg; not statistically significant) was higher than in the sham group (9.0 +/- 0.3 mm Hg; p less than 0.01). Cardiac output in the long-term portal hypertensive rats was similar to the sham-operated group and lower than in the short-term portal hypertensive group (19.4 +/- 1.0 and 20.6 +/- 1.5 vs. 32.7 +/- 2.0 ml X min-1 X 100 gm body weight-1; p less than 0.01). Portal venous inflow in the long-term portal hypertensive group was also similar to the sham group and lower than in the short-term portal hypertensive group (4.51 +/- 0.36 and 4.58 +/- 0.39 vs. 6.72 +/- 0.48 ml X min-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

An epidemiological study of blood pressure in school children (5-14 years) in Delhi.

Distribution patterns of blood pressure were studied in a randomised sample of 10,215 school children (5,709 boys 4,506 girls) in the age group 5-14 years in Delhi. The mean values of systolic and diastolic blood pressure (SBP and DBP) increased with age in both sexes. The cut-off points for high blood pressure were based on average SBP and/or DBP values of 95th percentile or greater for each age. The values for SBP ranged from 70 mm Hg to 140 mm Hg and for DBP from 36 mm Hg to 100 mm Hg for the age group 5-9 years. In the age group 10-14 years, the values for SBP and DBP ranged from 72 mm Hg to 160 mm Hg and from 46 mm Hg to 120 mm Hg, respectively. The prevalence of hypertension (systolic, diastolic or both) was 11.9 percent in boys and 11.4 percent in girls, an insignificant difference. Anthropometric variables like height, weight and body mass index showed positive correlation with systolic as well as diastolic blood pressure but the waist-hip ratio showed negative correlation coefficient with blood pressure. Family history of hypertension in one or both the parents was present in 20.4 percent children with high blood pressure compared to 6.8 percent in normotensives. Family history or diabetes was also significantly higher in hypertensive children (5.4%) than in normotensives (3.1%).     

Impairment of renal vasodilation with l-arginine is related to more severe disease in untreated hypertensive patients

Data remain insufficient to place the decreased response to L-arginine in hypertensive patients within a consistent pathophysiological sequence. The aim of the present study in patients with essential hypertension was to assess the relationships between the response to L-arginine and a set of relevant clinical and laboratory parameters. In this prospective, interventional study, we administered L-arginine to untreated hypertensive individuals and healthy control subjects and measured the clearance of inulin and of para-aminohippurate and a set of biochemical and clinical variables. L-Arginine infusion revealed major differences between control subjects and 1 subgroup (group B) of hypertensive individuals. Group B hypertensives (n=18) had no increase in inulin clearance and no decrease in renal vascular resistance with L-arginine; however, in another subset of hypertensive patients (group A, n=27), the insulin clearance increased and renal vascular resistance decreased similar to the control group (group C, n=11). The ambulatory blood pressure monitoring in group B showed both an increased mean diastolic pressure and a "nondipper" pattern in the nocturnal regulation of arterial pressure. These findings in group B were accompanied by significant alterations in optic fundus and left ventricle hypertrophy and increased microalbuminuria (all, P<0.05). Furthermore, group B individuals had significantly lower values of HDL cholesterol and a higher baseline atherogenic index, plasma insulin level, and glucose/insulin index. We disclose a previously undescribed relationship between end organ repercussion and decreased renal hemodynamic response to L-arginine. Our results may help to understand the mechanisms that lead to target organ damage in hypertension.     

Persistent remodeling of resistance arteries in type 2 diabetic patients on antihypertensive treatment

We hypothesized that resistance arteries from diabetic patients with controlled hypertension have less remodeling than vessels from untreated hypertensive subjects. Eight normotensive subjects (aged 44+/-3 years, 3 men; values are mean+/-SEM), 19 untreated hypertensive subjects (46+/-2 years, 9 men), and 23 hypertensive subjects with type 2 diabetes mellitus under antihypertensive treatment (58+/-1 years, 15 men) were studied. Resistance arteries dissected from gluteal subcutaneous tissue were assessed on a pressurized myograph. Most diabetic patients (70%) were being treated with angiotensin-converting enzyme inhibitors. Although systolic blood pressure was still above the normotensive range in these patients (144+/-2 versus 150+/-3 mm Hg in hypertensive and 114+/-4 mm Hg in normotensive subjects), diastolic blood pressure was well controlled (83+/-2 mm Hg) and significantly lower compared with that in untreated hypertensives (100+/-1 mm Hg; P<0.001) but higher than in normotensives (76+/-3 mm Hg; P<0.05). Thus, pulse pressure was higher in diabetic patients (P<0.05). The media-to-lumen ratio of resistance arteries was greater in hypertensives (0.083+/-0.002) compared with normotensive controls (0.059+/-0.003; P<0.05) and was even higher in diabetic hypertensive subjects (0.105+/-0.004; P<0.001 versus normotensive controls). The medial cross-sectional area was greater in diabetic and hypertensive patients compared with normotensive controls (P<0.001). Acetylcholine-induced relaxation was impaired in vessels from hypertensive patients and from patients with both diabetes mellitus and hypertension (P<0.05 versus normotensive controls), whereas endothelium-independent vasorelaxation was similar in all groups. Despite effective antihypertensive treatment, resistance arteries from hypertensive diabetic patients showed marked remodeling, greater than that of vessels from untreated, nondiabetic, hypertensive subjects, in agreement with the high cardiovascular risk of subjects suffering from both diabetes and hypertension.     

Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension.

OBJECTIVE: To examine the efficacy and tolerability of the neutral endopeptidase inhibitor, candoxatril (UK 79,300) as monotherapy in essential hypertension. DESIGN: Double-blind, placebo-controlled, parallel-group study of 28 days' duration. SETTING: Three hospital outpatient departments participating in the Glasgow Blood Pressure Clinic (Glasgow, UK). PATIENTS: Forty patients with essential hypertension with diastolic blood pressure 95-114 mmHg after a 2-4 week placebo run-in period. INTERVENTIONS: Twenty-eight days' treatment with candoxatril 200 mg twice daily or matching placebo capsules. MAIN OUTCOME MEASURES: Changes in supine and erect blood pressure, and volunteered side effects during double-blind treatment. RESULTS: When measured at the end of the dose interval, the fall in supine blood pressure following candoxatril was not significantly greater than that after placebo. Compared with placebo, a significant effect for candoxatril was seen only for systolic blood pressure in the erect posture; the fall in erect diastolic blood pressure attributable to candoxatril was insignificant. Median plasma atrial natriuretic peptide concentration increased in candoxatril-treated patients and decreased in the placebo group. No stimulation of the renin-aldosterone axis was seen. There was a non-significant trend towards greater urinary excretion of cyclic guanosine monophosphate after candoxatril. Mean plasma concentration of candoxatril at (UK 73,967--the active metabolite of candoxatril) reached a peak of 1010 +/- 437 ng/ml after acute dosing, and 1328 +/- 405 ng/ml after chronic dosing; time to maximum concentration was 2 h in each case. Candoxatril was well-tolerated; numbers of adverse events did not differ between active treatment and placebo. CONCLUSIONS: Although atrial natriuretic peptide levels were significantly increased, candoxatril 200 mg twice daily for 28 days did not produce a clinically relevant fall in blood pressure. Our results cast some doubt upon the role of neutral endopeptidase inhibition in the treatment of unselected hypertensive patients.     

Atrial natriuretic factor in hypertension: bioactivity at normal plasma levels

To ascertain whether small shifts in plasma atrial natriuretic factor (ANF) exerted biological effects in hypertension, we studied the renal, hemodynamic, and hormonal effects of ANF [human ANF-(99-126)] infused at a dose (0.75 pmol/kg/min for 3 hours) that would induce changes in plasma ANF confined to the normal, resting range, in a group of six young men with uncomplicated, mild essential hypertension. During ANF infusions, the patients excreted 11.8 +/- 2.0 mmol (mean +/- SEM) sodium more than during the time-matched placebo phase natriuresis (p less than 0.001, mean increase of 53% above placebo values). Urinary excretion of cyclic guanosine monophosphate rose to more than double (212%, p less than 0.001) placebo values. Plasma renin activity (0.4 +/- 0.05 vs. 0.9 +/- 0.12 nmol/l/hr, p less than 0.0001) and aldosterone concentrations (102 +/- 4 vs. 184 +/- 47 pmol/l, p less than 0.05) were clearly suppressed during administration of ANF. Plasma norepinephrine also fell significantly below placebo values (268 +/- 17 vs. 439 +/- 35 pg/ml, p less than 0.05). Urine volume, the excretion of electrolytes other than sodium, hematocrit, effective renal plasma flow, glomerular filtration rate, and filtration fraction were unaffected by ANF. Similarly, plasma concentrations of epinephrine, arginine vasopressin, adrenocorticotropic hormone, and cortisol were unchanged. Blood pressure and heart rate were unchanged. Minor perturbations in plasma ANF concentrations exert clear biological effects in patients with mild essential hypertension. These data suggest that such minor shifts in plasma ANF are of physiological relevance in mild hypertension and probably contribute to volume homeostasis in this condition.     

Short-term effect of dynamic exercise on arterial blood pressure

BACKGROUND. To quantify the duration of postexercise hypotension at different exercise intensities, we studied six unmedicated, mildly hypertensive men matched with six normotensive controls. METHODS AND RESULTS. Each subject wore a 24-hour ambulatory blood pressure monitor at the same time of day for 13 consecutive hours on 3 different days. On each of the 3 days, subjects either cycled for 30 minutes at 40% or 70% maximum VO2 or performed activities of daily living. There was no intensity effect on the postexercise reduction in blood pressure, so blood pressure data were combined for the different exercise intensities. Postexercise diastolic blood pressure and mean arterial pressure were lower by 8 +/- 1 (p less than 0.001) and 7 +/- 1 mm Hg (p less than 0.05), respectively, than the preexercise values for 12.7 hours in the hypertensive group. These variables were not different before and after exercise in the normotensive group. Systolic blood pressure was reduced by 5 +/- 1 mm Hg (p less than 0.05) for 8.7 hours after exercise in the hypertensive group. In contrast, systolic blood pressure was 5 +/- 1 mm Hg (p less than 0.001) higher for 12.7 hours after exercise in the normotensive group. When the blood pressure response on the exercise days was compared with that on the nonexercise day, systolic blood pressure (135 +/- 1 versus 145 +/- 1 mm Hg) and mean arterial pressure (100 +/- 1 versus 106 +/- 1 mm Hg) were lower (p less than 0.05) on the exercise days in the hypertensive but not in the normotensive group. We found a postexercise reduction in mean arterial pressure for 12.7 hours independent of the exercise intensity in the hypertensive group. Furthermore, mean arterial pressure was lower on exercise than on nonexercise days in the hypertensive but not in the normotensive group. CONCLUSION. These findings indicate that dynamic exercise may be an important adjunct in the treatment of mild hypertension.     

A double blind randomized trial to compare the effects of eprosartan and enalapril on blood pressure, platelets, and endothelium function in patients with essential hypertension

The renin-angiotensin system is the major contributor to development of hypertension, atherosclerosis, and many other cardiovascular diseases. Angiotensin II, one of the main effectors of this system, contributes to the pathogenesis of hypertension and plays an important role in monocyte, platelet, and endothelium interactions. The effects on platelet and endothelial function, either by angiotensin converting enzyme inhibitors or angiotensin receptor antagonists, are still not well understood. A double-blind, randomized, prospective trial of either enalapril (10-20 mg daily) or eprosartan (400-800 mg daily) over a 10-week period was conducted in 42 patients (27 males, 15 females). Platelet activation was evaluated by measuring platelet factor 4 (PF-4), beta-thromboglobulin (beta-TG), the ratio of platelet factor 4 to beta-thromboglobulin, and endothelial function by measuring total plasma nitrate levels, von Willebrand factor (vWF) levels, and blood flow using venous occlusive plethysmography. After a 10-week treatment with enalapril or eprosartan, the sitting blood pressure in both the enalapril group (from 152.2 +/- 18.7 mmHg to 141.9 +/- 23.5 mmHg, P < 0.05) and eprosartan group (from 151 +/- 10.0 mmHg to 142.3 +/- 12.9 mmHg, P < 0.05) was significantly reduced. Significant diastolic blood pressure (DPB) reduction (from 94 +/- 8.7 to 84.5 +/- 9.6 mmHg, P < 0.05) and a greater DBP reduction response were found in the eprosartan group (63% in eprosartan versus 25% in enalapril). Additionally, dose-dependent reductions in the indices of platelet activation and endothelial dysfunction were observed in patients administered high dose treatments of eprosartan and enalapril, and the beneficial effects of these agents were not correlated with the reduction of blood pressure using both agents. Eprosartan is effective and well-tolerated in the treatment of mid-to-moderate hypertension, and the DBP response reduction to eprosartin was better than that to enalapril. A high dose of either eprosartan or enalapril significantly decreased the indices of platelet activation and endothelial dysfunction in hypertensive patients. The benefits of both agents cannot be explained solely by their antihypertensive effects and possibly may be mediated through their unique effect on angiotensin blockade.