Prospects for the use of antioxidant therapy in hypertension.

The purpose of this review is to examine the indications and contraindications of antioxidant therapy in arterial hypertension. It has been suggested that oxidative stress plays a role in hypertension, increasing pressure values and leading to complications. Oxidative stress, at present, appears as one of several metabolic abnormalities described in essential hypertension. It is still uncertain whether this abnormality is primary or secondary; in any case, measurement of the main oxidant and antioxidant activities in plasma and blood cells may be useful in order to recognize and monitor oxidative stress. Antioxidant therapy could be useful to counteract the effects of oxidative stress on blood vessels, arterial pressure and low-density lipoproteins. Although antioxidant therapy with drugs or physiological substances in hypertensive subjects has been examined in some clinical trials, these experimental observations do not appear sufficient to draw definitive conclusions because long-term randomized, controlled studies do not exist. At present, it seems appropriate to propose some dietary recommendations which, apart from their antioxidant properties, are useful and do not have untoward effects. The safest approach to treat or to prevent oxidative stress consists of a diet that includes foods with a high antioxidant content (i.e. vitamins C and E and flavonoids). This diet consists fundamentally of fruits, vegetables and grains. Moreover it seems useful to use antihypertensive drugs that are able to decrease oxidative stress. The addition of physiologic antioxidant substances should be considered only in hypertensive subjects with a marked increase in oxidant or decrease in antioxidant factors. Indeed reactive oxygen species play a pivotal role in many physiological reactions, and their excessive inhibition could be dangerous. Further controlled, randomized long-term trials with antioxidants in hypertension are necessary to establish the efficacy and tolerability of antioxidants in the adjuvant therapy of hypertension.

Reactive oxygen species and antioxidant status in essential arterial hypertension during therapy with dihydropyridine calcium channel antagonists.

PURPOSE: To evaluate reactive oxygen species and antioxidant status in essential arterial hypertension during therapy with dihydropiridine calcium channel antagonists. PATIENTS AND METHODS: Fifteen patients, affected by essential arterial hypertension, were examined. They received once a day oral dihydropyridine calcium antagonists for 10 weeks: five patients received felodipine (5 mg), five amlodipine (10 mg) and five lercanidipine (10 mg). The levels of end products of lipid peroxidation, free radicals and hydroperoxides and total antioxidant capacity were determined in the plasma of all subjects before and during treatment. Values are expressed as mean +/- S.E. Systolic blood pressure decreased from 171 +/- 4 to 135 +/- 6 mmHg (p < 0.01) and diastolic blood pressure decreased from 99 +/- 5 to 82 +/- 3 mmHg (p < 0.01). Hydroperoxides and free radicals decreased from 321.3 +/- 8.96 to 247.9 +/- 8.69 units (p < 0.01) and the end products of lipid peroxidation decreased from 11.0 +/- 1.93 to 6.74 +/- 1.41 nmol/ml (p < 0.01). Total antioxidant capacity increased from 0.74 +/- 0.03 to 1.05 +/- 0.05 mmol/l (p < 0.01). RESULTS: Imbalance in the pro-oxidant-antioxidant equilibrium shifts in favour of antioxydant namely oxidative stress decreases. The calcium channel antagonists decrease peripheral arterial resistances and therefore decrease or abolish relative ischaemia, moreover decrease arterial pressure and therefore normalize parietal stress on endothelial cells. As a conseguence they act on two hypothesized mechanisms of oxidative stress in hypertension. CONCLUSIONS: Dihydropyridine calcium antagonists used in this trial seem useful in hypertension because they decrease oxidative stress, and normalize of pressure values.

[Reactive metabolites of oxygen, lipid peroxidation, total antioxidant capacity and vitamin E in essential arterial hypertension]. / Metaboliti reattivi dell'ossigeno, perossidazione lipidica, capacità antiossidante totale e vitamina E nell'ipertensione arteriosa essenziale.

Free radical oxidative stress has been implicated in the pathogenesis of a variety of human diseases. The purpose of this study was to explore the degree of oxidative stress in essential arterial hypertension (EAH). The study groups consisted of fifteen untreated EAH patients (WHO stages 1 and 2), aged 40 to 70 years, and fifteen, age and sex matched, normal controls. The levels of typical peroxidation products such as malondialdehyde and 4-hydroxyalkenals (with the LPO-586 test, Bioxytech), free radicals and other reactive oxygen metabolites (ROMs) (with the d-ROMs test, Diacron), vitamin E (with HPLC method) and total antioxidant capacity (with the TAS test, Randox) were determined in the plasma af all subjects. Compared to the control group EAH patients exhibited significantly higher ROMs levels (334.7 +/- 21.6 vs 249.2 +/- 23.3 Units, means values +/- S.E.M.), and of lipid peroxidation products (10.7 +/- 0.7 vs 8.09 +/- 0.9 nmol/ml). It must be noted that such increases were not observed in all EAH patients, but above all in those less young or with more severe hypertension. On the other hand no significant difference was found between EAH patients and normal controls as regards vitamin E concentration and total antioxidant capacity. These results suggest that EAH patients, in spite of their normal antioxidant defences, are more prone than normotensive subjects to oxidative stress because of an increased ROMs production. This could result in an inactivation of prostacyclin and NO, hence an enhancement of peripheral vascular resistance and an increase of hypertension. Another consequence might be an increased lipid peroxidation of low density lipoproteins, a condition which is known to be associated with accelerated atherosclerosis. The study of oxidant and antioxidant factors seems therefore useful in EAH patients in order to evaluate oxidative stress and to correct, if possible, the observed abnormalities with dietetic or pharmacologic therapy.

L-carnitine adjuvant therapy in essential hypertension.

This study was undertaken to demonstrate L-carnitine therapeutical effect in patients with essential hypertension. Two groups were tested, A and B. First group (A) was split in two subgroups, A1 and A2. Subgroup A1 included 14 patients with essential hypertension, they were treated with antihypertensive drugs and L-carnitine. Subgroup A2 included 14 patients with essential hypertension, that were treated with antihypertensive drugs only. Group B included 9 patients with essential hypertension and they were treated with L-carnitine only. Subgroup A1 patients were treated with oral L-carnitine 2 gm per day for 22 weeks; group B patients were treated with the same dose for 10 weeks. The asthenia symptom was evaluated, a resting and dynamic E.C.G. was carried out, serum triglycerides, serum total and high-density lipoprotein (HDL) cholesterol, serum sodium and potassium, serum creatinine, serum glucose and blood pressure were determined before and at the end of test in group A patients. Test procedure of group B patients included also serum evaluation of apolipoproteins A1 and B and radionuclide angiocardiography. In subgroup A1 patients extrasystoles as well as some electrocardiographic signs of minor changes of ventricular repolarization reversed or diminished, the asthenia symptom was improved significantly and triglyceride values decreased from 148 +/- 15.8 mg/dl to 121 +/- 14.3 mg/dl (p < 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

Coenzyme Q10 in essential hypertension.

This study was undertaken to clarify the mechanism of the antihypertensive effect of coenzyme Q10 (CoQ10). Twenty-six patients with essential arterial hypertension were treated with oral CoQ10, 50 mg twice daily for 10 weeks. Plasma CoQ10, serum total and high-density lipoprotein (HDL) cholesterol, and blood pressure were determined in all patients before and at the end of the 10-week period. At the end of the treatment, systolic blood pressure (SBP) decreased from 164.5 +/- 3.1 to 146.7 +/- 4.1 mmHg and diastolic blood pressure (DBP) decreased from 98.1 +/- 1.7 to 86.1 +/- 1.3 mmHg (P < 0.001). Plasma CoQ10 values increased from 0.64 +/- 0.1 microgram/ml to 1.61 +/- 0.3 micrograms/ml (P < 0.02). Serum total cholesterol decreased from 222.9 +/- 13 mg/dl to 213.3 +/- 12 mg/dl (P < 0.005) and serum HDL cholesterol increased from 41.1 +/- 1.5 mg/dl to 43.1 +/- 1.5 mg/dl (P < 0.01). In a first group of 10 patients serum sodium and potassium, plasma clinostatic and orthostatic renin activity, urinary aldosterone, 24-hour sodium and potassium were determined before and at the end of the 10-week period. In five of these patients peripheral resistances were evaluated with radionuclide angiocardiography. Total peripheral resistances were 2,283 +/- 88 dyne.s.cm-5 before treatment and 1,627 +/- 158 dyn.s.cm-5 after treatment (P < 0.02). Plasma renin activity, serum and urinary sodium and potassium, and urinary aldosterone did not change. In a second group of 11 patients, plasma endothelin, electrocardiogram, two-dimensional echocardiogram and 24-hour automatic blood pressure monitoring were determined.(ABSTRACT TRUNCATED AT 250 WORDS)

[The benefits of L-carnitine therapy in essential arterial hypertension with diabetes mellitus type II]. / Utilità della terapia con L-carnitina nell'ipertensione arteriosa essenziale con diabete mellito tipo II.

Carnitine is a natural substance essential for the mitochondrial oxidation of long-chain fatty acids and therefore regulates the energy metabolism of the cells. Tissue carnitine levels are altered under diabetes mellitus or hypertension. The aim of this study was to evaluate the efficacy and tolerability of L-carnitine therapy in essential hypertension with diabetes mellitus type II. A clinical trial was performed in two homogeneous groups with essential hypertension and diabetes mellitus type II. L-carnitine was given orally, 2 g twice daily, for 45 weeks. In the group of patients treated with L-carnitine in comparison with control group cardiac arrhythmias, chiefly extrasystoles, some disorders of A-V conduction and some electrocardiographic signs of ischaemia stopped or diminished and symptoms, chiefly asthenia, significantly improved. No side effects were observed during the treatment. These results show that treatment with L-carnitine is useful and well tolerated in patients with essential hypertension and diabetes mellitus type II.

[The combination of nifedipine and a low sodium diet with potassium supplement in the therapy of essential arterial hypertension]. / Associazione fra nifedipina e dieta iposodica con supplemento potassico nella terapia dell'ipertensione arteriosa essenziale.

Moderate dietary sodium restriction with moderate dietary potassium supplementation was used in patients with essential hypertension who were treated with nifedipine retard by mouth every twelve hours. Combination therapy of this diet with the nifedipine retard produced a significantly greater decrease in both lying and standing blood pressure that with the drug alone. No noticeable side effects were observed.

[Hormonal, beta-endorphin and renin activity changes in man during partial immersion, as a therapeutic method, in water at 38 degrees C]. / Modificazioni ormonali, della beta-endorfina e dell'attività reninica nell'uomo in corso di immersione parziale, con metodo terapeutico, in acqua a 38 gradi C.

This research was carried out to define the effects on men of head-out water immersion in a bath at 38.41 +/- 0.04 degrees C (mean +/- S.E.) with a method similar to that used for therapeutical rehabilitation and time of immersion of 30 minutes. Beta-endorphin, renin activity, aldosterone, cortisol, HGH, FSH, LH, TSH, T3, T4 and prolactin haematic levels were analysed. Seventeen healthy subjects (fourteen males and three females), aged 21-65 years (mean age 29.8 +/- 2.6) were studied. Water immersion caused a decrease in FSH and LH haematic concentrations; no significant changes occurred in beta-endorphin, renin activity, aldosterone, prolactin, cortisol, HGH, TSH, T3, T4 and FTI values. Thirty minutes after the end of immersion, FSH and LH levels returned to pre-immersion values. The probable pathogenesis of these observations is suggested.

[Hemorheologic and blood cell changes in humans during partial immersion, with a therapeutic method, in 38 C water]. / Modificazioni emoreologiche ed ematiche nell'uomo in corso di immersione parziale, con metodo terapeutico, in acqua a 38 degrees C.

This research was carried out to define the effects on man during head-out water immersion in a bath at 38.41 +/- 0.04 degrees C (mean +/- S.E.) with a method similar to that used for therapeutical rehabilitation and time of immersion of 30 minutes. Hemorheological, hematic and hemodynamic parameters were analysed. Seventeen healthy subjects (fourteen males and three females), between the ages of 21-65 years and mean age of 29.8 +/- 2.6 years were studied. Head-out water immersion resulted in: 1) decrease in blood viscosity, red blood cells count, C-Hct and M-Hct, without significant changes in leukocytes and platelets count, MCV, plasma viscosity, erythrocyte filtration time and RCDI; 2) an increase in heart rate and a decrease in systolic and diastolic blood pressure. Thirty minutes after the end of immersion, heart rate, diastolic blood pressure and blood viscosity, measured at 0.512 sec-1 shear rate, returned to pre-immersion values; systolic blood pressure showed a slight increase but was still significantly below the basal levels; erythrocytes count, C-Hct, M-Cct and blood viscosity, measured at 94.5 sec-1 shear rate, significantly exceeded pre-immersion values. The probable pathogenesis of these observations is suggested. A matter of great interest is the study of the same parameters in elderly subjects, with or without cardiovascular diseases, or in patients using drugs affecting blood pressure, blood viscosity or hemocoagulation process.

[Plasma beta endorphin in man during partial immersion in water using the therapeutic method]. / Beta-endorfina plasmatica nell'uomo in corso di immersione parziale in acqua con metodo terapeutico.

The following study was designed to evaluate plasma beta-endorphin (beta-EP) variations in healthy volunteers during thermoneutral head-out water immersion while prevalently in the standing position. The type of immersion was similar to that currently adopted for therapeutic rehabilitation. Plasma beta-EP was evaluated by RIA previous beta-lipotropin stripping and Sep-Pack cartridge methanol extraction. Plasma beta-EP levels significantly decreased during water immersion from a value of 12.71 +/- 2.04 pmol/l to 7.46 +/- 1.09 pmol/l at 15 min (P less than 0.05) and to 6.08 +/- 1.87 pmol/l at 30 min (P less than 0.01). Thirty min after the end of immersion, plasma beta-EP levels showed a slight increase to 6.98 +/- 1.88 pmol/l but were still significantly below the basal level (P less than 0.05). These results are consistent with the previously demonstrated decrease of ACTH and prolactin and the increase of plasma dopamine and decrease of norepinephrine, suggesting that thermoneutral head-out water immersion is not a stressful condition in healthy subjects. Further studies are necessary in order to clarify the mechanism involved in beta-EP decrease in normal subjects during thermoneutral head-out water immersion.

[Flowmetric, thermometric and rheologic studies in obliterating arterial diseases of the lower extremities treated with buflomedil]. / Studio flussimetrico, termometrico e reologico nelle arteriopatie obliteranti degli arti inferiori trattate con buflomedil.

Ten subjects with peripheral arterial occlusive disease were treated with buflomedil, analysing the effect of every single intravenous administration of the drug, and the effect of the administration repeated for a period of 5 days. This controlled study was aimed at evaluating the state of the peripheral blood flow, not just relating to the flowmetric parameters, but also to those more directly connected to the metabolic and functional conditions of the microcirculation. During every single administration, blood flow, skin and muscular temperatures were recorded. As concerned the drug's chronic effect, endurance limit, skin and muscular temperatures, whole blood viscosity, plasma viscosity and red cell filterability were recorded before beginning the treatment and after 15 days. The results of this study show that during a single buflomedil infusion no modifications have been observed in blood flow and muscular temperature, whereas skin temperature showed a slight increase. On the contrary, after a 15 days treatment, muscular temperature and endurance limit significantly increased, without flowmetric changes. A significant decrease in values of blood viscosity at high shear-rate was recorded too. The overall results seem to indicate that after treatment with buflomedil there is an improvement of the metabolic muscular conditions, probably due to a stimulant effect of the drug on microcirculatory blood flow.

Magnesium in tumoral tissues, in the muscle and serum of subjects suffering from neoplasia.

Mg2+ content is significantly increased in malignant neoplastic mammary tissue compared with normal mammary tissue and benign neoplastic tissue of the breast. Significant variations of the ion were not found in the skeletal muscle tissue (rectus abdominis and pectoral muscle) of subjects suffering from malignant neoplasia with diffused metastasis. It seems that the variation of Mg2+ content in malignant neoplastic mammary tissue is a local factor linked with the biological anomalies of the neoplastic cell.

[Lysosomal lesions during a course of acute experimental muscular ischemia. Protective effect of a polypetitide proteinase inhibitor]. / Lesione lisosomiale in corso di ischemia muscolare acuta sperimentale. Effetto protettivo di un polipeptide inibitore delle proteinasi

Three groups of rabbits were used: a) with acute ischaemia in a rear limb; b) with acute ischaemia in a rear limb and treated with i.v. 100,000 KIU of a proteinase-inhibitor polypeptide extracted from ox lung; c) normal controls. Acute ischaemia was obtained by ligature of the ipsilateral common iliac, external iliac, inferior epigastric and femoral arteries. Soluble and total activity of 3 lysosomal enzymes (cathepsin, acid phosphatase and N-acetyl-glucosaminidase) were determined in gastrocnemius muscle from all 3 groups. The mean ratio between bound and soluble activity for all 3 enzymes in normal gastrocnemius muscle was higher than in ischaemic muscle, but not significantly different from that in ischemic muscle of animals treated with the polypeptide. Furthermore, this ratio in ischemic muscle was significantly lower than that of ischemic muscle of the rabbits treated with the polypeptide. These data suggest that the polypeptide offers protection against lysosomal lesion in the course of experimental ischaemia of the skeletal muscle.

Effect of a proteinase inhibitor on intermittent claudication or on pain at rest in patients with peripheral arterial disease.

Twenty patients with peripheral arterial disease and 10 normal controls were submitted to i.v. injection of aprotinin, polypeptide (mol.wt. 6512) extracted from bovine lung, in order to examine its effects on: (a) lower limbs pain, (b) lower limbs sensibility, (c) calf blood flow. Aprotinin (100,000 Ku i.v. diluted in NaCl 0.9%) was given in a single dose or twice a day for a week; for control the same subject received, before or after aprotinin, an equivalent volume of diluent (0.9% NaCl). The results demonstrate that aprotinin is able to increase the initial pain limit walking tolerance and to decrease the intensity of pain at rest and of myalgic or "trigger" areas. No variation was observed on skin sensibility and on calf blood flow, both basal resting and hyperemic. The favorable effect of examined polypeptide on ischemic pain can be attributed neither to increase of calf blood flow nor to influence on perception of painful stimuli. It seems therefore to suggest that aprotinin acts on biochemical mechanisms that cause the ischemic pain. Presumably it inhibits kininogenases and tissue protein-hydrolyzine enzymes activated in the course of ischemia.