T Cell-based RAS Activity and Insulin Levels in Obese Subjects with Low Grade Inflammation.

BACKGROUND: Obesity is a major contributor to inflammation and oxidative stress that are key underlying causes for insulin resistance (IR) and diabetes. Accumulated evidence suggest that RAS may serve as a strong link between IR and obesity. We investigated RAS activity in circulating T cells by obese subjects with and without angiotensin (Ang) II stimulation in presence or not of IR and of low-grade inflammation. METHODS: We studied 29 obese and 10 healthy subjects. After T-lymphocytes isolation, mRNAs for angiotensin converting enzyme (ACE) and angiotensin 1-receptor (AT1-R) were quantified by reverse transcription polymerase chain reaction (RT-PCR). High-sensitivity C-reactive protein (hs-CRP), insulin and inflammatory cytokines serum levels, plasma renin activity (PRA) and ACE activity in cell pellet and supernatant, and angiotensin (Ang) II T cell content were also measured. RESULTS: Under baseline conditions, RAS gene expressions, ACE activity and Ang II levels in T cells, but not PRA, of obese subjects with or without IR and with or without hs-CRP ≥3mg/dl were higher than in controls (p < 0.05). The increase in all parameters induced by Ang II was significantly higher in T cells from the obese subjects with hs-CRP ≥3 mg/dl than in controls or in the obese subjects with hs-CRP <3 mg/dl. In the obese subjects with low grade inflammation and IR, the cytokine serum levels and T cells RAS gene expression was inversely correlated with insulin serum concentration. CONCLUSIONS: Low grade inflammation amplifies the T cell RAS response to Ang II stimulation. T cell RAS gene expressions and serum levels of inflammatory cytokines were inversely related with insulin serum concentration. A protective role of insulin towards the development of inflammatory events can be hypothesized.

Activation of cardiac renin-angiotensin system in unstable angina.

OBJECTIVES: The aim of this study was to investigate the activity of the cardiac renin-angiotensin system (RAS) in unstable angina (UA). BACKGROUND: Angiotensin (Ang) II locally produced by continuously operating cardiac RAS may affect the pathophysiology of UA. METHODS: In 35 patients with UA, 32 with stable effort angina (SA) and 21 with atypical chest pain (controls), cardiac RAS was investigated during coronary angiography after five days of Holter monitoring by combining the measurement of aorta-coronary sinus gradient for Ang I and Ang II with the kinetics study of 125I-Ang I. Messenger RNAs (mRNA) for all the components of RAS were also quantified with the reverse transcriptase-polymerase chain reaction (RT-PCR) and localized by in situ hybridization in myocardial biopsy specimens from patients who underwent aorta-coronary bypass surgery. RESULTS: Cardiac Ang II generation was higher in patients with UA than it was in patients with SA or in controls (p < 0.001) due to increased de novo cardiac Ang I formation and its enhanced fractional conversion rate to Ang II. Messenger RNA levels for angiotensinogen (AGTN), angiotensin-converting enzyme (ACE) and Ang II type 1 (AT1) subtype receptors were higher in patients with UA (p < 0.01) than they were in patients with SA or in control hearts. Messenger RNAs for AGTN and ACE were almost exclusively expressed on endothelial and interstitial cells. Angiotensin II formation was correlated with ischemia burden (p < 0.001). However, the amount of Ang II formed and the expression levels of mRNAs for AGTN, ACE and AT1 were not related to the time that had elapsed since the last anginal attack. CONCLUSIONS: In patients with UA, cardiac RAS is activated, resulting in increased Ang II formation. Myocardial ischemia is essential for RAS activation, but it is unlikely to be a direct and immediate cause of RAS activation.

Human vascular renin-angiotensin system and its functional changes in relation to different sodium intakes.

A growing body of evidence supports the existence of a tissue-based renin-angiotensin system (RAS) in the vasculature, but the functional capacity of vascular RAS was not investigated in humans. In 28 normotensive healthy control subjects, the metabolism of angiotensins through vascular tissue was investigated in normal, low, and high sodium diets by the measurement of arterial-venous gradient of endogenous angiotensin (Ang) I and Ang II in two different vascular beds (forearm and leg), combined with the study of 125I-Ang I and 125I-Ang II kinetics. In normal sodium diet subjects, forearm vascular tissue extracted 36+/-6% of 125I-Ang I and 30+/-5% of 125I-Ang II and added 14.9+/-5.1 fmol x 100 mL(-1) x min(-1) of de novo formed Ang I and 6.2+/-2.8 fmol x 100 mL(-1) x min(-1) of Ang II to antecubital venous blood. Fractional conversion of 125I-Ang I through forearm vascular tissue was about 12%. Low sodium diet increased (P<.01) plasma renin activity, whereas de novo Ang I and Ang II formation by forearm vascular tissue became undetectable. Angiotensin degradation (33+/-7% for Ang I and 30+/-7% for Ang II) was unchanged, and vascular fractional conversion of 125I-Ang I decreased from 12% to 6% (P<.01). In high sodium diet subjects, plasma renin activity decreased, and de novo Ang I and Ang II formation by forearm vascular tissue increased to 22 and 14 fmol x 100 mL(-1) x min(-1), respectively (P<.01). Angiotensin degradation did not significantly change, whereas fractional conversion of 125I-Ang I increased from 12% to 20% (P<.01). Leg vascular tissue functional activities of RAS paralleled those of forearm vascular tissue both at baseline and during different sodium intake. These results provide consistent evidence for the existence of a functional tissue-based RAS in vascular tissue of humans. The opposite changes of plasma renin activity and vascular angiotensin formation indicate that vascular RAS is independent from but related to circulating RAS.

Effects of indenolol on blood pressure, lower limb blood flow, adrenergic reflexes, and plasma renin activity.

The antihypertensive effects of indenolol, a new not-cardioselective beta-blocking agent, were evaluated in patients with WHO grades I and II essential hypertension (range 160/95 to 200/115 mm Hg) in a double-blind, placebo-controlled study after acute (12 patients) and 2-week treatment (seven patients). Indenolol (30 to 120 mg) reduced blood pressure in a dose-dependent fashion. Maximum reduction was 26 mm Hg for systolic and 17 mm Hg for diastolic pressure. Hypotensive activity commenced within 10 minutes, peaked in 60 minutes, and persisted for about 7 hours. Lower limb vascular resistance (strain-gauge plethysmography) was significantly lowered, thus suggesting an intrinsic sympathomimetic activity. Heart rate was progressively reduced at 30 and 60 mg without any additional effect at 120 mg. Indenolol did not alter adrenergic reflexes (standing, cold application, and hand-grip) and did not induce any side effect. In conclusion, indenolol possesses an antihypertensive activity associated with reduction of vascular resistance.

Disappearance of motor tics after Wernicke's encephalopathy in a patient with Tourette's syndrome.

Tourette's syndrome (TS) is a disease characterized by multiple motor and vocal tics as well as behavioral abnormalities. The anatomic substrates of this syndrome are not defined. We report a 48-year-old man with TS in whom motor tics disappeared after the onset of a midbrain syndrome related to thiamine deficiency (Wernicke's encephalopathy). MRI study showed a lesion in the dorsal area of the midbrain. This case suggests that loops located in the midbrain tegmentum may influence the presence of motor tics in patients with TS.

Renal endothelin in heart failure and its relation to sodium excretion.

BACKGROUND: Recent studies have shown that endothelin-1 (ET-1) antagonists increase sodium excretion and improve renal blood flow in experimental heart failure (HF). However, despite a number of investigations that have reported a significant increase in ET-1 plasma levels in patients with HF, it is still not known whether increased renal synthesis and urinary excretion of ET-1 occur. Our aim was to investigate renal ET-1 formation and its relation to sodium excretion in patients with HF. METHODS: One hundred forty-seven patients with HF, subdivided according to New York Heart Association (NYHA) functional classes, and 28 healthy controls were studied. ET-1 and big ET-1 were measured in plasma and in 24-hour urine by radioimmunoassay. Atrial and brain natriuretic peptide, arginine vasopressin, plasma renin activity, and hemodynamic variables were also investigated. RESULTS: Urinary ET-1 excretion was already increased in NYHA class II patients (P <.001 vs controls), whereas plasma ET-1 increased only in NYHA class III and IV patients (P <.001). In the 71 subjects who were not receiving diuretic treatment, urinary ET-1 was selected as the strongest predictor of sodium excretion by multivariate stepwise analysis. CONCLUSIONS: Urinary ET-1 excretion increases in an earlier phase of HF than plasma ET-1 and appears to be closely correlated with sodium excretion, indicating renal ET-1 is a target for ET-1 antagonists in patients with HF.

Reduced prostacyclin production in patients with different manifestations of ischemic heart disease.

Prostacyclin, a substance produced by vessel wall, has a sustained vasodilating and platelet antiaggregating activity and therefore the variations in its production in patients with ischemic heart disease are of interest. Prostacyclin production was assessed in 59 patients with ischemic heart disease and 59 control subjects matched for age, sex, body weight, smoking habits, blood pressure and serum cholesterol levels. Of the 59 patients examined, 23 had had a myocardial infarction 3 to 12 months earlier; 21 had had spontaneous angina and 15 effort angina for at least 3 months. Patients with myocardial infarction and spontaneous angina were also classified in subgroups with and without acute coronary insufficiency, according to the occurrence of ischemic attacks in the week preceding the study. Both circulating prostacyclin levels and prostacyclin produced after 3 minutes of ischemia were measured by bioassay. Circulating prostacyclin was significantly less in patients with ischemic heart disease than in matched control subjects independent of the clinical type of ischemic heart disease. Circulating prostacyclin was particularly reduced in patients with acute coronary insufficiency in comparison to patients without, both in the group with myocardial infarction (1.11 +/- 0.22 ng/ml and 2.09 +/- 1.32, respectively) and in the group with spontaneous angina (1.24 +/- 0.42 and 2.17 +/- 1.16, respectively). No differences could be found for prostacyclin produced after 3 minutes of ischemia in relation to the presence of acute coronary insufficiency. The lower level of prostacyclin production in patients with ischemic heart disease and especially in those with acute coronary insufficiency may be an important factor in the occurrence of coronary occlusion or spasm.

Pulmonary hypertension associated with long-standing thrombocytosis.

A case of thromboembolic pulmonary hypertension associated with long-standing thrombocytosis is presented. In this patient we found a significant local pulmonary platelet activation and thrombin generation as indicated by the existence of a transpulmonary gradient for thromboxane A2, beta thromboglobulin and fibrinopeptide A. Prolonged heparin and acetylsalicylic acid treatment resulted in improvement of clinical and hemodynamic conditions. These findings support the usefulness of anticoagulating and antiaggregating therapy in selected cases of pulmonary hypertension.

Increase in number of myocardial ischemic episodes following nifedipine administration in two patients. Detection of silent episodes by Holter monitoring and role of heart rate.

Out of 34 consecutive patients with angina and treated with nifedipine, two subjects (5.8 percent) showed a significant increase of transient myocardial ischemic episodes during the period of treatment, as assessed by continuous Holter ECG monitoring. In both these patients, a large proportion of ischemic episodes happened to be asymptomatic. A relationship between nifedipine intake, heart rate increase, and number of ischemic episodes was observed. This occasional aggravation of myocardial ischemia could be related to an increase in myocardial oxygen demand medicated through a drug-induced reflex tachycardia.

Antihypertensive action of nifedipine: effects on arteries and veins.

Nifedipine is a calcium-channel antagonist with effective antihypertensive activity and has been suggested for the treatment of high blood pressure as an alternative to vasodilators. The aim of this study was to define the acute effect of nifedipine and in particular the dose-effect relationship, effects on veins, influence on adrenergic reflexes, and effectiveness on hypertension according to severity and etiologic type. The effects of nifedipine on blood pressure, heart rate, forearm blood flow, peripheral vascular resistance, orthostatic and cold reflexes, and venous tone were examined in 45 patients with hypertension of different etiologies (essential, renovascular, and renal parenchymal) and different World Health Organization grades. The antihypertensive effect was dose dependent, but a dose of 20 mg has nearly maximal activity with acceptable side effects. The drug acts by lowering peripheral vascular resistance, and this lowering is directly related to baseline values; therefore, the antihypertensive effect increases with severity of the hypertension. Nifedipine had the same effect in all three etiologic groups of hypertension studied. The drug seems to increase venous tone, since it caused venoconstriction when locally injected in hand veins. Nifedipine did not alter adrenergic reflexes induced by both cold application and standing and was well tolerated. In conclusion, the calcium antagonist nifedipine for its characteristics of action, at least in acute administration, seems to be a useful alternative in the treatment of various forms of hypertension.

Intravenous dilazep reduces blood pressure and peripheral vascular resistance in humans.

Dilazep, a coronary vasodilating drug with adenosine-mediated activity, was tested (acute double-blind study versus placebo) for its antihypertensive activity in 12 patients who had mild to moderate hypertension. Dilazep (0.2 mg/kg body weight by IV infusion for ten minutes) significantly reduced systolic and diastolic blood pressure (random-zero sphygmomanometer) on average by 13.3 and 10.6 mm Hg respectively. The antihypertensive effect started rapidly, reached its maximum 20 minutes after administration, and lasted for 90 minutes. Heart rate significantly increased between 10 and 30 minutes. The antihypertensive effect of dilazep was associated with a relevant vasodilating effect as demonstrated by the changes in upper limb blood flow (strain-gauge plethysmography, +32%; P less than .001) and vascular resistance (-29%, P less than .001). The maximal reduction of vascular resistance was directly correlated to its baseline value. For these characteristics of action, at least in acute administration, dilazep would be useful agent for the treatment of high blood pressure in mild to moderately hypertensive patients.

Renal and limb vasodilatation during acute beta-adrenoceptor blockade with indenolol.

Indenolol is a noncardioselective beta-adrenoceptor blocking drug with partial agonist activity. The mechanism of its acute antihypertensive activity has been evaluated in a double-blind, inpatient, crossover, randomized study versus placebo in 12 patients (eight men, four women, mean age 53 +/- 13 yr) with I and II WHO grade essential hypertension. Patients discontinued all antihypertensive and diuretic drugs at least 4 weeks before entry into the study. The effects of indenolol (120 mg) and placebo (2 weeks apart) were measured, in the same patient, 2 hours after a single oral administration. Variations of cardiac function were assessed by radionuclide angiocardiography, renal blood flow by sequential scintigraphy, and leg blood flow by strain-gauge plethysmography. Compared with placebo, indenolol reduced systolic blood pressure by 27.9 mm Hg and diastolic blood pressure by 17.1 mm Hg. Heart rate was also significantly decreased. The hemodynamic profile of indenolol activity was characterized by a decrease of cardiac index, without significant changes in systemic vascular resistance. Both renal and leg blood flow were increased by indenolol, and vascular resistance in these districts was considerably reduced. The percent reduction of renal vascular resistance was correlated significantly with the percent reduction of mean blood pressure. In conclusion, acute administration of indenolol exerts a considerable antihypertensive activity associated with a marked vasodilation in vascular districts involved in the progression of hypertensive disease such as the renal and muscular vasculature.

Effects of calcium channel blockers on platelet aggregation and thromboxane A2 formation: an in vivo double blind randomized study.

In this double blind cross over study against placebo the in vivo effects of diltiazem, nifedipine and verapamil on platelet aggregation and Thromboxane A2 (TxA2) formation were evaluated in eighteen healthy adults. No significant inhibition of platelet aggregation or TxA2 formation was found either after acute or short term (8 days) administration of the three calcium channel blockers at the usual therapeutical dosages. Our study indicate that diltiazem, nifedipine and verapamil are unable to significantly affect platelet aggregation and TxA2 formation in healthy subjects.

Acute reversible reduction of PGI2 platelet receptors after iloprost infusion in man.

Platelet sensitivity to PGI2 and platelet PGI2 receptors were investigated in eight subjects with peripheral artery disease (stage IV according to Fontaine) treated for 14 consecutive days with six hour iv infusion of Iloprost (Schering, FRG) 2 ng/kg/min. Platelet studies were performed on the 1st, the 2nd, the 7th and the 14th day of therapy, immediately before infusion (between 8.00 and 9.00 a.m.), at the end and 6 and 18 hours (the following morning) after the end of the infusion. Platelet sensitivity to PGI2 was assessed by determining the PGI2 inhibitory dose 50(ID 50) on platelet aggregation induced by 5 microM ADP. PGI2 platelet receptors were investigated by a direct radioligand binding assay. PGI2 ID 50 after the infusion was significantly higher than that at baseline(p less than 0.01) and six hours later the baseline sensitivity was restored. After the six hour Iloprost iv infusion a significant reduction in the number of high affinity PGI2 platelet receptor (HAR) was observed (p less than 0.005) without any change in their affinity for the ligand. Six hours after the end of the infusion the number of the HAR was still significantly reduced (p less than 0.05). The following morning the receptor number of HAR was restored. The baseline values of PGI2 HAR, when reassessed after seven and fourteen days of treatment, were not significantly different from those recorded on the first day of therapy. These data indicate that the reduction of platelet PGI2 sensitivity following short-term Iloprost infusion is rapidly reversible and is related to a contemporary down-regulation of PGI2 platelet receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of extraplatelet thromboxane A2 in unstable angina investigated with a dual thromboxane A2 inhibitor: importance of activated monocytes.

BACKGROUND: The role of thromboxane A2 (TxA2) in unstable angina has not yet been defined. TxA2 receptor antagonists may be of value in studying this role. METHODS: To investigate whether TxA2 has a pathogenetic effect on the occurrence of myocardial ischemia and from what source TxA2 originates, we studied TxA2 formation by unstimulated monocytes from patients with unstable angina (n = 40), stable effort angina (n = 20), and controls (n = 20). We also compared the effects of picotamide (1200 mg/day), a TxA2-synthase inhibitor and TxA2-receptor antagonist, with those of aspirin (325 mg/day) on myocardial ischemia and TxA2 formation by monocytes and platelets. The double-blind randomized study was performed on patients with unstable angina on continuous Holter monitoring. RESULTS: In the presence of autologous lymphocytes, unstimulated monocytes from patients with unstable angina formed significantly (P < 0.001) more TxA2 than those from controls or from patients with effort angina. Although TxA2 formation by circulating monocytes and platelets was inhibited to a greater degree by aspirin than by picotamide (88 +/- 6 and 98 +/- 2%, respectively, versus 65 +/- 2 and 74 +/- 1%, P < 0.001), aspirin failed to affect the occurrence of myocardial ischemia whereas picotamide significantly (P < 0.001) reduced the number of anginal attacks (84.8%), silent ischemic episodes (64.2%), and overall duration of ischemia (69.8%), in comparison to the run-in period. CONCLUSIONS: These results indicate that TxA2 formed by monocytes contributes to the pathogenesis of myocardial ischemia in unstable angina. TxA2 formation occurs mainly in extravascular spaces, probably within the coronary vascular wall. Picotamide appears to control myocardial ischemia effectively in patients with unstable angina.

A study of the antihypertensive effect and some pharmacodynamic aspects of nifedipine in medium-term treatment.

The antihypertensive activity of nifedipine in medium-term treatment has been studied in 30 patients affected by II and III WHO grade essential hypertension. After a 6-day period of placebo, patients were randomly allotted to group A (treated with single 10-mg doses of nifedipine) and group B (treated with single 20-mg doses). Treatment with nifedipine continued for 18 days. Patients in both groups were given one daily dose during the first 6 days, two daily doses in the following 6 days and three daily doses in the last 6 days. 1. Antihypertensive effect: In both groups, only three daily doses gave a satisfactory 24-hour antihypertensive activity. Nifedipine as monotherapy administered in single doses of both 10 mg (group A) and 20 mg (group B) normalized blood pressure (BP) and the measured antihypertensive effect was not statistically different in the two groups. The antihypertensive effect lasted between 7 and 8 hours after drug administration (both doses) and did not diminish with increasing duration of treatment or number of daily doses. 2. Change in heart rate: Nifedipine induced an increase in HR which diminished with shortening of the time interval between daily administrations. The effect on HR was unaltered throughout the whole experimental period. 3. Side-effects: Nifedipine did not induce orthostatic hypotension in any patient. Eleven of the 30 patients complained of side-effects, the most common being headache and palpitations. Incidence and severity of side-effects were not correlated with dose, whereas duration was longer with 20 mg. Side-effects never necessitated withdrawal of the drug.

Efficacy of mexiletine in chronic ventricular arrhythmias: a multicentre double-blind medium-term trial.

In a multicentre double-blind, inpatient, placebo-controlled trial the effects on premature ventricular beats (PVBs) of mexiletine in a standard, submaximal dose were studied by Holter monitoring in 144 outpatients. After wash-out, mexiletine was administered for 14 days. The effects were re-tested, after one week of a placebo, in a second 14-day period of mexiletine administration. Of the patients 73% in the first period and 82.5% in the second period responded to mexiletine (a reduction of 75% or more of PVBs/24 h--p less than 0.001 compared with the placebo for both periods). Mexiletine also significantly reduced the Lown class of PVBs and the frequence of paired PBVs, ventricular tachycardia, multiform beats and R on T wave phenomenon. Mexiletine showed an equivalent effectiveness in the four main aetiological groups of arrhythmias. Fifty nine patients complained of adverse effects (gastrointestinal or neurological) the intensity of which led to the stopping of the treatment in 16 of them. These results show that mexiletine is highly effective, even in submaximal doses, in preventing ventricular arrhythmias of whatever origin.

Pentoxifylline treatment in patients with occlusive peripheral arterial disease. Circulatory changes and effects on prostaglandin synthesis.

Pentoxifylline has recently been reported to stimulate in vitro the synthesis of prostacyclin. However it is not known so far whether the drug is able to stimulate prostacyclin synthesis in man also in vivo. In the present study the effects of pentoxifylline on prostaglandin synthesis and several circulatory parameters were studied in 10 controls and 10 patients with occlusive arterial disease after acute i.v. and medium term oral treatment. Prostacyclin (as 6-keto-PGF1 alpha) and PGE2 plasma concentrations have been measured together with arterial blood flow, peripheral vascular resistance, platelet aggregation and red blood cell deformability. Pentoxifylline was found both in healthy subjects and patients to significantly increase prostacyclin plasma concentration after i.v. treatment. In medium term oral treatment prostacyclin concentration was found to increase only two hours after administration and not 8 hours after. No significant variations in PGE2 plasma concentration were found at any time in both groups. Pentoxifylline significantly enhanced resting and post-ischemic blood flow of the lower limbs and simultaneously decreased peripheral vascular resistance both in healthy subjects and patients. Different grades of delayed platelet aggregation and increased red blood cell deformability were also observed. In conclusion results of the present placebo controlled study show that pentoxifylline increases arterial blood flow in patients with occlusive arterial disease. Moreover pentoxifylline induces a temporary stimulation of prostacyclin synthesis which can be suggested to contribute to the clinical activity of the drug as far as an antithrombotic effect in terms of inhibition of platelet aggregation is concerned.

Transcutaneous oximetry in evaluation of the initial peripheral artery disease in diabetics.

This study was performed to evaluate the reliability of transcutaneous oximetry as compared with strain gauge plethysmography and with Doppler in the assessment of the initial peripheral vascular disease in diabetics who are still asymptomatic. Twenty-five diabetics (38 lower extremities) with different degrees of peripheral vascular disease, classified according to Fontaine, were investigated. Ten healthy subjects (16 lower extremities) served as controls. In the first group of patients (still asymptomatic) it was possible to select by transcutaneous oximetry and by plethysmography a subpopulation that presented a significant reduction in the arterial flow of the limbs. Moreover, a significant correlation between data obtained by strain gauge plethysmography and transcutaneous oximetry was found (p less than 0.001), whereas correlation with data from Doppler was lacking.