Effect of losartan on heart rate and blood pressure variability during tilt test and trinitroglycerine vasodilation.

OBJECTIVE: To define the changes in variability of heart rate and of blood pressure during vasodilation in a group of hypertensive patients treated with an angiotensin II type I (AT1) receptor inhibitor. DESIGN: Losartan (50 mg/day at 0800 h) or placebo were administered for 3 weeks according to a single blind, crossover, randomized protocol, to 18 hypertensive patients (16 men and two women, mean age 42 + 3.6 years). Continuous ECG recording and beat-to-beat blood pressure monitoring were carried out with subjects in the supine position and during a head-up tilt test, as well as after sublingual administration of trinitroglycerine. The elaboration of ECG traces in the frequency domain, was carried out using an autoregressive method and measured using the autoregressive moving average technique. RESULTS: Orthostatic stimulus, both during treatment with losartan and with placebo, caused a significant decrease in the heart rate high frequency power; on the other hand, the low frequency power appeared unchanged after placebo and was significantly reduced with losartan. Five minutes after the administration of trinitroglycerine, the low frequency power with placebo showed a significant increase (817 -+ 221 versus 465 + 101 ms2, P < 0.03). No change was recorded in total power nor in low frequency or high frequency power during losartan therapy. The ratio of low frequency to high frequency powers showed a sympathetic prevalence during vasodilation only during placebo treatment, whereas a mainly unchanged balance was maintained during losartan treatment Blood pressure variability showed a sympathetic prevalence after upright and trinitroglycerine stimulation only in placebo-treated subjects. CONCLUSIONS: Our study demonstrated that vasodilation is not able to evoke an unbalancing of the autonomic modulation in hypertensive patients treated with an AT1 receptor inhibitor, but permits the maintenance of a significant vagal component, thus highlighting the favorable profile of this drug in the autonomic control of circulation.

Decrease of platelet intracellular pH and adhesion by ticlopidine in patients with vascular disease.

BACKGROUND: Ticlopidine inhibits platelet aggregation by preventing the binding of fibrinogen to its platelet receptor. We examined whether this inhibition involved platelet transduction system such as Na+/H+ pump and platelet intracellular calcium. METHODS: Platelet adhesion in 13 patients with peripheral vascular disease treated with ticlopidine, 250 mg b.i.d for 30 days, was measured in culture microplates before and after therapy. The microplate wells were coated with human plasma, fibrinogen or collagen, and platelet adhesion was studied in the resting condition and after stimulation with 1 and 10 microM ADP. At the same time, platelet intracellular calcium and ADP-induced calcium increases were measured with the fluorescent indicator Fura 2. In addition, intracellular pH and thrombin-induced pH variations were measured with the fluorescent probe BCECF. RESULTS: Platelet adhesion to plasma and fibrinogen was significantly reduced (about 50%) after treatment with ticlopidine, while adhesion to collagen was not modified. Basal calcium and ADP-induced calcium increase were not significantly different before and after ticlopidine. Platelet basal intracellular pH was reduced (from 7.44+/-0.009 to 7.41+/-0.017, p<0.05), but agonist-induced alkalinisation was not significantly different. Early acidification, not dependent on Na+/H+ exchange, was also reduced (p<0.05). CONCLUSIONS: These data do not seem to support the hypothesis that ticlopidine-induced reduction of platelet adhesion depends on alteration of the mechanisms determining signal transduction, at least as far as basal and post-stimulation intracellular calcium is concerned. On the contrary, the possibility that ticlopidine inhibits the Na+/H+ antiport remains open to consideration.

Intralymphocyte free magnesium and calcium and insulin tolerance test in a group of essential hypertensive patients.

In order to assess the links which are claimed to exist between peripheral insulin resistance and intracellular magnesium and calcium concentrations, we measured free intralymphocyte magnesium (Mg(i)) and calcium (Ca(i)) concentrations as well as the rate constant of plasma glucose disappearance (K(itt)) after insulin injection (insulin tolerance test: ITT) in a group of 16 normotensive control subjects (NC) and 34 essential hypertensive subjects (EH). Mg(i) and Ca(i) were measured in triplicate by means of a fluorimetric technique based on the dyes furaptra and fura-2 respectively. K(itt) values proved significantly reduced in EH as compared to NC (M +/- SD, EH: 4.49 +/- 1.31 vs 5.28 +/- 1.19, P <0.05; 95% confidence limits: 0.23-1.5). Mg(i) and Ca(i) were not statistically different in EH as compared to NC subjects (Mg(i), NC: 266 +/- 20 micromol/l; EH: 245 +/- 50 micromol/l; Ca(i), NC: 47 +/- 9 nmol/l EH: 46 +/- 13 nmol/l). We found a statistically significant inverse correlation in the whole study group between K(itt) and body mass index (R= -0.363, P<0.01) and a statistically significant positive correlation between K(itt) and Mg(i) (R=0.347, P=0.013) was found. In a step-up multivariate regression analysis including blood pressure, plasma lipids, BMI, plasma magnesium, fasting insulin, fasting glucose, Mg(i) and Ca(i), the dependent variable K(itt) is statistically significantly correlated with body mass index and Mg(i). In a first attempt to study the relationships between insulin resistance, Mg(i) and Ca(i) in nucleated cells, the chosen index of peripheral resistance seems to be linked to intracellular free magnesium.

[Peripheral insulin resistance and free intralymphocyte magnesium and calcium concentrations in patients with essential hypertension]. / Résistance périphérique à l'insuline et concentration intralymphocytaire de magnésium et de calcium ionisés chez des patients avec hypertension artérielle essentielle.

To ascertain the claimed links between peripheral insulin resistance and intracellular magnesium and calcium concentrations, we measured free intralymphocyte magnesium (Mg(i)) and calcium (Ca(i)) concentrations, as well as the rate constant of plasma glucose disappearance (K(itt)) after insulin injection (insulin tolerance test: ITT), in a group of 15 normotensive control subjects (NC) and 29 essential hypertensive subjects (EH). Mg(i) and Ca(i) were measured in triplicate by means of a fluorimetric technique based on the dyes furaptra and fura-2 respectively. K(itt) value were significantly reduced in hypertensive subjects as compared to control subjects (M +/- SD, EH: 4.54 +/- 1.31 vs 5.63 +/- 1.07; p < 0.02; 95% confidence limits: 0.22-1.96). Mg(i) and Ca(i) were not statistically different in hypertensive subjects as compared to control subjects (Mg(i), NC: 0.274 +/- 0.02 mmol/L; EH: 0.248 +/- 0.05 mmol/L; Ca(i), NC: 47.6 +/- 9 mmol/L, EH: 46.7 +/- 13.6 mmol/L). A statistically significant inverse correlation was found in the whole study group between K(itt) and body mass index (R = -0.394, p = 0.01) and a statistically significant positive correlation between K(itt) and Mg(i) (R = 0.386; p = 0.012). The latter correlation was no longer statistically significant if adjusted for body mass index. Our data are in favour of a link between index of peripheral insulin resistance and body mass index. A dependence from Mg(i) is possible but the study lack so far the statistical power to demonstrate it.

Oxidized LDL and reduction of the antiaggregating activity of nitric oxide derived from endothelial cells.

Oxidized LDL has been observed to induce abnormalities in endothelial function which may be relevant for the progression of atherosclerotic lesions. We studied in vitro the possible effects of oxidized LDL on the antiaggregating activity of endothelial cells, which is dependent on release of prostacyclin and nitric oxide. We used an experimental model in which cultured human endothelial cells were placed in the aggregometer in contact with human platelets, after blockade of cyclo-oxygenase by adding acetylsalicylic acid. In this way the antiaggregant effect of endothelial cells was dependent on the release of nitric oxide alone; prevention of antiaggregant activity by preincubation of endothelial cells with 300 microM L-NG-mono-methylarginine confirmed this. When this system was used, endothelial cells (2-7.5 x 10(5)/ml) almost completely inhibited thrombin-induced (0.02-0.08 U/ml) platelet aggregation (2 x 10(8) platelets/ml), measured according to Born (11.1% +/- 8.5 vs 68.6% +/- 12.6, M +/- SD). This antiaggregating activity was reduced when slightly oxidized LDL 100 micrograms/ml (35.2% +/- 14.9, p < 0.001), but not native LDL 100 micrograms/ml (7.5% +/- 7.6), was added immediately before aggregation was induced. Incubation of endothelial cells with oxidized LDL 100 micrograms/ml for 1 h did not affect the antiaggregating capacity, unless oxidized LDL was present during aggregation (18.3% +/- 10.2 vs 35.8% +/- 9.6, p < 0.02). No significant direct effect of either oxidized or native LDL on stimulated platelet aggregation was observed. Our results indicate that slightly oxidized LDL can reduce the antiaggregating properties of the endothelium, probably by interaction with NO rather than through inhibition of its synthesis.

Early agonist-induced intracellular acidification is increased in platelets from patients with essential hypertension.

Enhanced Na+/H+ exchange has been reported to be increased in patients with essential hypertension. However, early variations of intracellular pH, although influenced by the antiport, are only partially dependent on the exchange. In this study, we measured the initial platelet pH response to agonists in a group of untreated subjects with essential hypertension (EH, n = 24) and in a group of age- and sex-matched normotensive control subjects (CS, n = 24). Intracellular pH was measured with the specific fluorescence indicator 2'7'bis(carboxyethyl)-5,6-carboxyfluorescein. Measurements were performed on platelets in the presence or absence of extracellular calcium, in a carbonate-free medium. Intracellular calcium was measured by the Fura 2 method. Mean pH values were slightly higher in the platelets of EH (7.469 +/- 0.017 U) compared with CS (7.423 +/- 0.012 U, P < .05), although there was a substantial overlap. When stimulated with physiologic agonists ADP and thrombin and with the calcium ionophore ionomycin, a biphasic response consisting of early acidification followed by alkalinization was observed, the second phase not being detectable with ADP. The initial acidification was greater in EH, particularly with ADP (EH, -0.046 +/- 0.002 U; CS, -0.036 +/- 0.002 U, P < .001) and with ionomycin (EH, -0.074 +/- 0.007 U; CS, -0.051 +/- 0.005 U, P < .05). This acidification proved in some way calcium dependent, as it was reduced in the absence of extracellular calcium (EGTA) in both EH and CS. After incubation with amiloride a further decrease in intracellular pH, more marked in EH, was observed. Alkalinization induced by thrombin was increased in EH (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of ketanserin in the therapy of Raynaud's phenomenon: thermometric data.

After a two-week washout (WO) period with placebo 1 capsule/bid, 12 patients suffering from stable Raynaud's phenomenon were treated with ketanserin (K) 40 mg/bid for fifteen days. Blood pressure, heart rate, and laboratory parameters were evaluated at the end of each period. Patients used diary cards to record the number, duration, and intensity of attacks. Computerized thermometry of the fingers was evaluated at basal temperature after acclimatization, 23 degrees C for thirty minutes; after cold test, 10 degrees C for five minutes; and after thermal recovery, 23 degrees C for eighteen minutes. Results were analyzed statistically by use of Student's t-test for paired data (p less than 0.05). No marked changes were observed in the symptoms of the attacks, but K proved effective in significantly reducing the number and duration of daily attacks and in promoting their spontaneous regression. Thermometry revealed a parallel increase in temperatures, particularly basal and recovery values. The data suggest increased flow and decreased vasospasm following 5-HT2 receptor blockade.

Increased platelet aggregation and intracellular calcium in hypertensive patients: effects of cyclo-oxygenase blockade.

Increased platelet aggregation induced by ADP and arachidonic acid was observed in 12 patients with essential hypertension compared with 12 control subjects, but not after pretreatment with acetylsalicylic acid. The increase in intracellular calcium induced by ADP was also greater in the hypertensive patients, and again this difference disappeared after cyclo-oxygenase blockade. Urinary excretion of 2,3-dinor-thromboxane B2, the main metabolite of platelet thromboxane A2, was slightly, but not significantly increased in the hypertensive patients. These data suggest that thromboxane system activity is increased in the platelets of hypertensive patients.

Haemodynamic parameters in hypertensive patients: changes induced by lacidipine and nifedipine.

We conducted a randomly allocated, double-blind study in 16 essential hypertensive patients, eight of whom were treated with nifedipine and eight with lacidipine. The antihypertensive efficacy was evaluated and any modifications to peripheral haemodynamic parameters were observed in the brachial artery by a mechanographic method and B-mode scanner with a 10-MHz probe. Statistically significant reductions in blood pressure from basal values were observed after 1 and 6 months' treatment. Enhanced compliance (P less than 0.005), reduced characteristic impedance (P less than 0.001) and lower peripheral resistances (P less than 0.01) were also noted. Variations in pulse wave velocity and mean blood pressure showed a statistically significant correlation as early as the first month of treatment (P less than 0.01). Our results suggest that therapy with nifedipine and lacidipine allows an improvement in peripheral haemodynamics in hypertensive patients. This response is maintained in chronic treatment, even just before the next dose administration at the end of the longest dose interval.

Increased urinary 6-keto-PGF1 alpha excretion during water immersion is blunted by metoclopramide in normal man.

Urinary excretion of 6-keto-PGF1 alpha and 2,3 dinor-6-keto-PGF1 alpha, as indices of the renal and systemic production of prostaglandins, was measured during water immersion in a group of 6 healthy volunteers both in the presence and absence of dopamine blockade by the dopamine receptor antagonist, metoclopramide. Urinary flow rate and excretion of both sodium and 6-keto-PGF1 alpha increased during water immersion, while plasma renin activity and plasma aldosterone were reduced. Urinary kallikrein and 2,3 dinor-6-keto-PGF1 alpha also tended to increase during water immersion. Administration of metoclopramide significantly reduced 6-keto-PGF1 alpha and sodium excretion during water immersion, but produced no changes in plasma renin activity or in 2,3 dinor-6-keto-PGF1 alpha. Plasma aldosterone concentrations after metoclopramide were similar to those observed in the pre-immersion period. An increased synthesis of the vasodilator and natriuretic prostacyclin in the kidney might play a role in the response to water immersion. The reduced sodium and 6-keto-PGF1 alpha excretion observed after metoclopramide administration suggests that dopamine might induce prostacyclin synthesis in the kidney during water immersion.

Comparative efficacy of ketanserin and pentoxiphylline in treatment of Raynaud's phenomenon.

In a randomized, placebo-controlled, crossover study, 15 ambulatory patients with Raynaud's phenomenon, treated for three weeks with ketanserin 80 mg/day and pentoxiphylline 1,200 mg/day, were evaluated by subjective symptom scores, daily frequency and duration of attacks, and photoplethysmography, at room temperature and after cold test. Reduced subjective symptoms and duration of attacks, together with improved cold test plethysmography, were significant only after ketanserin. All subjective symptom scores also improved after ketanserin but only for cyanosis and paresthesia after pentoxiphylline. Excellent results were obtained in 4 cases after ketanserin and in 1 case with pentoxiphylline. The authors discuss the greater importance of antivasospastic action over antiaggregating and hemorheologic effects in Raynaud's phenomenon therapy, as well as the pathogenetic role of serotonin.

Altered excretion of prostaglandin and thromboxane metabolites in pregnancy-induced hypertension.

The renal and systemic metabolites (the latter as 2,3-dinor derivatives) of prostacyclin and thromboxane A2 were measured, along with renal prostaglandin E2 and kallikrein, in the urine of 15 patients with pregnancy-induced hypertension, 15 normotensive pregnant women matched for both age and gestational age, and 15 normotensive nonpregnant control women. Urinary excretion of all prostaglandin and thromboxane metabolites studied proved significantly higher in normotensive pregnant women than in controls. Prostaglandin E2, 6-keto-prostaglandin F1 alpha, and 2,3-dinor-6-keto-prostaglandin F1 alpha were significantly lower in pregnancy-induced hypertensive women than in normotensive pregnant women, whereas thromboxane B2 and 2,3-dinor-thromboxane B2 showed no significant differences in the two groups. A significant negative correlation (r = -0.636, p less than 0.01) was found between urinary 2,3-dinor-6-keto-prostaglandin F1 alpha and mean blood pressure in the two groups of pregnant women taken as a whole. These data indicate that, in pregnancy-induced hypertension, there is an imbalance between vasodilator and vasoconstrictor factors, not only in the kidneys, but also at the systemic vascular level. This imbalance, which may in itself produce vasoconstriction, may also potentiate the hypertensive effect of catecholamines and angiotensin II.

Reduced excretion of vasodilator prostaglandins in preeclampsia.

The role of prostaglandin (PG) system in preeclampsia (pre-E) was investigated. Urinary excretion of PGE2,6-keto PGF1 alpha,2,3 dinor 6-keto PGF1 alpha, TxB2 and 2,3-dinor-TxB2 and kallikrein were determined in 10 normotensive pregnant women and 14 with pre-E. 6-keto PGF1 alpha and 2,3-dinor 6-keto PGF1 alpha (the main renal and extrarenal metabolites of vasodilator PGI2) and PGE2 excretion was lower in pre-E. TxB2 metabolites in urine were similar in the two groups of women. Our data are consistent with the hypothesis of an imbalance between vasodilator and vasoconstrictor PGs in pre-E.