Nano-HPLC-MS analysis of phospholipids in cerebrospinal fluid of Alzheimer's disease patients--a pilot study.

There is emerging evidence that lipids play an important role in many neurodegenerative processes, for example in Alzheimer's disease (AD). Although different lipid alterations in the AD brain have been reported, there have only been very few investigations of lipid changes in the cerebrospinal fluid (CSF). Recent developments in mass spectrometry (MS) have enabled fast and sensitive detection of lipid species in different biological matrixes. In this study we developed an on-line HPLC-MS method for phospholipid profiling in the CSF based on nano-HPLC separation using an Amide column and detection with electrospray (ESI) quadrupole-time of flight (QTOF) MS. We achieved good separation, reproducibility, and sensitivity in monitoring of the major phospholipid classes, phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylinositol (PI), and sphingomyelin (SM) in CSF. To emphasize the applicability of the method, a pilot study was performed on a group of CSF samples (N = 16) from individuals with probable AD and non-demented controls. We observed a statistically significant increase of SM levels (24.3 ± 2.4%) in CSF from probable AD individuals vs. controls. Our findings indicate that SM levels in the CSF could potentially provide a new lead in AD biomarker research, and show the potential of the method for disease-associated CSF phospholipid screening.

Vascular reserve in the lower limbs of cirrhotic patients: a duplex Doppler ultrasound study.

AIM: To evaluate femoral artery impedance at rest and during reactive hyperaemia. PATIENTS: Study population comprised 11 cirrhotic patients without ascites, 10 with ascites and 16 age- and sex-matched healthy subjects. METHODS: Echocardiographic assessment of systemic haemodynamics; duplex Doppler ultrasound measurement of femoral artery pulsatility index and vascular reserve [pulsatility index rest/pulsatility index hyperaemia). RESULTS: Cirrhotic patients had elevated cardiac index and low systemic vascular resistance. Pulsatility index (right femoral artery) was not statistically different either at rest or after reactive hyperaemia (controls: rest 10.6 +/- 0.4, hyperaemia 2.6 +/- 0.2; compensated cirrhosis: rest 10.1 +/- 0.8, hyperaemia 3.4 +/- 0.4; ascitic cirrhosis: rest 11.4 +/- 1.6, hyperaemia 2.9 +/- 0.4. Vascular reserve was 4.38 +/- 0.35 in controls, 3.33 +/- 0.39 in compensated and 4.70 +/- 0.89 in ascitic cirrhosis (p = not significant). No correlation was found between systemic haemodynamic parameters and either pulsatility index or vascular reserve. CONCLUSIONS: The lower limb vascular reserve is preserved in cirrhosis.

The normal sequence of right and left atrial contraction.

OBJECTIVE: To study the sequence of atrial activation and the interatrial electromechanical delay (IEmD) noninvasively in healthy subjects during sinus rhythm (SR). METHODS AND RESULTS: In 66 SR healthy subjects P-wave activation was analyzed by means of vectorcardiography. The timing of atrial contractions was measured as the intervals between the P-wave and the A-wave of the Doppler right and left ventricular inflows (P-A(t) and P-A(m)), and IEmD was calculated as the algebraic difference P-A(m)- P-A(t). In the horizontal plane the vectorcardiographic P-loop was anteroposterior ("typical", 41 subjects), anterior (18), or posterior (7). IEmD (mean +/- SE 17 +/- 8 ms) was directly related to R-R and P-R intervals. IEmD was significantly shorter in anterior and posterior P loops than in the typical (6.5 +/- 5.3 and 8.1 +/- 10.1, respectively, vs 24.2 +/- 3.1 ms). In the posterior P-loop group, who exhibited longer P-A(t), mitral E-wave velocity and E/A ratio were reduced, and left atrial booster function was increased. CONCLUSION: IEmD was widely variable in SR, reflecting the origin site of sinus impulse, which independently influenced ventricular filling dynamics.

Hemodynamic, renal, and endocrine effects of acute inhibition of nitric oxide synthase in compensated cirrhosis.

To assess whether an increased production of nitric oxide is involved in the circulatory and renal alterations of cirrhosis, we evaluated systemic hemodynamics (echocardiography), renal hemodynamics, and sodium handling (lithium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 +/- 2 years) with compensated cirrhosis, portal hypertension, and hyperdynamic circulation during intravenous N(G)-monomethyl-L-arginine (L-NMMA) (3 mg/kg bolus plus 0.05 mg/kg. min for 120 minutes) or placebo (the vehicle) in a randomized, placebo-controlled, crossover study. Administration of L-NMMA resulted in significant reductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synthase. L-NMMA also significantly reduced cardiac index (-13%) and increased systemic vascular resistance (+26%), arterial pressure (+9%), renal blood flow (+12%), glomerular filtration rate (+12%), and sodium excretion (+25%). Changes in sodium excretion were caused by both enhanced filtered sodium load and reduced sodium reabsorption in the proximal tubule. Plasma norepinephrine significantly decreased in response to L-NMMA, and there was a trend for reductions in PRA and PAC. Placebo had no appreciable effect on any of the measured parameters. These results indicate that in patients with compensated cirrhosis, portal hypertension and hyperdynamic circulation inhibition of nitric oxide synthase corrects the altered systemic hemodynamics and improves renal function and sodium excretion.

Cardiovascular function in pregnancy: effects of posture.

OBJECTIVE: To evaluate the cardiovascular response to active postural changes in pregnancy. DESIGN: Prospective study. SETTING: Outpatient Clinic, Fetal Maternity Unit. PARTICIPANTS: Sixteen healthy women referred prior to pregnancy. METHODS: Heart rate, arterial pressure, echocardiographic end-diastolic and end-systolic left ventricular volumes (Teichholz' s formula) were measured in the three months before pregnancy, at the end of the first and second trimester, at mid third trimester, and six months after delivery in the supine and standing position, in thirteen women (mean age 33, range 25-38 years). RESULTS: Cardiac output (supine position) significantly increased (28%): it reached its maximum at the second trimester, remained steadily elevated in the mid third trimester, and returned to baseline after delivery. Cardiac output increased during pregnancy also in the active orthostatic position, the percentage increase being greater (70%) since the standing pre-conception value was lower. The postural stress induced similar changes in heart rate, arterial pressure and left ventricular ejection fraction before, during and after pregnancy. However, the reduction in cardiac output associated with early standing attenuated significantly at the second trimester and it was absent at mid third trimester (F = 3.13, P = 0.021). This was due to the interplay between the significantly lesser increase in systemic vascular resistance, occurring since the first trimester, and the significantly lesser decrease in left ventricular end-diastolic volume which was observed in the mid third trimester. CONCLUSION: These data indicate that the elevated cardiac output is adequately maintained in pregnancy during the postural challenge, due to optimisation of the responses of preload and afterload.

Effects of low-dose adrenomedullin on cardiac function and systemic haemodynamics in man.

The cardiovascular effects of low-dose adrenomedullin (ADM, 1, 2 and 3 pmol kg-1 min-1 for 30 min each) were evaluated in six healthy subjects in a placebo controlled, cross-over study by determining cardiac volumes, systolic and diastolic function (echocardiography) and systemic haemodynamics before, during and after ADM or placebo. High-resolution ultrasound was used to evaluate changes in carotid artery distension. ADM caused a +85% increment in its plasma levels and significantly increased plasma cyclic adenyl monophosphate (cAMP). Compared with placebo, ADM induced significant decrements in left ventricular (LV) systolic diameter and systemic vascular resistance, and increments in LV posterior wall thickening, ejection fraction and cardiac index. Right and left atrial emptying fraction and carotid artery distention increased. LV diastolic function, heart rate, and plasma renin activity did not change, whereas packed cell volume increased. These results indicate that ADM influences cardiovascular function and systemic haemodynamics at physiological plasma levels in man mainly because of its vasodilating activity, leading to reduced afterload.

Cardiovascular effects of parathyroid hormone: a study in healthy subjects and normotensive patients with mild primary hyperparathyroidism.

The aim of the study was to evaluate: 1) the cardiovascular function and the autonomic drive to the heart in patients affected by primary hyperparathyroidism (pHPT) with no evidence of renal and cardiovascular complications; 2) the cardiovascular effects of acute administration of PTH in normal subjects. In 14 patients affected by mild asymptomatic pHPT echocardiographic assessment of cardiovascular function and of the mechanic properties of the brachial and carotid artery, heart rate variability and the dispersion of QT interval were performed before and 6 months after successful surgery. Twenty age- and sex-matched healthy subjects were included in the study. Five healthy volunteers underwent a single blind, placebo-controlled, random order, cross-over study with infusion of PTH (hPTH 1-34, 200 U in saline over 5 min) or placebo. Echocardiographic assessment of cardiovascular function, heart rate variability, and QT interval were performed between 20 and 25 min after the start of the infusion and repeated after 15 min of tilting at 60 degrees. In pHPT patients the echocardiographic parameters were normal; left ventricular isovolumetric relaxation time was always in the normal range, but significantly shorter than in control subjects, suggesting an increased sympathetic stimulation. Arterial diameters and thickness, blood pressure, and QT interval were not significantly different with respect to normal subjects and were unchanged 6 months after surgery. pHPT patients lacked the circadian rhythm of the low frequency to high frequency ratio, suggesting an increased sympathetic drive to the heart at nighttime. In normal subjects there were no significant differences in basal echocardiographic measurements during PTH infusion with respect to placebo and in the hemodynamic response to tilt. These results suggest that cardiovascular function is substantially normal in normotensive pHPT patients with mild hypercalcemia. A modulation of the adrenergic control of circulation seems to be associated with hypercalcemia and/or chronic PTH excess, but its biological relevance needs further investigations.

Simultaneous dobutamine stress echocardiography and 99mTc-tetrofosmin three-head single-photon emission computed tomography in patients with suspected coronary artery disease.

OBJECTIVES AND BACKGROUND: Dobutamine stress echocardiography and 99mTc-tetrofosmin single-photon emission computed tomography (T-SPECT) were performed simultaneously in subjects in whom coronary artery disease (CAD) had been proven or excluded at coronary angiography, in order to establish their accuracy and agreement in the diagnosis of CAD, and in localisation and evaluation of the extension of ischaemia. No simultaneous comparison of the two techniques has been performed previously. METHODS: Seventy patients (50 men, mean age 63 +/- 10 years, 21 with previous myocardial infarction) underwent simultaneous dobutamine stress echocardiography and T-SPECT. The response to stress was blindly and independently analysed, adopting a 16-region segmentation and referring to the three major coronary arteries. RESULTS: Sixty-two patients (agreement 89%, kappa = 0.776) and 91% of left ventricular regions (kappa = 0.665) were classified concordantly, independently of the presence or absence of previous myocardial infarction (90%, kappa = 0.740 versus 91%, kappa = 0.589, respectively). At coronary angiography, 47 patients had CAD (disease prevalence 67%). The sensitivity and specificity of stress echocardiography for the diagnosis of anterior descending, circumflex and right coronary artery disease were 62, 78 and 73%, and 79, 79 and 83%, respectively. The corresponding values for T-SPECT were 70, 75 and 78%, and 94, 79 and 90%, respectively. CONCLUSIONS: These data indicate a high concordance between wall motion abnormalities observed using stress echocardiography and perfusion defects observed using T-SPECT; their sensitivity in identifying critical stenoses was similar. Inadequate stressor amounts, and less frequently hyperdynamic regional response may reduce the accuracy of stress echocardiography, while dobutamine effects on coronary flow may prevent T-SPECT from showing subtle flow maldistributions in the presence of worsened wall motion.

Cardiovascular and renal function in normotensive and hypertensive patients with compensated cirrhosis: effects of posture.

BACKGROUND/AIMS: The aim of this study was to evaluate cardiovascular and renal function in patients with compensated cirrhosis and essential hypertension in the supine position and in response to standing up. METHODS: Twenty-four patients with compensated cirrhosis (12 with elevated arterial pressure) and 20 healthy volunteers underwent echocardiographic evaluation of left ventricular end-diastolic and stroke volumes, ejection fraction, cardiac index, arterial pressure, peripheral resistance, creatinine clearance and sodium excretion in both the supine and the standing position. RESULTS: When supine, only normotensive patients had a hyperdynamic circulation, with increased left ventricular end-diastolic and stroke volumes, cardiac index, and ejection fraction, and reduced peripheral resistance. Creatinine clearance and sodium excretion were comparable in patients and controls. Standing induced a decrease in end-diastolic volume in all subjects. Healthy volunteers maintained cardiovascular homeostasis by increasing ejection fraction and heart rate, while both normotensive and hypertensive cirrhotic patients experienced a fall in stroke volume and cardiac index, despite a marked activation of the renin-aldosterone and sympathetic nervous system. Creatinine clearance decreased only in normotensive patients, who experienced the greatest reduction in sodium excretion. CONCLUSIONS: Compensated cirrhotic patients with arterial hypertension had no evidence of hyperdynamic circulation. Like their normotensive counterparts, hypertensive patients had an impaired cardiovascular response to the postural challenge, but a lesser degree of renal dysfunction during standing.

Post-ejection thickening as a marker of viable myocardium. An echocardiographic study in patients with chronic coronary artery disease.

The study aim was to assess whether post-ejection thickening (PT) is an useful marker of viable myocardium in patients with chronic coronary artery disease. Twenty-three patients with critical coronary stenoses were submitted to dobutamine and dipyridamole stress-echocardiographies and dipyridamole-early-redistribution 201Tl SPECT within 15 days from coronary arteriography. They were selected for the presence of PT in segments that could be optimally studied by M-mode echocardiography and were hypo-akinetic in basal conditions. PT (occurring between end-ejection and mitral valve opening) was found in 58% of dysfunctional, critically perfused regions. Ninety-eight percent of the regions with PT and 6% of those without PT improved during low-dose dobutamine stress-echocardiography. Segments with PT had, respectively, higher and lower SPECT early-redistribution thallium activity than dysfunctional segments without PT and normokinetic regions. Therefore, regions with PT were viable and had a moderate decrease in coronary perfusion. Akinetic segments without PT did not show any inotropic reserve. After revascularization almost all the segments with PT improved. In conclusion, PT is a pattern of myocardial contraction easily detected by M-mode echocardiography in the clinical setting. If the results of this study are further confirmed, PT may become a sign for the recognition of myocardial viability.

Effects of exercise on natriuretic peptides and cardiac function in man.

We evaluated cardiac function and the plasma levels of atrial (ANP) and brain (BNP) natriuretic peptides during bicycle (B) and hand-grip (HG) exercises in eight healthy males. Each test was preceded by a control protocol in resting conditions. Left ventricular (LV) function (echocardiography) was evaluated during both exercises. Atrial function was assessed only during HG. Plasma ANP significantly increased during B (+236%) and HG (+77%), while there was a significant trend towards higher plasma BNP levels during B (+41%) and HG (+30%) than during the corresponding control tests. Plasma ANP correlated with heart rate in both tests, with left atrial volume, pulmonary vein flow systolic fraction and mitral flow E/A ratio in HG; BNP in both test correlated with LV dimensions and function. These data suggest that during exercise the cardiac release of ANP and BNP is differently regulated and related to changes in left atrial and LV function, respectively.

Cardiac autonomic modulation and incidence of late potentials in essential hypertension: role of age, sex, ventricular mass and remodeling.

The influence of age, sex, left ventricular hypertrophy (LVH) and geometry on the autonomic activity to the heart was investigated in 96 hypertensive out-patients (53 men, mean age 53 +/- 9 years) and 39 healthy subjects (19 men, mean age 43 +/- 1 years). Using 24-h Holter recordings, time [the standard deviation of all RR intervals (SDNN) and the square root of the mean of the squared differences between adjacent normal RR intervals (RMSSD)] and power spectral analysis of RR intervals [Fast Fourier algorithm, low/high frequency (LF/HF) ratio] were calculated over 24 h, daytime (D) and nighttime (N) periods in all subjects. Signal averaged electrocardiogram was recorded in 50 patients to detect late potentials. Stepwise multiple linear regression analysis showed that the 24-h LF/HF ratio was influenced by age and sex, D-LF/HF by age and N-LF/HF by sex, a higher LF/HF ratio being found in younger patients and in men. These data suggest a more prominent sympathetic modulation of cardiac activity in these groups. No differences in RR period variations were observed between patients with or without LVH. Late potentials were observed in 10 patients, and did not correlate with any of the measured parameters.

Low-dose C-type natriuretic peptide does not affect cardiac and renal function in humans.

In experimental animals, C-type natriuretic peptide (CNP) has vasodilating, hypotensive, and natriuretic activities. The role of circulating CNP in the overall regulation of cardiac and renal function in humans is less defined, in both health and disease. We measured cardiac volumes, diastolic and systolic functions, systemic (Doppler echocardiography) and renal hemodynamics, intrarenal sodium handling (lithium clearance method), plasma and urinary cGMP, plasma renin concentration, and plasma aldosterone level in six healthy volunteers (mean age, 33+/-3 years) receiving CNP (2 and 4 pmol/kg per minute for 1 hour each) in a single-blind, placebo-controlled, random-order, crossover study. During CNP infusion, plasma CNP increased from 1.17+/-0.23 to 41.52+/-4.61 pmol/L (ie, 4- to 10-fold higher levels than those observed in disease states) without affecting plasma and urinary cGMP, cardiac volumes, dynamics of left and right heart filling, cardiac output, arterial pressure, renal hemodynamics, intrarenal sodium handling, sodium excretion, or plasma levels of renin and aldosterone. The finding that increments in plasma CNP within the pathophysiological range have no effects on systemic hemodynamics, renal function, or the renin-angiotensin system do not support the hypothesis that CNP may act as a circulating hormone in humans.

Regional and temporal nonuniformity of shape and wall movement in the normal left ventricle.

Asymmetry of left ventricular (LV) shape and asynchrony of regional LV movement have been described in the normal human heart, but never correlated to each other. In 16 normal subjects, right anterior oblique ventriculography was used to obtain volumes, regional wall motion (centerline method) and curvature (windowed Fourier series approximation of contours) over the entire cardiac cycle. The apex had the greatest curvature, while the posterior wall had a negative end-diastolic curvature that decreased further at early-systole and became positive at end-systole. The anterior region had the greatest and the anteroapical region the least fractional shortening. Asynchrony was evident as a delayed contraction of the infero- and anteroapical regions, and as a greater rate of late-systolic shortening of the anterior wall than that of the apex. Shape changes and shortening were dyssynchronous in the apical regions where the greatest changes occurred at early diastole. Temporal and regional nonuniformity of shape and movement exists in normal subjects. Dyssynchrony between shape and regional contraction of the apical regions deserves further studies.

Altered cardiovascular responsiveness to active tilting in nonalcoholic cirrhosis.

BACKGROUND & AIMS: The hyperdynamic circulation of cirrhosis has been related either to plasma volume expansion (increased preload) or peripheral arterial vasodilation (reduced afterload). The aim of this study was to evaluate cardiovascular function in patients with nonalcoholic cirrhosis by echocardiography. METHODS: Nineteen patients with abnormal sodium handling (11 sodium excretors and 8 sodium retainers) and 15 healthy volunteers underwent echocardiographic evaluation of left ventricular end-diastolic volume index (LVEDVI) and left ventricular end-systolic volume index (LVESVI), left ventricular ejection fraction (LVEF), cardiac index (CI), mean arterial pressure, and systemic vascular resistance (SVR) during supine resting and after 5 minutes of standing. RESULTS: Supine patients had increased LVEF and CI and reduced LVESVI and SVR. LVEDVI was increased only in sodium excretors. Standing induced a decrease in LVEDVI in all subjects. Healthy volunteers maintained cardiovascular homeostasis by increasing LVEF and heart rate, whereas cirrhotic patients experienced a decrease in SVI and CI despite marked increments in heart rate, plasma renin activity, and plasma norepinephrine level. CONCLUSIONS: In patients with cirrhosis, the increased LVEF and reduced LVESVI while in a supine position point at reduced afterload as an important determinant of the hyperdynamic circulation. Evidence of an increased preload secondary to increased blood volume, indicated by a high LVEDVI and increased plasma atrial natriuretic peptide levels, was found only in sodium excretors. The altered response to active tilt in cirrhotic patients suggests an impaired myocardial contractility.

Parallel increase in carotid, brachial and left ventricular cross-sectional areas in arterial hypertension.

Few data have been published about the relation between the vessels geometry and development of left ventricular (LV) hypertrophy in patients with arterial hypertension. The aim of this study is to describe arterial and LV geometry changes due to mild-to-moderate arterial hypertension in an untreated hypertensive population. In 95 untreated patients with mild-to-moderate hypertension and 23 age- and sex-matched healthy normotensives, we measured the end-diastolic diameter and wall thickness of the left ventricle and the internal diameter and intimal-medial thickness (IMT) of carotid and brachial arteries. From these data, the cross-sectional areas (CSAs) of arterial and myocardial walls were calculated. Hypertensive patients were further subdivided on the basis of the presence of LV hypertrophy defined according to Devereux et al as anatomical LV mass >125 g/m. In hypertensive patients with hypertrophy, carotid and brachial CSAs increased, without significant changes in thickness/diameter ratio (arterial 'enlargement'), while the left ventricle developed 'concentric' hypertrophy. Arterial and LV CSAs showed a significant direct correlation with systolic blood pressure (BP). However, when data were corrected for BP, the correlation between the increase in arterial and LV CSAs became much improved than for the raw data. In conclusion patients with untreated mild-to-moderate hypertension, both carotid and brachial arterial walls showed an enlargement that was proportional to the development of LV hypertrophy. These results suggest that the effects of arterial hypertension on carotid, brachial and LV wall geometry have a common modulation.

Cerebral autoregulation in patients with cirrhosis and ascites. A transcranial Doppler study.

BACKGROUND/AIMS: Patients with cirrhosis and ascites usually show alterations of systemic hemodynamics and are thus prone to develop arterial hypotension, which might result in cerebral hypoperfusion if cerebral autoregulation is impaired. METHODS: We evaluated cerebral autoregulation in 15 patients with cirrhosis and ascites and 15 healthy subjects by monitoring mean blood flow velocity in the middle cerebral artery and arterial pressure during supine rest and passive tilting. RESULTS: Tilt provoked a drop of arterial pressure in both groups. Control subjects had a prompt recovery of mean flow velocity and a progressive recovery of arterial pressure, so that, after 120 s, both parameters had returned to baseline: at 20 s the recovery of flow velocity was faster (p<0.01) than that of blood pressure. By contrast, patients with cirrhosis had a delayed and incomplete recovery of both parameters (p<0.01 vs healthy subjects). In eight patients, the recovery of mean flow velocity paralleled that of arterial pressure, indicating an impaired cerebral autoregulation. These patients had a worse liver function, a higher cardiac index and lower peripheral resistance. CONCLUSIONS: Cerebral autoregulation is often impaired in patients with cirrhosis and ascites. These patients can develop cerebral hypoperfusion if arterial pressure falls abruptly.

T-wave alterations at the onset of wall motion abnormalities during dobutamine echocardiographic stress test.

At the onset of wall motion alterations during dobutamine echocardiographic stress testing, a steeper increase in the overall T-wave amplitude in the precordial leads was observed in 17 patients with baseline normal wall motion, electrocardiogram, and critical coronary stenoses compared with 11 control subjects. Eleven patients with increasing T-wave amplitude had localized apical dyssynergy, whereas 6 patients with downward displacement of the ST segment had widespread wall motion alterations also located at the basal and midsegments.

Cardiovascular effects of brain natriuretic peptide in essential hypertension.

We evaluated the cardiovascular effects of pathophysiological plasma levels of brain natriuretic peptide in seven patients with mild to moderate essential hypertension by performing equilibrium radionuclide angiocardiography at baseline and during brain natriuretic peptide infusion at increasing doses (4, 8, 10, and 12 pmol/kg per minute for 20 minutes each). Brain natriuretic peptide induced a progressive reduction of left ventricular end-diastolic volume (from 107.5 +/- 10.3 to 89.0 +/- 11.0 mL at the end of all infusion periods) and end-systolic volume, whereas stroke volume did not show any significant change (from 64.9 +/- 5.9 to 62.7 +/- 7.8 mL). Cardiac output, arterial pressure, and peripheral vascular resistance did not change significantly. The lack of effects on systemic hemodynamics was probably due to compensatory activation of the sympathetic nervous system, as indicated by the significant increase in plasma norepinephrine levels (from 1.75 +/- 0.18 to 2.19 +/- 0.21 nmol/L), heart rate (from 68 +/- 6 to 81 +/- 6 beats per minute), peak ejection rate, and peak filling rate. These results indicate that brain natriuretic peptide, at the pathophysiological plasma concentrations reached in this study, influences cardiovascular homeostasis mainly by reducing cardiac preload.