Rheological properties of erythrocytes in patients with high risk of cardiovascular disease.

Rheological properties of erythrocytes from patients with high risk of cardiovascular disease (CVD) were analyzed in relation to individual patient risk factors as well as to the medication. Additionally, comparative statistical analysis was performed considering plasma concentration of the selected mediators of vascular endothelium: 6-keto-prostaglandin F(1alpha) (PGF(1alpha)), sVCAM-1 and E-selectin adhesion molecules and interleukin-6 (IL-6). It was found that antihypertensive therapy with angiotensin-converting enzyme inhibitor (ACEI) is accompanied by improvement of RBC rheology: the increase of deformability and the decrease of aggregability. This improvement is probably mediated by endothelial prostacyclin and nitric oxide which are generated by ACEI. A correlation was observed between RBC deformability/aggregability and the patient's hematocrit level, what implicates that the hematocrit level should be explicitly taken into consideration when investigating rheological properties of erythrocytes. A strong relationship was also found between the plasma concentration of sVCAM-1 and patient's age.

Secretory dysfunction of vascular endothelium limits the effect of angiotensin converting enzyme inhibitor quinapril on aggregation of erythrocytes in experimental hypertension.

Using automatic erythrocyte aggregometer type MA-1 (Myrenne gmbh, Germany), we investigated the hypothesis that therapeutic effectiveness of quinapril--angiotensin converting enzyme inhibitor (ACEI)--in the treatment of hypertension would correlate with improvement of red blood cell (RBC) aggregability. Experiments were performed on commercially available inbred strain of spontaneously hypertensive male rats (SHR) aged 19-21 weeks. Age-matched normotensive Wistar-Kyoto (WKY) rats genetically related to SHR were used as a control. Aggregability of RBC in hypertensive rats was significantly higher than in control WKY animals. Quinapril (100 microg/kg) administered i.p. for 8 days improved RBC aggregability in normotensive rats but surprisingly not in SHR animals. Beneficial effect of quinapril on RBC aggregation observed in normotensive animals did not occur when this drug was injected in combination with aspirin (1 or 50 mg/kg) or with indomethacin (20 mg/kg) or with L-NAME (10 mg/kg). However, much the same damaging effects on RBC aggregability were observed when aspirin, indomethacin or L-NAME were each administered into normotensive animals without quinapril. In contrast with normotensive rats, aggregability of RBC in SHR was not affected either by quinapril or by indomethacin and by L-NAME, given separately or in combination. The only compound significantly worsening RBC aggregability in SHR was aspirin but this effect was not dose-dependent. Quinapril-induced improvement of RBC aggregability in normotensive rats (but not in SHR) was completely abolished by simultaneous administration of B2 receptor antagonist icatibant and successfully mimicked by 8 days of treatment with bradykinin. In vitro aggregability of RBC isolated from WKY was not affected by previous incubation (30 min at 37 degrees C) with quinapril, indomethacin or L-NAME. Only aspirin (3 mM) significantly increased RBC aggregability as compared to placebo. It is concluded that under physiological conditions quinapril efficiently inhibits RBC aggregability and this effect is modulated by secretion of endothelial mediators, mainly prostacyclin and nitric oxide. In hypertension quinapril, in spite of lowering of arterial blood pressure, is unable to display its beneficial effects on RBC aggregability possibly due to the hypertension-induced/accompanied dysfunction of vascular endothelium. Aspirin revealed unique erythrocyte damaging properties, presumably independent of inhibition of cyclooxygenase but related to a direct membrane protein acetylation.

Endothelial secretogogues and deformability of erythrocytes.

Many diseases of the heart and circulatory system have been linked with both dysfunction of vascular endothelium and insufficient deformability of erythrocytes. Using shear stress laser diffractometry we investigated whether deformability of erythrocytes would be regulated endogenously by generation of two endothelial secretogogues: prostacyclin and nitric oxide. Experiments were performed in rats ex vivo and with whole blood or isolated erythrocytes in vitro. Iloprost--a stable analogue of prostacyclin (10 microg/kg i.v.) and SIN-1 (NO-donor) at a dose of 2 mg/kg/min i.v induced a significant improvement of deformability of erythrocytes ex vivo. Improvements of deformability by these two compounds were also evident in vitro when they were applied at a range of concentrations of 1 microM and 3 microM, respectively. Cyclooxygenase (indomethacin 20 mg.kg i.v.) and nitric oxide synthase (L-NAME 10 mg/kg i.v.) inhibitors while worsening deformability ex vivo, they did not affect (3 mM and 10 microM, respectively) rheological functions of erythrocytes in vitro. Aggravating effects of these inhibitors on erythrocyte deformability ex vivo were reversed by prostacyclin and nitric oxide supplemented exogenously. Aspirin at a low (1 mg/kg i.v.) and high dose (50 mg/kg i.v.), contrary to indomethacin and L-NAME, aggravated erythrocyte deformability either ex vivo or in vitro. It is concluded that autocrine function of vascular endothelium plays an important role in regulation of rheology of red blood cells in flowing blood. The mechanism of this phenomenon is unclear but some possible explanations are discussed. In addition, in our experiments aspirin revealed unique erythrocyte damaging properties, possibly independent of inhibition of cyclooxygenase, but related to a direct protein acetylation.

Prolactin--not only lactotrophin. A "new" view of the "old" hormone.

Prolactin (PRL) is a hormone mainly secreted by the anterior pituitary. Recent studies have shown that it may also be produced by many extrapituitary cells. The PRL gene expression is controlled by two independent promoter regions, which may be differentially regulated in the pituitary and extrapituitary organs. Proteolytic modifications of PRL generate variants of the hormone. A16 kDa PRL fragment, acting through a specific receptor, has both an antiangiogenic activity as well as an inhibitory effect on tumor growth. Stimulation of the PRL receptor involves many signal transduction pathways, for example JAK2/STAT, MAPK, c-src and Fyn kinase cascade, and these pathways may vary in different tissues. PRL synthesis and secretion is mainly regulated by the inhibitory influence of dopamine but other hormones are also involved in these mechanisms. The essential biological action of PRL is the stimulation of lactogenesis and galactopoesis. Apart from its classical functions, PRL affects other aspects of human body function including osmoregulation, metabolism and regulation of the immune and the central nervous system. Hyperprolactinemia is a common syndrome affecting both men and women. It is manifested by the presence of galactorrhoea and through the symptoms of hypogonadotrophic hypogonadism. Following on from the fact that PRL has so many pleiotropic tissue specific effects it is not surprising to learn that hyperprolactinaemia is a systemic condition which may predispose to numerous cardiovascular and immune-mediated reactions. The exact effects of PRL on both immune and cardiovascular systems are being currently unraveled and may lead to the introduction of novel therapeutic approaches in the future.

Evolution of rheological properties of erythrocytes and left ventricular geometry in cardiovascular disease risk patients.

The evolution of rheological properties of erythrocytes and geometrical parameters of left ventricle during therapies aimed at reducing cardiovascular disease (CVD) risk has been investigated. The study group consisted of 29 individuals who were diagnosed with the presence of at least one CVD risk factor at the time of entry to the study. Appropriate therapies were applied and the patients were followed for two years. Two groups of patients could be distinguished. The first group consisted of 12 individuals who were rigorously applying the therapy and for whom blood pressure, total cholesterol, LDL and glucose returned to normal levels. The second group included 17 patients for whom the above mentioned parameters remained pathological in spite of the applied therapy. In the first group, erythrocyte deformability as well as LVMI improved: deformability increased on average by 17% (p < 0.025), whereas LVMI decreased by 8% but not in a statistically significant manner (p < 0.27). In the second group, the results indicate worsening of both hemorheological properties and left ventricular geometry: RBC deformability became lower by 15% (p < 0.00001) and LVMI increased by 18% although this change was not statistically significant (p < 0.19). The results indicate that blood rheology improves when the CVD risk is reduced by administered therapy and worsens when the risk increases. Similar behavior shows LVMI. It is very likely that left ventricular geometry is influenced by blood rheology.

Left ventricular geometry and rheological properties of erythrocytes in patients at cardiovascular disease risk.

The relationship between erythrocyte deformability and aggregability with left ventricular mass index has been examined in patients diagnosed with at least one cardiovascular risk factor but without ongoing coronary heart disease. The group consisted of 66 individuals, 30 men and 36 women, of the average age 57.7 years. For each patient, deformability and aggregability of red blood cells (RBCs) as well as end-diastolic left ventricle diameter (LVD), interventricular septum thickness (IVST) and posterior wall thickness (PWT) were measured. On the basis of the echocardiographical parameters and anthropometric data, left ventricular mass index (LVMI) was calculated. The analysis revealed statistically significant correlation between the LVMI and erythrocyte deformability and aggregability: the LVMI increases with decreasing deformability and is higher in patients with higher aggregability. This finding indicates that the worsening of RBC rheological properties is one of the main factors contributing to alterations of cardiac geometry through the increase of peripheral resistance which, in turn, significantly augments the heart afterload. Given that left ventricular hypertrophy (LVH) is a predictor of cardiovascular morbidity and mortality, the association between hemorheological parameters and left ventricular geometry may be important in clinical practice.