Amlodipine alters hemorheological parameters: Increased efficacy at the cost of edema?

BACKGROUND: Despite several decades of use of calcium channel blockers, the side effect of edema persists as a class effect, and its mechanism is unresolved. Amlodipine has effects on hemorheology (HR), and its hemodilutory property may partly contribute to its antihypertensive action. This aspect is not well studied, and the literature is sparse in this regard. OBJECTIVE: This experiment was planned to determine effect of a single-dose administration of amlodipine on HR parameters in normal human volunteers. METHODS AND RESULTS: Amlodipine (5 mg) or S (-) amlodipine (2.5 mg) was administered to 27 normal human volunteers. Whole-blood viscosity (WBV) at different shear rates, plasma viscosity (PV), red cell rigidity (RCR), red cell aggregation (RCA), hematocrit (Hct), plasma hemoglobin, along with plasma drug concentration were determined at time intervals, t = 0, 4, 8, 12, and 24 h. Statistically significant reductions were observed at tmax = 4 h in WBV at shear rates of 0.512 s-1 (p < 0.005), WBV at shear rates of 5.26 s-1 (p < 0.01), PV (p < 0.05), and Hct (p < 0.01). At t = 8 h, as drug concentration reduced, some of the changes persisted and later slowly decreased with the decreasing drug concentration till t = 24 h. Red blood cell-related parameters such as RCA and RCR remained unaltered. WBV values at all shear rates, when corrected for Hct = 0.45, did not show deviation from their original values at any time. CONCLUSIONS: Amlodipine causes a reduction in Hct and blood viscosity, along with hemodilution. These effects persist as long as the drug remains in plasma. Edema resulting from chronic dosing may be explained by the aforementioned effects. It is possible that antihypertensive action of the drug may be due to a combination of vasodilatation and an improvement in the HR properties.

A decrease in effective diameter of rat mesenteric venules due to leukocyte margination after a bolus injection of pentoxifylline--digital image analysis of an intravital microscopic observation.

The ability of leukocytes to adhere to endothelial cells (EC) and then to migrate out of the blood stream into tissues enable them to perform their surveillance functions. Adhesion of leukocytes to EC is, however, only possible if the cells have marginated as a result of rheological interaction with other blood cells in flow. Using Pentoxifylline (PTX), a rheologically active drug, to manipulate this interaction, we have imaged and quantified this margination phenomenon in vivo. A system has been developing to perform this imaging via an intravital microscope connected to an image processing system. Albino rats were anesthetized and cannulated for intravenous bolus injection (0.5 ml) of PTX (1.25 mg/ml) through the femoral vein. A longitudinal incision exposed the mesentery, part of which was observed under microscope to visualize microcirculation. The image of interest was then stored on computer hard drive. Individual leukocyte velocities were determined before and after PTX infusion. The leukocytes, marginating and sticking after PTX infusion either remained attached, constituting the peripheral marginating leukocyte pool in the postcapillary venules, or detached with different step velocities. The reduction in effective venular diameters as a result of leukocyte margination was estimated to be 32-44%. These results demonstrate the biological importance of hemodynamic displacement leading to docking, adhesion, rolling and migration processes of leukocytes in blood.

Association of hemorheological parameters and risk of stroke in hypertensives of Indian origin.

The blood viscosity parameters of one hundred and fifty cases of WHO grade I and II hypertension of Indian origin, on treatment with calcium antagonists, were measured and a six-monthly follow up was conducted for a period of three years. The whole blood viscosity (WBV), plasma viscosity (PV), red cell rigidity (RG) and hematocrit (Hct) were monitored. Occurrence of stroke was considered as the outcome variable and it was observed that sixteen cases of stroke occurred during the follow up period (10.7% incidence). After excluding known risk factors of age, sex, addictions, blood pressure levels, cholesterol levels and underlying diseases, it was observed that an increased whole blood viscosity > 6 centiPoise was associated with an increased risk of stroke (Relative risk 2.9, 95% confidence interval 2.2 to 3.7). An increased red cell rigidity in a hypertensive patient was found to be an independent risk factor for stroke. Patients with red cell rigidity greater than 4 had 4 times (Relative risk 3.6, 95% confidence interval 3.2 to 4) higher risk of stroke as compared with patients with red cell rigidity levels less than 4. Treatment with drugs modifying the rheological profile and aiming at improving the red cell deformability should thus be considered in hypertensive patients in an attempt to prevent the occurrence of stroke.

Analysis of dynamic surface properties of therapeutic surfactants and lung phospholipids.

Exogenous surfactant is a specialized biomaterial used for substitution of the lipoprotein mixture normally present in lungs--pulmonary surfactant. Respiratory Distress Syndrome is a disease of preterm infants mainly caused by a deficiency of mature lung surfactant. Pulmonary surfactant is known to stabilize small alveoli and prevent them from collapsing during expiration due to its unique surface properties. A pulsating bubble surfactometer was used for in vitro analysis of surface parameters of therapeutic surfactants and of test formulations to be used for exogenous therapy in Respiratory Distress Syndrome. Surface parameters that were considered for comparison were minimum surface tension (gamma(min)) at three different frequencies (20, 40 and 60 cpm), adsorption at two extreme bubble radii (Rmin and Rmax), stability index at the three frequencies, recruitment index and the surface viscoelastic parameters. Survanta, ALEC and Exosurf were compared with formulations consisting of the main phospholipids of pulmonary surfactant, namely dipalmitoyl phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) as well as binary mixtures of these phospholipids in the ratio 2:3. Survanta performed much better than the non-protein therapeutic surfactants in all parameters and at all three frequencies. Exosurf had a very low stability index and a very low modulus of surface dilatational elasticity at all three frequencies. The test compounds showed a frequency dependence in their performance. At 20 cpm, PC:PG (2:3) was the best test combination. It achieved a gamma(min) and stability index equivalent to Survanta at this frequency. None of the test compounds were comparable to Survanta at 40 and 60 cpm. These findings may have important therapeutic implications for exogenous surfactants.

Thromboviscometry as a tool for evaluation of thrombotic risk in systemic hypertension.

In the present study, thromboviscometry was used to analyse the dynamic coagulation of blood in patients with severe systemic hypertension. Fibrinogen levels and whole blood viscosity, corrected for 45% haematocrit, were also monitored. The efficacy of thromboviscometry as an adjunct diagnostic tool, for determination of thrombogenic potential, was compared with that of detection of fibrinogen levels in the blood. Twenty-five cases of severe systemic hypertension (HT) in the 40 to 50-year age group were compared with 50 age and sex-matched normal controls (NC). The changes in whole blood viscosity were monitored with time at a constant shear rate, in a concentric cylinder viscometer, during the clotting process. The total thrombus formation time was significantly less in the HT group when compared with NC (238.9 +/- 38.72 s vs 315.1 +/- 32.93 s, P < 0.0005). The time required for a sudden increase in viscosity during clotting was also significantly lower in the HT group (205.9 +/- 34.37 s vs 272.9 +/- 28.83 s, P < 0.0005) and the overall rate of increase of thrombus viscosity was significantly higher in HT (245.2 +/- 36.44 centiPoise/s vs 183.6 +/- 16.32 centiPoise/s, P < 0.0005). There was, however, no significant change in the fibrinogen levels of the two groups. Thus, thromboviscometry was a more sensitive indicator of the thrombogenic potential of blood in HT than fibrinogen levels. The increased thrombogenic potential of hypertensive blood could be due to acceleration of the initial part of the coagulation process during the activation of factor Xa and the formation of thrombin.

Exogenous surfactant therapy and mucus rheology in chronic obstructive airway diseases.

Exogenous surfactant is a specialized biomaterial used for substitution of the lipoprotein mixture normally present in the lungs-pulmonary surfactant. Respiratory Distress Syndrome is a disease of preterm infants mainly caused by pulmonary immaturity as evidenced by a deficiency of mature lung surfactant. Pulmonary surfactant is known to stabilize small alveoli and prevent them from collapsing during expiration. However, apart from alveoli, surfactant also lines the narrow conducting airways of the tracheobronchial tree. This paper reviews the role of this surfactant in the airways and its effect on mucus rheology and mucociliary clearance. Its potential role as a therapeutic biomaterial in chronic obstructive airway diseases, namely asthma, chronic bronchitis, and respiratory manifestations of cystic fibrosis, are discussed. This paper also attempts to elucidate the exact steps in the pathogenic pathway of these diseases which could be reversed by supplementation of exogenous surfactant formulations. It is shown that there is great potential for the use of present day surfactants (which are actually formulated for use in Respiratory Disease Syndrome) as therapy in the aforementioned diseases of altered mucus viscoelasticity and mucociliary clearance. However, for improved effectiveness, specific surfactant formulations satisfying certain specific criteria should be tailor-made for the clinical condition for which they are intended. The properties required to be fulfilled by the optimal exogenous surfactant in each of the above clinical conditions are enumerated in this paper.

Effects of clove oil-phospholipid mixtures on rheology of gum tragacanth - possible application for surfactant action on mucus gel simulants.

The present study evaluates the effectiveness of specialised biomaterials consisting of clove oil- phospholipid mixtures as possible substitute surfactants in diseases of altered mucus viscosity by studying their effect on the viscosity of mucus gel simulants in vitro. Test surfactants consisting of phospholipid-clove oil mixtures in the ratio of 1 part of oil to 9 parts of phospholipid were prepared. The phospholipids used were dipalmitoyl phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) and binary mixtures of PC: PE and PC: PG in the ratio of 2 parts of PC to 3 parts of PE or PG. The effects of the phospholipid-clove oil mixtures on the viscosity of mucus gel simulant (MGS: a polymeric gel consisting predominantly of gum tragacanth and simulating respiratory mucus), was studied by application of steady shear rates ranging from 0.512 to 51.2/s in a concentric cylinder viscometer at 37 degrees C. The change in MGS viscosity, after incubation with surfactants, was found to have a non-Newtonian character and to follow the power law model with R2 values >0.8. The addition of clove oil-phospholipid mixtures caused a decrease in the MGS viscosity when compared with the effect of the phospholipid alone at low shear rates in case of PC, PG and PCPG. The combination of PC : PG with clove oil caused ratios of change in MGS viscosity < 1 i.e., caused a decrease in the MGS viscosity. PC: PG with clove oil was capable of lowering MGS viscosity and should be further researched as possible therapies for diseases of altered mucus rheology.

Effects of exercise on rheological and microcirculatory parameters.

The physiological changes occurring during exercise and its possible consequences have been receiving considerable attention lately. In this paper, we studied the changes in hemorheological and microcirculatory parameters, before and after the exercise, in the subjects undergoing mild exercise (n = 20). A cycle ergometer adjusted at 2.5 kilopounds was used for 15 minutes. The whole blood viscosity showed a significant increase after exercise at all shear rates (0.512-51.2/s) except at the high shear rate (94.5/s). However, the significant level was more (P < 0.005) at low shear rates (0.512-4.39/s). A significant elevation in plasma viscosity was observed after the exercise (P < 0.0008). Red cell rigidity showed a significant increase after the exercise (P < 0.001) while red cell aggregation and hematocrit failed to show any significant change. Microcirculatory studies showed a significant increase in the basal perfusion level after exercise (P < 0.0002) when compared to the resting state value. There was a significant decrease in reactive hyperaemia perfusion index after exercise (P < 0.0007). Hence, it is evident from this study that short-term exercise significantly alters hemorheological and microcirculatory parameters.

Hemorheological changes in nephrotic syndrome.

Hemorheological parameters of childhood nephrotic syndrome cases, in relapse and remission (n = 60 in each group), were studied and their results were compared with those of an equal number of age and sex matched normal children free from any renal disease. During relapse, it was noticed that the viscosity parameters, viz. plasma viscosity, red cell rigidity and whole blood viscosity, were deranged when compared to the values obtained in the remission period. These observations were statistically analyzed using t-test with the level of significance p = 0.05. It was also noted that serum/plasma biochemistry played an important role with regards to the fluidity of blood. During relapse period, fibrinogen level was significantly high, which persisted at a high level even during remission when compared to normal controls. The high cholesterol and triglyceride levels during relapse were responsible for a high plasma viscosity, increased red cell rigidity and thereby contributed directly to a marked increase in whole blood viscosity. Total protein and albumin levels were significantly decreased during relapse when compared to remission period. Hence, hemorheological parameters can be used for early detection of cases prone to relapse and could be of prognostic significance.

The diagnostic relevance of red cell rigidity.

Red cell rigidity is an important hemorheological parameter determining the passage of erythrocyte through narrow capillaries and the reduction of blood viscosity under high shear rates. The changes in red cell rigidity in various diseases of altered blood flow - hypertension (HT), diabetes mellitus (DM), myocardial infarction (MI) and cerebrovascular accidents (CVA), using equal sample sizes of 25 each, have been analysed in this paper. One of the essential elements of red cell rigidity is the structural and functional properties of erythrocyte membrane which, in turn, is determined by the membrane biochemistry. Since cholesterol-rich erythrocytes have increased rigidity, the serum cholesterol and triglycerides levels have been monitored in order to detect the extent to which they affect red cell rigidity. No significant change in red cell rigidity have been found in CVA. RBC rigidity is found to be significantly increased in the other diseases. Significant increase in triglyceride levels have been found in all the diseases studied. Cholesterol levels were significantly increased in all diseases except CVA. Hence, increased cholesterol levels have been found to consistently cause a simultaneous increase in RBC rigidity. Triglycerides levels, on the other hand, have not shown a consistent change with changes in RBC rigidity, but have been shown to be a more sensitive marker for early detection of diseased status.

Hemorheological parameters for biocompatibility evaluation.

Biomaterials have been extensively used for various clinical applications. Since blood is very sensitive to the presence of any foreign substances, testing for hemocompatibility is a major part of biocompatibility evaluation. At present, blood viscosity parameters are being used as screening tests for biomaterial compatibility. Successful use of these parameters will help eliminate many incompatible materials from being subjected to extensive testing. In this study, we evaluated the blood viscosity parameters (n = 10)--whole blood viscosity, plasma viscosity, red cell rigidity, hematocrit, and biochemical parameters (total proteins and albumin). A significant increase in hemorheological parameters after incubation with material was found to be an indicator of incompatibility.

Hemorheological changes in blood transfusion-treated beta thalassemia major patients.

Beta thalassemia major is an inherited impairment of haemoglobin structure, in which there is partial or complete failure to synthesize a specific type of globin chain. The study was undertaken to assess the hemorheological changes in beta thalassemic major patients. We studied hemorheological parameters in thalassemic patients (n = 37) immediately after blood transfusion. The parameters studied were whole blood viscosity (WBV), plasma viscosity (PV), red cell rigidity (RCR) and hematocrit (Hct). Blood samples from age-and sex-matched normal controls were also analysed for comparison. Statistical analysis was done using Student's t-test and p values were recorded. The results showed a significant decrease in level of WBV and Hct in patients when compared to normal controls. However, the red cell rigidity was higher when compared to normal controls. Increase in RCR should show an increase in WBV. But in our study cases there was a significant decrease in WBV which was probably due to the significant decrease in level of hematocrit.

Hematological aspects of biocompatibility--review article.

The development and improvement of medical devices and artificial organs is critically dependent on the realisation of the importance of the interactions between materials and body tissues. In this regard, the evaluation of biocompatibility assumes paramount importance. This paper reviews the hematological aspects of biocompatibility--the responses evoked by the material as well as the methods for their detection. The paper also mentions a few methods of improvement of material compatibility.

The response of skin microcirculation to hyperthermic stress in tumour patients.

Hyperthermia and its effect on tissues are topics of great interest to scientists working in the area of radiation biology and medicine. It has been shown by many workers, that blood flow in malignant tissue displays a different response to heating than that in normal tissue. Initially, the blood flow in tumour tissue is greater than that in normal tissue, and when heat is applied there is an increase in blood flow. The extent of the increase in flow with increasing temperature is greater in normal tissue than in tumour tissue. In our laboratory we studied the effect of temperature on skin blood flow. The skin overlying tumour tissue was compared with skin with no underlying abnormality in cancer patients, and with the skin in healthy control subjects. The instrument used was a Laser Doppler Perfusion Monitor, Pf3 (Perimed, Stockholm, Sweden). We found that the skin overlying tumour tissue showed higher basal perfusion than the skin at the contralateral site with no underlying abnormality. The skin above tumour tissue showed a reduced perfusion response to an increase in temperature (vascular sluggishness) compared to skin at the contralateral site and skin in healthy controls. The reduction in thermal response depends on the size of the tumour.

Haemorheology in diabetic foot.

A prospective study was undertaken to study the haemorheology in patients with diabetic foot lesions. Haemorheology of 30 patients with foot lesions and 30 age and sex matched controls was studied. The haemorheological parameters evaluated were whole blood and plasma viscosity and RBC filter ability. Plasma viscosity was significantly increased (p < 0.05). It substantiates the need for using rheomodulators in management of diabetic foot lesions.

Long-term assessment of efficacy and safety of L1, an oral iron chelator, in transfusion dependent thalassaemia: Indian trial.

From August 1989 to May 1991, 52 patients with transfusion dependent thalassaemia major received L1 (1,2-dimethyl-3- hydroxypyrid-4-one), the oral iron chelator, for a period of 3-21 months (mean +/- SD: 14.2 +/- 6.8). Mean (+/- SD) urinary iron excretion varied from 6.2 +/- 4.6 mg/d on 25 mg/kg/d of L1 to 42.3 +/- 37.1 mg/d on 100 mg/kg/d of L1. Mean (+/- SD) drop in S ferritin was 1465 +/- 990 micrograms/l after 5.0 +/- 0.8 months to 3641.2 +/- 2299.3 micrograms/l after 20.1 +/- 0.9 months of therapy. There was no evidence of neutropenia, thrombocytopenia, ear or eye toxicity. L1-related arthralgia, which was reversible on dose reduction or stoppage, was seen in 20 patients (38.5%), while minor gastrointestinal (GI) tract symptoms occurred in seven (3.5%) cases. We conclude that although L1 is an effective iron chelator, further studies are required to understand the mechanism of L1 related arthralgia and also to find a safer but effective dose on which incidence of L1 related arthralgia is minimal.

Hematocrit and whole blood viscosity in newborns: analysis of 100 cases.

Hematocrit (Hct) and whole blood viscosity was studied at a mean age of ten hours in 100 neonates. Group A (n = 25), were term normal newborns, Group B (n = 25) were preterms, Group C (n = 20) were term small for gestation (SGA) and Group D (n = 30) had perinatal hypoxia. Blood viscosity was estimated in all cases at shear rates 94.5, 51.2, 20.4 and 8.1 and intergroup variability in viscosity compared at shear rate 51.2. The mean hematocrit (Hct) (59.4%) and viscosity (8.2 cps) was higher in Group A as compared to other groups, but the difference was not significant (p greater than 0.05). The upper limit of viscosity in Group C (11.9 cps) was higher than in all other groups but this difference was also not significant (p greater than 0.05). With decrease in shear rates a reciprocal increase in viscosity was noted in all four groups. Seventeen neonates (17%) had polycythemia of which eight (47.5%) were SGA. Twelve per cent preterms were polycythemic. Only 3% of neonates had hyperviscosity. The mean Hct and viscosity of the 17 cases with polycythemia was 70.9 and 9.21 cps, respectively, which was significantly higher than mean Hct and viscosity of Group A (p less than 0.05). Partial exchange transfusions were done in five neonates with Hct greater than 75%, of which only one had hyperviscosity. Post-exchange viscosity was not estimated. Whereas, three neonates with polycythemia were symptomatic, none of these had hyperviscosity. A linear correlation between Hct and viscosity was observed (r = 0.67).

Blood viscosity parameter correlation with types of leukemia.

We investigated the hemorheological, hematological and biochemical parameters in 30 cases of acute lymphocytic leukemia (ALL), 21 cases of acute myelogenous leukemia (AML) and 30 cases of chronic myelogenous leukemia (CML). The parameters studied include whole blood viscosity, plasma viscosity, erythrocyte sedimentation rate (ESR), red cell filterability, hematocrit, platelet count and aggregation, fibrinogen, hemoglobin, leucocyte count, bleeding time and lactate dehydrogenase activity (LDH). In the cases of ALL we observed significant decrease in whole blood viscosity, hemoglobin, hematocrit and platelet count but an increase in plasma viscosity, fibrinogen, bleeding time and LDH activity. In the cases of AML, we observed increase in whole blood viscosity, plasma viscosity, ESR, fibrinogen, leucocyte count, bleeding time and LDH activity but decrease in the hemoglobin, hematocrit and platelet count. In the cases of CML, we observed an increase of whole blood viscosity, plasma viscosity, ESR, fibrinogen elevation but decreases in bleeding time. In all cases, red cell filterability was unaffected.