Beneficial Effect of α-Blocker on Hemorheology in Patients With Essential Hypertension

AJH

1997;10:886 – 892

Beneficial Effect of a-Blocker on Hemorheology in Patients With Essential Hypertension Tomoko Gomi, Toshio Ikeda, and Fumiaki Ikegami

To assess the effect of antihypertensive therapy on hemorheology in essential hypertension, blood viscosity and red blood cell deformability were examined in 45 patients with essential hypertension and 20 age-matched normotensive control subjects. Hypertensive patients were randomly assigned to monotherapy with five different antihypertensive drugs for 6 months and change of blood viscosity and red blood cell deformability were reexamined after the end of the monotherapy with each antihypertensive drug. Blood viscosity increased and red blood cell deformability decreased in hypertensive patients compared to normotensive control subjects. Monotherapy with each drug resulted in sufficient blood pressure control in all hypertensive patients. After the monotherapy with the a-blocker, terazosin, blood viscosity decreased significantly at

shear rates from 22.5/sec to 450/sec, and red blood cell deformability, estimated by red blood cell filtration rate, increased by 15% (from 65 6 10 to 75 6 12 mL/sec, P < .05). The decrease in blood viscosity induced by a-blocker monotherapy may relate to an improvement of red blood cell deformability. It is possible that the treatment with a-blocker has a beneficial effect on the peripheral microcirculation due to an improvement of hemorheology in patients with essential hypertension. Am J Hypertens 1997;10:886 – 892 © 1997 American Journal of Hypertension, Ltd.

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tive correlation with blood pressure levels1–3 and left ventricular mass,2,4 which indicates that a hyperviscosity state may play some role in the development of hypertension itself and hypertensive vascular complications. Several reports have indicated that decreased RBC deformability estimated by RBC filterability is involved in the hyperviscosity state of hypertension.5–9 Antihypertensive medications may alter hemorheology in hypertension, but their exact influence remains unknown.10 –15 Even though a number of antihypertensive drugs have been reported to affect hemorheological determinants in hypertensive patients, we have only limited information on the long-term effects of antihypertensive medication fol-

any alterations of hemorheological determinants have been reported in patients with essential hypertension.1–9 These include increases in blood viscosity, plasma viscosity, fibrinogen concentrations, hematocrit values, and decreased red blood cell (RBC) deformability. Blood viscosity has a significant posi-

Received June 5, 1996. Accepted December 30, 1996. From the Department of Nephrology and Health Care Center, Nippon Telegraph and Telephone (NTT) Kanto Teishin Hospital, Tokyo, Japan. Address correspondence and reprint requests to Tomoko Gomi, MD, Department of Nephrology, NTT Kanto Teishin Hospital, 5-9-22 Higashigotanda Shinagawa, Tokyo 141, Japan.

© 1997 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.

KEY WORDS:

Blood viscosity, red blood cell deformability, a-blocker, calcium antagonist, hypertension.

0895-7061/97/$17.00 PII S0895-7061(97)00095-2

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lowing a clinically relevant and properly designed study. In this study, we sought to determine whether the long-term monotherapy of antihypertensive drugs could affect the hemorheological parameters in patients with essential hypertension. METHODS Subjects This study was conducted on 45 patients (30 men and 15 women; mean age, 53.0 years) with essential hypertension and 20 age matched normotensive control subjects (10 men and 10 women, mean age 50.0 years). Hypertension was diagnosed when blood pressure measured at the outpatient clinic was .160 mm Hg systolic and 95 mm Hg diastolic on three consecutive visits at least 1 week apart after 8 weeks of placebo treatment. Patients with other causes of hypertension, manifest atherosclerotic vascular complications, glucose intolerance, and kidney or heart failure were excluded from the study. The normotensive control subjects were selected from volunteers who visited the Health Care Center for physical checkups and exhibited no abnormalities in routine laboratory tests. The nature of the study and its potential associated risks were explained to all subjects, who gave their signed, informed consent before participating in the study. The study protocol was approved by the Institutional Review Board on Human Investigations of NTT Kanto Teishin Hospital. Study Protocol Control studies were carried out during fasting over 12 h in the morning in hypertensive patients when they were taking a placebo and in normotensive control subjects. Subjects rested in the supine position in a temperature-controlled (25°C) and humidity-controlled (55%) quiet room. Blood pressure and pulse rate values used for analysis were averaged from five measurements taken every 3 min after 30 min of resting in the supine position. Following the measurements of blood pressure and pulse rate, venous blood was drawn with a minimum of stasis and anticoagulated with 12.5 U/mL sodium (Na) heparin. Within 1 h of blood sampling, the following hemorheological parameters were measured: whole blood viscosity, plasma viscosity, RBC deformability, hematocrit, plasma levels of albumin, fibrinogen, glucose, creatinine, and lipids. After basal clinical and laboratory data were taken, the hypertensive patients were divided into five groups at random and were placed on the monotherapy of five different kinds of antihypertensive drugs. The following groups were defined and treated with diuretic: trichlormethiazide (group I, n 5 9); b-blocker: atenolol (group II, n 5 9); a-blocker: terazosin (group III, n 5 9); calcium (Ca) antagonist: nicardipine (group IV, n 5

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9); angiotensin converting enzyme inhibitor (ACEI): captopril (group V, n 5 9). The dose of each antihypertensive drug was increased every 4 weeks until the diastolic blood pressure fell below 90 mm Hg. During the study, no patient was allowed to take any medication with vasoactive or rheological properties. The same measurements as in the control period were repeated after 6 months of monotherapy with each antihypertensive drug. Blood Viscosity and Red Blood Cell Deformability Blood viscosity was measured at 37°C in a WellsBrookfield Cone/Plate Viscometer (Brookfield Engineering Laboratory, Stoughton, MA), which enabled blood viscosity to be measured at eight different shear rates (2.25, 4.4, 11.25, 22.5, 45, 90, 225, and 450 per sec) and plasma viscosity was measured at a shear rate of 450/sec. The results are expressed as centipoise (millipascal z second, mPa z sec). RBC deformability was assessed by the modified RBC filtration method described by Yamaguchi et al.16 Briefly, 10 mL of blood collected in Na heparin (12.5 U/mL of whole blood) was centrifuged at 5000 rpm for 10 min. The plasma, buffy coat, and upper 5 mm of the RBC zone were removed, and replaced with N-(2hydroxyethyl) piperazine-N9-2-ethanesulfonic acid Na salt (HEPES-Na)-buffered NaCl solution (HBS: 141 mmol/L NaCl, 10 mmol/L HEPES-Na buffer, 287 mOsm/kg H2O, pH 7.4). RBC were washed twice by repeated resuspension with HBS at room temperature (22°C) and suspended in an amount giving a hematocrit of 20%. One-half milliliter of 20% RBC suspension in HBS was allowed to pass by gravity through a polycarbonate filter (Nucleopore, Cambridge, MA) with a pore size of 5 mm. The RBC filtration rate (RFR, in microliters/second) was calculated according to the formula below, after standardization of a measured passage time of 0.5 mL of HBS by its ideal passage time of 2 sec for the proper filter: RFR 5

0.5 mL 3 FT of HBS 3 1000 2 sec 3 FT of 20% RBC suspension

where FT is flow time in seconds. Analytical Methods Plasma levels of albumin, creatinine, Na, and glucose were measured by an automatic analyzer (Model H736, Hitachi, Tokyo, Japan). Fibrinogen was measured by thrombin time on a Coagrex-700 (Shimazu, Tokyo, Japan). Cholesterol and triglycerides were measured by an enzymatic technique with an automatic analyzer. High-density lipoprotein (HDL) cholesterol was measured after precipitation of low-density lipoprotein, very low-density lipoprotein, and chylomicrones with dextran sulfate, magnesium chloride, and polyethylene glycol.

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TABLE 1. CLINICAL AND LABORATORY VARIABLES IN NORMOTENSIVE CONTROL SUBJECTS AND HYPERTENSIVE PATIENTS

Age, years Men/women Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Pulse rate, beats/min Hematocrit Albumin, g/L Fibrinogen, g/L Creatinine, mmol/L Glucose, mmol/L Total cholesterol, mmol/L HDL cholesterol, mmol/L Triglycerides, mmol/L

Control (n 5 20)

Hypertensive (n 5 45)

P

50 6 3 10/10 120 6 15 76 6 9 70 6 10 0.44 6 0.08 42 6 2 2.47 6 0.29 56 6 12 5.2 6 0.5 5.2 6 0.7 1.6 6 0.2 1.4 6 0.6

53 6 9 30/15 163 6 12 103 6 9 73 6 10 0.42 6 0.04 42 6 3 2.28 6 0.68 79 6 19 5.6 6 0.6 5.3 6 0.9 1.3 6 0.4 1.6 6 1.4

NS NS ,.001 ,.001 NS NS NS NS ,.001 ,.02 NS ,.02 ,.001

Values are mean 6 SD.

Statistical Methods All data in the text, tables, and figures are expressed as mean 6 standard deviations of the mean (SD). Significant differences among groups were analyzed by one-way fractional ANOVA. Pairwise mean comparisons among groups were done by Scheffe´’s test.

cose declined significantly from 5.6 6 0.5 to 5.3 6 0.3 mmol/L in group V treated with angiotensin converting enzyme inhibitor (ACEI), captopril (P , .05). Serum creatinine decreased in all groups (P , .05), but

RESULTS Table 1 shows the clinical and laboratory variables in normotensive control subjects and hypertensive patients. Hypertensive patients had higher serum creatinine, glucose, and triglycerides and lower HDL cholesterol than control subjects. There was no difference in hematocrit or plasma fibrinogen between the two groups. Blood viscosity in hypertensive patients increased and the significant difference was over the range 4.5 to 450/sec rather than 2.25/sec compared with those of the control subjects (Figure 1). The averaged value of RFR in the hypertensive patients was 22% lower than that of the control subjects (66.2 6 21.2 v 84.8 6 15.0 mL/sec, P , .05, Figure 2). Both systolic and diastolic blood pressures decreased significantly throughout the treatment periods during 6 months of monotherapy with each antihypertensive drug. The daily dose at the end of each monotherapy was 3.3 6 1.6 mg of trichlormethiazide in group I, 54 6 9 mg of atenolol in group II, 3.5 6 2.0 mg of terazosin in group III, 52 6 19 mg of nicardipine in group IV, and 43 6 12 mg of captopril in group V, respectively. Percentage decrease in systolic and diastolic blood pressure after each monotherapy was 11.7% and 12.1% in group I, 10.8% and 14.4% in group II, 11.2% and 14.9% in group III, 16.2% and 16.2% in group IV, and 12.5% and 15.4% in group V. Pulse rate decreased significantly by 11% only in group II treated with the b-blocker, atenolol (Table 2). The fasting glu-

FIGURE 1. Blood viscosity in normotensive control subjects and hypertensive patients. Open and closed circles show normotensive control subjects and hypertensive patients, respectively. Bars denote 1 SD. * P , .05 compared with normotensive control subjects.

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no change was observed in the other variables (Table 2). Blood viscosity before treatment was identical at all shear rates from 2.25 to 450/sec (Figure 3) and plasma viscosity was the same at the shear rate of 450/sec in all treatment groups. After treatment, a significant decrease of blood viscosity was observed in group III treated with the a-blocker, terazosin, at shear rates from 22.5/sec to 450/sec (P , .05), and in group IV treated with the Ca antagonist, nicardipine, at shear rates from 2.25/sec to 22.5/sec (P , .05). There was no change of plasma viscosity after treatment in all groups. Table 3 shows the change of RFR after each antihypertensive treatment. RFR increased by 15% (from 65 6 10 to 75 6 12 mL/sec, P , .01) only in group III, indicating that an improvement of RBC deformability resulted from terazosin monotherapy. FIGURE 2. Red blood cell filtration rate (mL/sec) in normotensive control subjects and hypertensive patients. Bars denote 1 SD.

DISCUSSION It is common to find an increase of blood viscosity in patients with borderline and sustained hypertension. Many authors have emphasized the pathophysiologic

TABLE 2. MEAN LEVELS AND STANDARD DEVIATIONS OF CLINICAL AND LABORATORY VARIABLES BEFORE AND AFTER EACH ANTIHYPERTENSIVE TREATMENT Group Variables Before treatment Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Pulse rate, beats/min Hematocrit Albumin, g/L Fibrinogen, g/L Creatinine, mmol/L Glucose, mmol/L Total cholesterol, mmol/L HDL cholesterol, mmol/L Triglycerides, mmol/L After treatment Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Pulse rate, beats/min Hematocrit Albumin, g/L Fibrinogen, g/L Creatinine, mmol/L Glucose, mmol/L Total cholesterol, mmol/L HDL cholesterol, mmol/L Triglycerides, mmol/L

I

162 99 73 0.42 42 2.20 86 5.7 5.2 1.3 2.3

6 6 6 6 6 6 6 6 6 6 6

II

14 8 14 0.04 2 0.46 22 0.4 1.0 0.7 2.5

143 6 16* 87 6 8* 70 6 6 0.41 6 0.02 42 6 4 2.28 6 0.40 71 6 18* 5.6 6 0.3 5.2 6 0.7 1.4 6 0.7 1.5 6 0.9

158 104 70 0.42 42 2.21 78 5.7 5.6 1.2 1.9

6 6 6 6 6 6 6 6 6 6 6

III

15 12 6 0.04 2 0.69 12 0.6 0.7 0.3 1.3

141 6 14* 89 6 6* 62 6 3* 0.42 6 0.04 43 6 3 2.19 6 0.45 70 6 14* 6.6 6 1.6 5.7 6 0.8 1.2 6 0.3 2.7 6 1.7

161 101 72 0.42 43 2.19 70 5.6 5.4 1.3 1.7

6 6 6 6 6 6 6 6 6 6 6

IV

12 5 9 0.06 2 0.78 17 0.5 0.9 0.3 1.3

143 6 6* 86 6 6* 78 6 16 0.41 6 0.05 43 6 3 2.11 6 0.48 56 6 13* 5.4 6 0.7 5.3 6 1.0 1.4 6 0.3 1.2 6 0.7

Values are mean 6 SD. * P , .05 compared with before treatment. I, trichlormethiazide group; II, atenolol group; III, terazosin group; IV, nicardipine group; V, captopril group.

167 105 72 0.42 41 2.71 78 5.6 5.7 1.3 1.6

6 6 6 6 6 6 6 6 6 6 6

V

15 10 8 0.04 4 1.05 18 0.7 0.8 0.1 0.6

140 6 12* 88 6 4* 74 6 13 0.42 6 0.03 42 6 3 2.86 6 1.03 69 6 22* 5.5 6 0.8 5.8 6 1.3 1.6 6 0.5 1.7 6 0.7

160 104 69 0.43 43 2.21 88 5.5 5.1 1.3 1.8

6 6 6 6 6 6 6 6 6 6 6

9 11 9 0.04 3 0.31 27 0.5 0.8 0.3 0.7

140 6 13* 88 6 7* 66 6 9 0.44 6 0.03 43 6 2 2.34 6 0.50 71 6 18* 5.3 6 0.3* 5.1 6 0.9 1.4 6 0.4 1.8 6 1.3

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FIGURE 3. Blood and plasma viscosity before and after each treatment. Open and closed circles show blood viscosity before and after treatment, respectively. Open and closed columns show plasma viscosity before and after treatment. Bars denote 1 SD. I, trichlormethiazide group; II, atenolol group; III, terazosin group; IV, nicardipine group; V, captopril group. * P , .05 compared with before treatment.

role of increased blood viscosity on elevation of blood pressure1–9 and development of vascular complications induced by hypertension.2,4 Letcher et al1 reported that borderline hypertensive patients showed a significant increase in blood viscosity compared with that of normotensive controls. Increases in hematocrit, plasma viscosity, and plasma fibrinogen concentration were indicated as the determinant factors for increases in blood viscosity. On the other hand, Longhini et al5

reported that a significant increase of blood viscosity was seen in essential hypertensive and secondary hypertensive patients compared with that of normotensive controls without a difference in hematocrit values. Vaya´ et al6 showed that increased blood viscosity in mild essential hypertensive patients could not be attributed to increased hematocrit, because their patients’ hematocrit did not differ from normotensive control subjects. Moreover, Zannad et al7 observed an

TABLE 3. RED BLOOD CELL FILTRATION RATE (mL/sec) BEFORE AND AFTER EACH ANTIHYPERTENSIVE TREATMENT Group

Before treatment After treatment

I

II

III

IV

V

62 6 11 64 6 13

62 6 11 65 6 11

65 6 10 75 6 12*

65 6 9 57 6 13

65 6 9 62 6 14

Values are mean 6 SD. * p , .01 compared with before treatment. I, trichlormethiazide group; II, atenolol group; III, terazosin group; IV, nicardipine group; V, captopril group.

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increase in blood viscosity in patients with essential hypertension who had a lower value of hematocrit when compared with normotensive controls. Zannad et al7 suggested that hemorheological change in hypertensive patients was not only related to quantitative changes of blood, ie, plasma protein or erythrocyte concentration, but it was also a consequence of qualitative changes in the rheological characteristics of erythrocytes. An impaired RBC deformability has been repeatedly reported by a RBC filtration method or a reciprocal apparent viscosity assessed at low shear rate in patients with essential hypertension.5–9 The hemorheological findings in this study confirm previous reports in which an elevated blood viscosity is closely related to an impaired RBC deformability.5–9 Although the exact mechanisms of impaired RBC deformability in hypertension still remains unclear, some investigators propose an abnormality of transmembrane Ca ion transport17,18 or a change of the lipid component of the membrane.18,19 In this study, we compared the effects of monotherapy with five different kinds of antihypertensive drugs, such as a diuretic, b-blocker, a-blocker, Caantagonist, and ACEI, on hemorheology in patients with essential hypertension. The a-blocker terazosin decreased blood viscosity at a moderate to high shear rate. This was associated with an improvement of RBC deformability without changing other rheologic components of blood viscosity, ie, plasma viscosity, hematocrit, plasma concentration of albumin, or fibrinogen. These findings indicate that a decrease in blood viscosity induced by a-blocker monotherapy may be related to an improvement of RBC deformability. Only one report is available describing the change of blood viscosity after treatment with an a-blocker. Letcher et al10 reported that treatment with the a-blocker, prazosin, induced a decrease in blood pressure concomitant with a reduction of blood viscosity. They observed that the reduction of blood viscosity showed a significant correlation with the decrease in blood pressure and was parallel to the change of hematocrit. A similar relation between blood pressure and blood viscosity associated with decreased hematocrit was observed in the study using the centrally acting a-adrenergic receptor agonist, methyldopa.11 These results suggest that the reduction of blood viscosity after treatment with a-blocker and a-adrenergic receptor agonist is mainly related to the decrease in hematocrit induced by hemodilution resulting from these antihypertensive drugs. However, this mechanism could not explain our results, because neither a reduction of the hematocrit nor serum albumin that indicated hemodilution were observed. Moreover, the a-blocker decreased blood viscosity without change of plasma viscosity. Alternatively, it is conceivable that decreased blood viscosity after a-blocker treatment seen in this

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study is more probably a result from the improvement of RBC deformability rather than hemodilution or changes in plasma factors. The exact mechanisms by which a-blockers improve the blood viscosity associated with RBC deformability in hypertension remain to be clarified. Its effect on hemorheology, as well as on lipid metabolism20,21 and platelet function22,23 may be beneficial for the treatment of hypertension. The Ca antagonist decreased blood viscosity only at a low shear rate but showed no effect on plasma viscosity or RBC deformability in this study. Ca antagonists, which reduce a slow inward transmembrane influx of Ca ions by specific inhibition of voltage-operated Ca channels, may prevent an accumulation of intracellular Ca and theoretically induce a favorable effect on hemorheology. However, results of earlier clinical studies concerning this issue are conflicting.13,14,24,25 Monotherapy with diltiazem induced a decline of blood viscosity at low share rates of 0.7/sec and 2.4/sec along with an increase in RBC filterability.13 Slonim et al14 reported that isradipine improved RBC filterability and showed a greater effect when it was administered to patients whose RBC filterability was worse than that of others. On the other hand, Rai and Murphy24 observed that monotherapy with the Ca antagonists, isradipine and nifedipine, had no significant effect on whole blood viscosity although both drugs lowered blood pressure significantly. Moreover, Lin et al25 compared the effects of three different kinds of Ca antagonists (nifedipine, verapamil, and diltiazem) with RBC deformability in hypertensive patients. Lin et al observed no effect of any kind of Ca antagonists used in their study on RBC deformability.25 Our results demonstrated no effect of the Ca antagonist, nicardipine, on RBC deformability, which is similar to the results of Rai and Murphy24 and Lin et al.25 Unfortunately, the change of transmembrane transport or intracellular concentration of Ca ions was not measured in this study, as well as earlier studies. We cannot exclude the possibility that nicardipine used in this study itself or the dosage of this drug may have a different effect on RBC deformability. REFERENCES 1.

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