evidence of an antiplatelet aggregation action of doxazosin in patients with hypertension: an ex...

Evidence of an antiplatelet aggregation action of doxazosin in patients with hypertension: An ex vivo study

Eighteen patients with a mean age of 54.7 years were included in the study. All patients had a diagnosis of mild or moderate essential hypertension (sitting diastolic blood pressure of 96 to 114 mm Hg). The study design was single blind and in two phases: phase I, placebo (4 weeks), and phase II, the active treatment (6 weeks) with increasing doses, if needed, of doxazosin every 2 weeks (1, 2, 4, and 6 mg/day). Results show that doxazosin has an antihypertensive effect that is dose dependent. Systolic, diastolic, and mean blood pressures were decreased significantly, and no effect on heart rate was observed. Doxazosin significantly inhibited the platelet aggregation induced by epinephrine, adenosine diphosphate, and collagen in a dose-dependent manner. In addition, treatment with doxarosin lowered total serum cholesterol and triglyceride levels, without changing other standard biochemical parameters. This indicates that doxazosin could offer a distinct therapeutic advantage in the modulation of atherogenic and thromboembolic factors associated with coronary heart disease. (AM HEART J 1991;121:395-401.)

Rafael Hernandez Hernandez, MD, Jaime Roberto Guerrero Pajuelo, MD, MSc, Atiff Rafael Carvajal, MSc, Maria Cristina Armas Padilla, MD, Maria Jose Armas de Hernandez, MD, Oscar Barragan, MD, and Jose Jesus Boada Boada, MD Barquisimeto, Venezuela

The risk of complications caused by hypertension depends on several factors, including systolic (SBP) and diastolic blood pressure (DBP) levels, blood lipid levels, hyperglycemia, smoking, and others. Platelet and endothelial functions are also involved in the pathophysiology of ischemic heart disease,lV3 and several studies have reported a very high platelet ag- gregability in hypertensive patients.4s 5

By treating hypertension pharmacologically, we can reduce the incidence of cerebrovascular accidents and death, as well as preventing heart and renal fail- ure. The Framingham Heart Study has shown that in general antihypertensive drug therapy reduces cardiovascular and cerebrovascular mortality end points in patients with varying degrees of hypertension and also reduces cardiovascular complications significantly.6-8 However, antihypertensive treatment mod- ifies coronary heart disease (CHD) morbidity and mortality rates only minimally.l, g

From the School of Medicine. Universidad Centro Occidental “Lisandro Alvarado:’

Reprint requests: Rafael Hernandez Hernandez, MD, Clinical Pharmacol- ogy ITnit, School of Medicine, Universidad Centro Occidental “Lisandro Alvarado,” Barquisimeto, Venezuela.

4/O/24893

Antihypertensive drugs should reduce not only blood pressure but also the other modifiable risk factors for CHD.1° For example, doxazosin reduces blood pressure and produces a favorable effect on the serum lipid profilell-l3 and left ventricular hyper- trophy.14, l5 Hernandez et a1.16 have also reported that doxazosin (in vitro) can reduce platelet aggregation when added to plasma of hypertensive patients and normotensive volunteers.

The purpose of this study was to examine the dose-dependent relationship of the antihypertensive effect of doxazosin and its inhibitory action on platelet aggregation. A group of patients with essential hypertension was treated with increasing doses of doxazosin, and platelet aggregation was assessed ex vivo.

METHODS

Patient selection. Eighteen patients were included in a single-blind study, of which 14 were women and 4 were men, with a mean age of 54.7 years. Sitting DBP ranged between 96 and 114 mm Hg. All patients had a diagnosis of essential hypertension and received no antihypertensive therapy or drugs that could modify platelet aggregation.

Procedure. Initially all patients received placebo tablets once a day for 4 weeks to evaluate the severity of the hypertension and establish the baseline parameters. At the

395

396 Hernandez et al. January 1991

American Heart Journal

0 2

Therapy week I I

4 6 8 IO 12

Placebo Doxazosin / I

1 w 2 n-4 4 mg Daily dose

Fig. 1. Protocol.

a w

Table I. Effect of doxazosin on SBP, DBP, mean arterial pressure, and heart rate in supine, sitting, and standing positions and after exercise

Daily dose of doxazosin (mg)

Placebo 1 2 8 ANOVA (n = 18) (n = IS) (n = 181 (n I’lS) (n = 14) p 1MlLUP

167.2 _t 3.8 104.9 i 1.2 125.6 I 1.8

75.0 2 1.3

159.9 zk 4.4 103.6 + 1.2 122.4 f 2.1

80.1 2 1.3

Supine SBP DBP MAP HR

Sitting SBP DBP MAP HR

Standing SBP DBP MAP HR

After exercise SBP DBP MAP HR

155.4 i- 4.8 103.1 + 1.4 120.6 k 2.2

83.8 5 1.3

166.2 + 4.8 96.9 i 2.4

120.0 i 3.0 104.7 t 2.8

156.7 + 4.6* 96.8 t 2.0*

116.7 f 2.6* 78.7 It 1.9t

151.3 t 4.8t 98.6 + 1.91

116.2 k 2.6t 85.6 + 2.7t

146.0 k 4.8'

96.3 _t 1.7* 113.0 I 2.4*

89.3 i 2.5t

157.7 * 5.0t 88.3 It 2.2*

111.4 t 2.8* 111.2 + 3.1t

153.3 I 4.6* 96.3 k 1.9*

115.3 -t 2.5* 78.7 + 1.6t

145.1 t 5.4* 93.8 e 2.1*

110.9 t 3.0* 82.7 t 1.7

141.4 t 5.7*

93.1 + 2.2* 109.2 t 3.1’

88.4 i 1.7t

150.0 I 5.4* 81.8 i 2.4*

104.0 _t 3.1* 110.0 t 2.9t

Data are f SEM. MAP. Mean arterial pressure; HR, heart rate. *p < 0.001; tp < 0.05; statistically significant from baseline (paired t test)

end of the placebo phase, all hematologic, biochemical, and platelet aggregation tests were performed. Blood pressure and heart rate were measured weekly during the placebo phase.

Patients then received active doxazosin for 8 weeks. During the first 2 weeks of phase II, 1 mg/day doxazosin was administered orally. The dose was then adjusted upward to 2,4, and 8 mg/day at intervals of 2 weeks (Fig. 1). The dose increase was based on the patient’s tolerance and antihypertensive response. The dose of doxazosin could be increased up to 8 mg/day if sitting DBP was > 80 mm Hg;

151.3 2 4.6* 93.2 -+ 2.0'

112.6 k 2.7*

75.6 + 1.9

140.3 f 4.7* 90.1 + 2.1*

106.8 + 2.8* 81.9 t 1.7

136.2 -+ 3.7* 90.2 It 2.1*

105.6 t 2.3’ 88.0 rt 2.1+

150.9 ? 4.3* 80.5 I 2.1*

103.0 T 2.4* 107.4 I! 3.1

146.3 + 3.5* 0.0003 91.4 + 1.7* 0.000:3

109.7 i 2.2* 0.0003 70.8 t 3.91 0.25 (NS)

136.8 i X9* 86.5 -t 1.6*

103.3 i 2.2* 78.6 k 1.5

131.7 k 3.8* 83.8 z!z 2.3*

99.8 t 2.5* 84.9 + 1.6

145.1 + 4.6* 79.2 k 2.6*

102.2 AZ 3.0” 108.4 i 3.1

0.0004 ct.0004 0.0003 0.32 (NS)

0.0002 0.000” 0.0002 0.21 (NS)

0.0005 0.0004 0.0004 0.31 (NS)

a final sitting DBP I 90 mm Hg was considered a good blood pressure response.

At the end of every 2 weeks of treatment with each doxazosin dose, blood pressure, heart rate, and platelet aggregation were reevaluated. During the last week of treatment (week S), the hematologic and biochemical parameters were also measured. All values obtained at the end of each new dose were compared with the baseline values.

At each visit to the clinic, blood pressure and heart rate were measured after the patient remained supine for 3 minutes, after sitting for 1 minute and standing for 1

Volume 121 Number 1. Part 2 Platelet antiaggregatory effect of doxazosin 397

D -25 J

Fig. 2. Doxazosin-induced changes in (A) supine, (B) sitting, (C)standing, and (0) postexercise SBP, DBP, mean arterial pressure (MBP), and heart rate (HR).O, Doxazosin, 1 mg/day (n = 18); 0,2 mg/day (n = 18);

4 mg/day (n = 18); n , 8 mg/day (n = 14). *p < 0.05; **p < 0.001; Student t test for paired data.

minute, and immediately after exercising by going up and down a 20 cm step 20 times in 1 minute. In every case the patients were examined 23 + 1 hour after the last dose of doxazosin.

Platelet aggregation was determined according to the method described by Born. l7 A 20 ml blood sample was taken with an l&gauge needle and mixed with 3.8% sodium citrate at a 9:l ratio (blood/citrate). Citrated blood was centrifuged at 160 g for 10 minutes to o&ain platelet- rich plasma. The precipitate was centrifuged at 1500 g for 15 minutes to obtain platelet-poor plasma. With a digital counter the platelet-rich plasma concentration was adjusted to 300,000 platelets/Ml. To obtain aggregate curves, a Chrono-Log aggregometer with two channels (Chrono- Log Corp., Havertown, Pa.) was used. The following were used as inducers of the platelet aggregation: epinephrine, 5,10, and 30 pmol/L (Parke-Davis); adenosine diphosphate (ADP), 1, 2.5, 5, and 10 pmol/L (Sigma Chemical Co., St. Louis, MO.); and collagen, 0.5,1, and 2 pg/ml (Horm). Per- cent aggregation was estimated 5 minutes after the ag- gregant (inducer) was added.

All values obtained from the quantification of blood pressure and heart rate, as well as those obtained from the platelet aggregation, were grouped according to the doxazosin dose administered. Mean values and standard devi-

Table II. Effect of doxazosin on platelet aggregation induced by epinephrine

Percentage of platelet aggregation

Doxazosin daily dose (mg) Epinephrine AN0 VA

(hmol/L) Placebo 1 2 4 8 p value

5.0 67.88 53.31 46.11 46.48 40.32 0.0018 SE 4.9 5.2 5.9 4.7 4.5 p Value* 0.05 0.05 0.05 0.02

10.0 70.57 55.27 46.00 46.50 40.64 0.045 SE 4.5 5.2 5.4 4.7 4.4 p Value* 0.02 0.01 0.02 0.001

20.0 69.33 52.59 50.06 47.15 41.01 0.00003 SE 4.7 4.7 5.9 4.7 4.5 p Value* 0.001 0.001 0.001 0.001

*Student t test (paired), compared with placebo.

ations were determined and compared with placebo values with the Student t test (paired) and an analysis of variance (ANOVA). Mean hematologic and biochemical values obtained during the last week of treatment were compared with those obtained at the end of the placebo phase with the Student t test.

398 Hernandez et al.

Epinephrine concentration (PM)

Fig. 3. Effect of doxazosin on platelet aggregation in- ine. n , Placebo (n =18 2 mglday (n = 18); Cl,4

D, 8 mg/day (n = 14). *p IS 0.05; **p 2 0.01; ***p 5 0.001, Student t test for paired data.

RESULTS Doxazosin effect on blood pressure and heart rate. In

14 of 18 patients (78%) the dose of doxazosin was adjusted upward to 8 mg/day. In four patients (22% ) the dose of doxazosin was not increased above 4 mg/ day because the investigators considered the blood pressure control to be adequate.

Mean SBP, DBP, mean arterial pressure, and heart rate values, resting and after exercise, can be seen in Table I. During the placebo phase, the mean blood pressures of the 18 patients were 167.2 Z!Z 3.8/104.9 f 1.2 mm Hg in the supine position, 159.9 + 4.4/103.6 i- 1.2 mm Hg sitting, 155.4 f 4.8/103.1 F 1.4 mm Hg standing, and 166.2 j, 4.8196.9 I 2.4 mm Hg after exercise. At the end of the doxazosin treatment phase, the mean blood pressure for the 14 patients taking 8 mglday doxazosin was 146.3 -t 3.51 91.4 k 1.7 mm Hg, 136.8 f 3.9/86.5 s 1.6 mm Hg, 1.31.7 + 3.8/83.8 +- 2.3mmHg,and145 + 4.6/79.2 Z!Z 2.6 mm Hg in each respective position. The doxazosin-induced decreases in SBP and DBP were dose dependent (Fig. 2), and all decreases in blood pressure were statistically significant (p < 0.05). Com- paring heart rate values obtained from the different doxazosin doses with the baseline, no statistical change was observed with ANOVA (Fig. 2).

Effect of doxazosin on platelet aggregation Epinephrine. The results in Table II indicate that

doxazosin decreased baseline aggregation values when epinephrine was used as the inducer. The degree of significance of this inhibitory effect varied between p < 0.05 and p < 0.001 for the different doxazosin doses. A dose-dependent inhibitory trend was

January 1991 American Heart Journal

Table III. Effect of doxazosin on platelet aggregation induced by ADP


Dorarosin daily dose (mg) ADP ANO VA

(PmollLJ Placebo 1 2 4 8 p ua/ue

1.0 42.14 23.20 20.19 20.79 18.28 0.036 SE 7.1 6.4 5.-i 5.2 3.8 p Value* 0.001 0.001 0.001 O.(Nl

2.5 63.58 47.21 42.81 43.62 38.72 0.049 SE 5.9 7.2 5.3 5.9 .5.0 p Value* 0.05 0.02 0.02 0.001

5.0 76.02 60.44 60.83 59.90 52.49 0.0003 SE 2. 6 4.6 3.1 4.0 :3.:3 p Value* 0.001 0.005 0.001 0.001

10.0 77.91 61.65 65.53 62.28 56.90 0.0008 SE 2.5 4.3 2.7 3.1 2.8 p Value” 0.005 0.005 0.001 0.001

*Student I test (paired) compared with placebo.

also observed, particularly with the highest inducing dose of epinephrine (20 hmol/L). These can be seen clearly in Fig. 3.

ADP. Baseline platelet aggregation percentages of 42.14%) 63.58%) 76.02%) and 77.91% obtained with the use of 1,2.5,5, and 10 pmol/L ADP were also reduced significantly (p < 0.05 and p < 0.001) with the four doxazosin doses (Table III). These decreases from baseline ranged between 44.9% and 56.6% for the 1 pmol/L inducing dose and 20.9 % and 27.0 % for the 10 pmol/L inducing dose (Fig. 4).

Collagen. The three collagen doses of 0.5,1, and 2 pg/ml produced a baseline platelet aggregation of 64.68%) 71.55%) and 74.60%) as can be seen in Ta- ble IV. Doxazosin produced a decrease from baseline of between 48.5% and 52.5% in the aggregation induced with 0.5 pg/ml, 28.2 % and 42.0% in the aggregation induced by 1 fig/ml, and 19.8% and 31% in the aggregation induced by 2 pglml of collagen, corre- sponding to the 1 and 8 mg/day doses of doxazosin, respectively (Fig. 5).

Reductions in the percentage of platelet aggregation were correlated with percentage reductions in mean sitting blood pressure for each inducer and dose of doxazosin (Table V). The linear correlations were significant for ADP and epinephrine (p 5 0.02) but not for collagen at any concentration.

Effect of doxazosin on biochemical and hematologic controls. The mean values obtained in standard biochemical determinations during the placebo phase and the last week of treatment with doxazosin showed no significant variations. Treatment with doxazosin reduced the mean cholesterol concentra-

“ol”ms 121 Number 1, Part 2

Table IV. Effect of doxazosin on platelet aggregation induced by collagen


Doxazosin daily dose (mg) Collagen ANOVA Ibdm 1) Placebo 1 2 4 8 p value

0.5 64.68 33.29 27.58 33.65 30.72 0.0004 SE 3.2 6.6 5.8 5.6 4.3

p Value* 0.001 0.005 0.02 0.005 1.0 71.55 51.40 52.27 50.29 41.49 0.002

SE 2.2 6.3 5.1 5.3 4.4

p Value* 0.02 0.02 0.02 0.001 2.0 74.60 59.86 58.43 59.15 51.44 0.0006

SE 1.9 4.7 3.7 3.2 2.9

p Value* 0.002 0.001 0.001 0.001

“Student t test (paired) compared with placebo.

Table V. Correlation between reduction in platelet aggregation and reduction in mean blood pressure (Pearson’s test)

Inducer

Epinephrine (rmol/L) 10 20

ADP (rmol/L) 5

10 Collagen (@g/ml)

1 2

r Correlation coefficient

0.3878 0.2773

0.4435 0.2876

0.2049 0.1709

p Value

0.001 0.018

0.001 0.014

0.084

0.151

tion from 254.5 mg/dl (6.59 mmol/L) at baseline to 233.4 mg/dl (6.05 mmol/L) (not statistically significant) (Table VI). Mean triglyceride values were decreased significantly by 28.1% (p < 0.05), from 117.5 mg/dl (1.33 mmol/L) at baseline to 84.6 mg/dl (0.95 mmol/L). There was a decrease in total cholesterol levels in 11 of the 18 patients treated. Bleeding time was not modified in any clinically or statistically significant manner after treatment with doxazosin.

Safety profile. Toleration of doxazosin was very good. Only two patients spontaneously reported side effects; one complained of sleepiness and the other of dyspnea. In both patients these side effects disap- peared with continued treatment.

DISCUSSION

This study shows that doxazosin, taken once daily, decreased mean SBP and DBP in a dose-dependent manner, at rest and after standard exercise. Ortho- static or postexercise hypotension was not observed,

Platelet antiaggregatory effect of douazosin 399

1.0 2.5 5.0 10.0

ADP concentration (PM)

Fig. 4. Effect of doxazosin on platelet aggregation in- DP. n , Placebo (n =18) oxazosin, 1 mg/day 2 mg/day (n = 18); q ,

mg/day (n’= g/day (n = 18); IX,8

14). *p 5 0.05; **p i 0.01; ***p _( 0.001; Student t test for paired data.

- 0.5 1.0 2.0

Collagen concentratipn (yglml)

Fig. 5. Effect of doxazosin on platelet aggregation in- en. H, Placebo (n =18); 2 mglday (n = 18); Cl,

q , 8 mg/day (n = 14). *p I 0.05; **p I 0.01; ***p 5 0.001; Student t test for paired data.

thus confirming previous reports.‘“, l8 No clinically significant changes in heart rate were observed after treatment with doxazosin, thus indicating selective inhibition at postsynaptic al-receptors.lY

Doxazosin treatment inhibited the platelet aggregation induced by epinephrine, ADP, and collagen at different concentrations in a statistically significant manner. A decrease in platelet aggregation from baseline of up to 52.5% for the maximum dose of doxazosin was observed. These results agree with previously reported data, in which doxazosin added in vitro to the plasma of hypertensive patients induced a dose-dependent decrease in the platelet

400 Hernandez et al. January 1991

American Heart Journal

Table VI. Doxazosin-induced changes in serum lipid levels

Total cholesterol Triglycerides

Mean baseline values mg/dl 254.5 mmol/L 6.59

Mean value after doxazosin treatment mg/dl 233.4 mmol/L 6.05

Mean % change -8.29* p Value NS

117.59 1.33

84.60 0.96

-28.06 < 0.05

*Levels of total cholesterol decreased in 11 of 18 (61%) patients, with a statistically significant (p 5 0.05) mean reduction from baseline of lgO<.

aggregation at concentrations similar to those obtained ex vivo after receiving doses of 1 to 8 mgfday doxazosin.16 Furthermore, this is also in accordance with a study by Ikeda et a1.,20 in which prazosin (an al-adrenergic inhibitor) normalized platelet function in patients with essential hypertension by reducing the &thromboglobulin values in these patients,

One should consider that the effect on platelet aggregation may be only partially dependent on the degree of blood pressure reduction, because Pearson’s r correlation coefficients range from 0.2773 to 0.4435 for ADP and epinephrine, according to the different concentrations of inducers. This suggests that reduction in blood pressure may be a factor that influences the degree of doxazosin- induced inhibition of platelet aggregation, as has been suggested by Ikeda et alzO in their studies with prazosin. However, no correlation between reduction in blood pressure and platelet aggregation was found for collagen, and that for ADP and epinephrine was not that strong.

Furthermore, doxazosin-induced inhibition of platelet aggregation has also been demonstrated in vitro (i.e., in the absence of blood pressure reduction).rG Thus aside from the inhibitory effect on the al-adrenergic receptors, doxazosin could also act through other mechanisms at the platelet level (e.g., interaction with the level of cyclic adenosine mono- phosphate or the entry of calcium ions). This would seem reasonable because doxazosin inhibits not only the platelet aggregation induced by epinephrine but also platelet aggregation induced by ADP and collagen. Because the inhibition of platelet aggregation observed is dose dependent, this suggests the involve- ment of a specific, rather than a nonspecific, pathway.

Drugs that inhibit platelet aggregation (e.g., aspirin) have been shown to decrease the incidence of myocardial infarction in primary prevention.21 Ticlopidinez2 has been shown to reduce the number of thromboembolic accidents and the incidence of

myocardialinfarctioninsecondaryprevention.Hence drugs such as doxazosin that control not only blood pressure but also reduce platelet aggregation could be very useful in the treatment of hypertension and the prevention of further complications, such as CHD or cerebral thromboembolic accidents.

Treatment with doxazosin produced statistically significant reductions in mean triglyceride levels and a nonsignificant reduction in total cholesterol levels. These results agree in part with those reported by Poo12” and Trost et al 24 who found that treatment with doxazosin for 52 and 24 weeks, respectively, significantly reduced serum levels of total cholesterol and triglycerides. It may be possible that in this study a statistically significant reduction in total cholesterol level was not seen because of the small sample size and very short treatment time (8 weeks). Reduc- tions in individual cholesterol values were evident in 11 of the 18 patients, with a mean 19% decrease for this group of 11 patients. As an antihypertensive agent, doxazosin offers a therapeutic advantage because it reduces the coronary risk associated with high levels of cholesterol and triglycerides. Indeed, for every 1% decrease in total cholesterol levels there may be a 2% reduction in the rate of CHD, as reported by the Lipid Research Clinic’s Coronary Primary Prevention Tria1.2’

CONCLUSIONS

The following conclusions can be drawn: (1) Dox- azosin exerted a dose-dependent antihypertensive effect in patients with mild or moderate essential hypertension. No significant effect on heart rate was seen, thus confirming the al-adrenergic receptor se- lectivity. (2) Treatment with doxazosin significantly reduced platelet aggregation induced by epinephrine, ADP, and collagen. (3) Doxazosin produced a significant decrease in serum triglyceride levels and a reduction in total cholesterol levels. (4) The antihypertensive effect, the ability to inhibit platelet aggregation, and the favorable effect on cholesterol and triglyceride levels could represent a therapeutic advantage; doxazosin could favorably modify the risk factors associated with thromboembolic disorders and CHD.

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evidence of an antiplatelet aggregation action of doxazosin in patients with hypertension: an ex...

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