Eur J Clin Pharmacol (1991) 41:4749 003169709100169R © Springer-Verlag 1991
A lack of effect of captopril on platelet aggregation in patients with congestive heart failure I. E Gow, A. D. Flapan, M. Morris, E. Davies, B. C. Williams, P. L. Padfield, T. R. D. Shaw, and C. R. W. Edwards Departments of Medicine and Cardiology, Western General Hospital, Edinburgh EH4 2XU, UK Received: December 12, 1990/Accepted in revised form: February 20, 1991
Summary. We have studied the acute and chronic effects of an A C E inhibitor (captopril) on platelet function and the renin-angiotensin system in patients with congestive heart failure. Plasma concentrations of angiotensin II fell significantly after a single dose of captopril (25 mg) and during long-term treatment with captopril (2 weeks, 75 mg/day). Plasma renin activity increased significantly after both the single and repeated doses. Captopril did not affect A D P - i n d u c e d platelet aggregation or concentrations. It seems unlikely that circulating angiotensin II affects A D P - i n d u c e d platelet aggregation in patients with congestive heart failure. Key words: Captopril, Blood platelets; angiotensin Ii, 5hydroxytryptamine, platelet aggregation
Angiotensin II modulates platelet function in vitro: low concentrations (e.g. 10 12 mol. 1-1) potentiate, whereas high concentrations (e. g. 10-7 mol. 1-1) inhibit the aggregation response [1, 2]. Similarly, reducing plasma angiotensin II concentrations in vivo by increasing the normal sodium intake results in an increase in platelet aggregation in vitro c o m p a r e d with a low-sodium diet (i. e. high concentrations of angiotensin II) in healthy m e n [3] and w o m e n [4]. There is also a reduction in plasma angiotensin II during treatment with the angiotensin-converting enzyme ( A C E ) inhibitor captopril [5]. In recent studies of patients with essential hypertension [6, 7] long-term captopril therapy resulted in a decrease in platelet aggregation in vitro. However, captopril also inhibits the b r e a k d o w n of bradykinin [8], a peptide which can stimulate the production of prostaglandins [9], some of which may have anti-aggregatory effects on platelet function (e. g. PGI2) [10, 11]. It has been suggested [6] that this decrease in aggregation may have b e e n due to an increase in prostaglandin production, since the addition of captopril in vitro had no direct effect on platelet aggregation.
Therefore, since platelets from patients with heart disease may be m o r e activated than normal platelets [e. g. 12, 13], and since A C E inhibitors are now used routinely to inhibit the production of angiotensin II in the treatment of heart failure, we have investigated the effect of captopril therapy on in vitro platelet aggregation in patients with congestive heart failure (CHF). Platelet and total 5hydroxytryptamine (5-HT) concentrations were also measured, since these reflect the degree of platelet activation in vivo [14].
Patients and methods We studied ten male patients with CHF (NYHA Classes III or IV) from out-patients attending the Cardiac Clinic of the Western General Hospital, Edinburgh. None of the patients had taken any drugs with proven anti-platelet effects for at least 10 days before the first study day. The cause of heart failure was ischaemic heart disease in all cases. All of the subjects had failed to respond to conventional diuretic therapy and would therefore be requiring further clinical intervention. The patients were supine for 30 min before venesection and blood was taken from the antecubital vein. Blood samples for aggregation studies and 5-HT analysis were taken immediately before captopril treatment, 1 and 4 h after a single oral dose (25 mg; E. R. Squibb & Sons, Hounslow, Middlesex, UK), and finally after two weeks of captopril therapy as out-patients (25 mg t. i. d.), during which time the patients resumed their normal activities. Since the maximum h aemodynamic effects of captopril are known to occur approximately I h after an oral dose [15], and in order to minimize the volume of blood removed from the patients, blood was taken for measurement of angiotensin II and plasma renin activity (PRA) at i h and 2 weeks only. The patients continued to take a diuretic throughout the trial period (frusemide 40-80 mg per day). For the 5-HT and aggregation studies, blood was collected into acid-citrate-dextrose (ACD) to prepare platelet-rich plasma (PRP) as previously described [16]; to minimize the volume of blood taken, only one aggregating agent was studied, adenosine diphosphate (ADP). We chose ADR since in aprevious study of the effects of captopril the most significant change in aggregation was obtained with ADP at a single concentration of 4 gmol. 1 1[6], and also since ADP is a major contributor to haemostatic events in vivo [17]. 5-HT concentrations were measured in samples of PRP by highpressure liquid chromatography with electrochemical detection [16], and in vitro platelet aggregation studies were performed using
I. E Gow et al.: Captopril and platelet aggregation
48
',-
A D P (Fig. 2). T h e r e were no changes in 5 - H T concentrations either w h e n expressed as nmol.1- ~ P R P or after correction for platelet n u m b e r (Fig. 3).
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T tO
s 10
E
4
0 f
A lack of effect of captopril on platelet aggregation in patients with congestive heart failure I. E Gow, A. D. Flapan, M. Morris, E. Davies, B. C. Williams, P. L. Padfield, T. R. D. Shaw, and C. R. W. Edwards Departments of Medicine and Cardiology, Western General Hospital, Edinburgh EH4 2XU, UK Received: December 12, 1990/Accepted in revised form: February 20, 1991
Summary. We have studied the acute and chronic effects of an A C E inhibitor (captopril) on platelet function and the renin-angiotensin system in patients with congestive heart failure. Plasma concentrations of angiotensin II fell significantly after a single dose of captopril (25 mg) and during long-term treatment with captopril (2 weeks, 75 mg/day). Plasma renin activity increased significantly after both the single and repeated doses. Captopril did not affect A D P - i n d u c e d platelet aggregation or concentrations. It seems unlikely that circulating angiotensin II affects A D P - i n d u c e d platelet aggregation in patients with congestive heart failure. Key words: Captopril, Blood platelets; angiotensin Ii, 5hydroxytryptamine, platelet aggregation
Angiotensin II modulates platelet function in vitro: low concentrations (e.g. 10 12 mol. 1-1) potentiate, whereas high concentrations (e. g. 10-7 mol. 1-1) inhibit the aggregation response [1, 2]. Similarly, reducing plasma angiotensin II concentrations in vivo by increasing the normal sodium intake results in an increase in platelet aggregation in vitro c o m p a r e d with a low-sodium diet (i. e. high concentrations of angiotensin II) in healthy m e n [3] and w o m e n [4]. There is also a reduction in plasma angiotensin II during treatment with the angiotensin-converting enzyme ( A C E ) inhibitor captopril [5]. In recent studies of patients with essential hypertension [6, 7] long-term captopril therapy resulted in a decrease in platelet aggregation in vitro. However, captopril also inhibits the b r e a k d o w n of bradykinin [8], a peptide which can stimulate the production of prostaglandins [9], some of which may have anti-aggregatory effects on platelet function (e. g. PGI2) [10, 11]. It has been suggested [6] that this decrease in aggregation may have b e e n due to an increase in prostaglandin production, since the addition of captopril in vitro had no direct effect on platelet aggregation.
Therefore, since platelets from patients with heart disease may be m o r e activated than normal platelets [e. g. 12, 13], and since A C E inhibitors are now used routinely to inhibit the production of angiotensin II in the treatment of heart failure, we have investigated the effect of captopril therapy on in vitro platelet aggregation in patients with congestive heart failure (CHF). Platelet and total 5hydroxytryptamine (5-HT) concentrations were also measured, since these reflect the degree of platelet activation in vivo [14].
Patients and methods We studied ten male patients with CHF (NYHA Classes III or IV) from out-patients attending the Cardiac Clinic of the Western General Hospital, Edinburgh. None of the patients had taken any drugs with proven anti-platelet effects for at least 10 days before the first study day. The cause of heart failure was ischaemic heart disease in all cases. All of the subjects had failed to respond to conventional diuretic therapy and would therefore be requiring further clinical intervention. The patients were supine for 30 min before venesection and blood was taken from the antecubital vein. Blood samples for aggregation studies and 5-HT analysis were taken immediately before captopril treatment, 1 and 4 h after a single oral dose (25 mg; E. R. Squibb & Sons, Hounslow, Middlesex, UK), and finally after two weeks of captopril therapy as out-patients (25 mg t. i. d.), during which time the patients resumed their normal activities. Since the maximum h aemodynamic effects of captopril are known to occur approximately I h after an oral dose [15], and in order to minimize the volume of blood removed from the patients, blood was taken for measurement of angiotensin II and plasma renin activity (PRA) at i h and 2 weeks only. The patients continued to take a diuretic throughout the trial period (frusemide 40-80 mg per day). For the 5-HT and aggregation studies, blood was collected into acid-citrate-dextrose (ACD) to prepare platelet-rich plasma (PRP) as previously described [16]; to minimize the volume of blood taken, only one aggregating agent was studied, adenosine diphosphate (ADP). We chose ADR since in aprevious study of the effects of captopril the most significant change in aggregation was obtained with ADP at a single concentration of 4 gmol. 1 1[6], and also since ADP is a major contributor to haemostatic events in vivo [17]. 5-HT concentrations were measured in samples of PRP by highpressure liquid chromatography with electrochemical detection [16], and in vitro platelet aggregation studies were performed using
I. E Gow et al.: Captopril and platelet aggregation
48
',-
A D P (Fig. 2). T h e r e were no changes in 5 - H T concentrations either w h e n expressed as nmol.1- ~ P R P or after correction for platelet n u m b e r (Fig. 3).
20
10 8
T tO
s 10
E
4
0 f
