Platelet Angiotensin II in Cerebrovascular Accident and the Effect of Angiotensin-converting Enzyme Inhibitors M
HAYAKAWA
Department of Geriatrics, Nagoya University School of Medicine, Nagoya City, Japan
Platelet angiotensin II concentrations were significantly (P < 0.01) elevated in 16 patients with a history of cerebral infarction, compared with 12 control subjects. The angiotensin-converting enzyme inhibitors, captopril, enalapril and delapril hydrochloride, were evaluated in 20 hypertensive patients with a history of cerebral infarction. Each agent was administered orally each day for 12 weeks using an open randomized crossover design. After 4 weeks' treatment, 75 mg/kg captopril significantly (P < 0.01) increased platelet angiotensin II concentrations and the increase was maintained for a further 8 weeks. Treatment with 5 mg/day enalapril resulted in no significant change in angiotensin II. Treatment with 30 mg/day delapril hydrochloride significantly (P < 0.05) decreased platelet angiotensin II concentrations at 4 weeks and the change persisted for 12 weeks (P < 0.01). During delapril hydrochloride treatment platelet angiotensin II concentrations approached normal values. It is concluded that delapril hydrochloride may be used to treat patients with arteriosclerosis disorders and may inhibit the tendency for atherosclerotic changes and thrombosis. KEY WORDS: ENALAPRIL; CAPTOPRIL; DELAPRIL; CEREBRAL INFARCTION; PLATELET ANGIOTENSIN
II
289
INTRODUCTION verified by computerized tomography of the brain 3 months before the study. None of the subjects had received any medication in the 2 weeks before the study.
Angiotensin II, a vasoactive peptide, plays an important role in the maintenance of fluid homeostasis and blood pressure, and in the regulation of blood flow in various vascular beds.' Angiotensin-converting enzyme (ACE) is localized in the endothelial cells of many mammalian tissues, 2 as well as in the kidney," intestine! brain,' cultured human monocytes" and platelets.' The platelets interact with the vascular endothelium during local processes such as haemostasis and inflammation, but the precise role of platelet angiotensin II in this interaction is unclear. In the present studies the role of platelet angiotensin II in patients with thrombotic disorders was examined and evaluation was made of the effects of three different ACE inhibitors administered orally on the angiotensin II content of platelets: captopril (1- [(2 S)-3-mercapto-2 -methyl propionyl]-Lproline); enalapril ([N-[(S)-l-ethoxycarbonyl3-phenylpropyl]-L-alanyl]-L-proline maleate); and delapril hydrochloride (N-[N-[N-[(S)-lethoxycarbonyl-3-phenyl propyll-t-alany1] -N(indan-2-yl)]glycine hydrochloride) were studied.
EFFECTS OF ACE INHIBITORS. A total of 20 hypertensive patients with cerebral infarction and no other medication history before or during treatment with ACE inhibitors were studied. Patients were defined as hypertensive if systolic blood pressure was greater than 160 mmHg and/or diastolic blood pressure was greater than 95 mmHg measured twice in resting position prior to enrolment. Selection was made according to the criteria used in patients in whom platelet angiotensin II concentrations were determined.
STUDY DESIGNS DETERMINA nON OF ANGIOTENSIN II. Blood for measurement of angiotensin II concentrations was drawn from an antecubital vein of supine subjects into tubes containing 3.18% sodium citrate as the anticoagulant. In patients with a history of previous cerebrovascular accident, blood samples were obtained 12 weeks after the event. Platelet angiotensin II was measured using a modification of the method of Ferri et al" A 1 ml blood sample was centrifuged for 13 min at 130 g to obtain platelet-rich plasma. This was further centrifuged for 10 min at 900 g and washed three times with Tris buffer (0.5 mM, pH 7.4) to obtain platelet pellets. The pellets obtained from 1 ml blood were resuspended in Tris buffer and the count confirmed as 431000 ± 31 OOO/mm" by the method of Preibisz et aI.'I This suspension was sonicated to obtain platelet lysate and centrifuged, and the supernatant was used for the radio-immunoassay of angiotensin II. W The concentration of angiotensin II is given in
PATIENTS AND METHODS PATIENTS All subjects provided written informed consent before enrollment. DETERMINA TION OF ANGIOTENSIN II. Subjects were evaluated in three groups: 12 healthy controls (mean age 73.2 ± 2.3 years), 16 patients with a prior (more than 3 months before the study) cerebral infarction (mean age 74.1 ± 3.1 years) and 14 patients with cerebral bleeding (mean age 73.8 ± 2.9 years). Patients with cerebrovascular accidents all had a history of typical onset, course, signs and symptom of stroke that had also been
290
patients with cerebral bleeding. Mean blood pressure in the healthy patients was 138 ± 6/ 72 ± 4 mmHg compared with 136 ± 5/78 ± 2 and 140 ± 4/80 ± 6 mmHg, respectively, in patients with cerebral infarction and cerebral bleeding. There was no significant correlation between platelet angiotensin II concentration and blood pressure in any group.
pg/ml of platelet suspension (platelet count of 431 OOO/mm'). EFFECTS OF ACE INHIBITORS. In an open, randomized crossover manner the 20 hypertensive patients each received 75 mg/day captopril, 5 mg/day enalapril and 30 mg/day delapril hydrochloride taken orally for 12 weeks with a 4-week washout period between treatments. Blood was sampled immediately before therapy and again after 4, 8 and 12 weeks of drug administration, and platelet angiotensin II concentrations were determined. The sodium intake of the patients was maintained at 120 mmol/day.
EFFECT OF ACE INHIBITORS The mean blood pressure of the patients included in this study was 176 ± 8.6/98 ± 2.4 mmHg. In the 20 patients given captopril in the randomized crossover study, the mean platelet angiotensin II concentration was significantly (P < 0.05) increased from pretreatment concentrations after 4 weeks and remained elevated (P < 0.01) throughout the 12-week study period (Fig. 2). With the administration of delapril hydrochloride, the mean platelet angiotensin II concentration was significantly (P < 0.01) decreased at 4 weeks and remained so for 12 weeks. The administration of enalapril produced no significant effect on platelet angiotensin II concentrations. During the washout periods, platelet angiotensin II concentrations returned to pretreatment values.
STATISTICAL METHODS Data are expressed as means (± SD). Student's t-test was applied to determine the significance of differences between groups; the level of significance was set at P < 0.05.
RESULTS PLATELET ANGIOTENSIN II CONCENTRA TIONS A total of 16 patients with cerebral infarction had an occlusion of the middle cerebral artery and showed no electrocardiographic abnormalities. Blood chemistry and blood coagulation parameters were within normal limits. Examination of the carotid artery by Xrays revealed no atheromatous lesions; thus, in most patients, the stroke diagnosis was thrombosis of the middle cerebral artery due to arteriosclerosis. The mean platelet angiotensin II concentration was 11.2 ± 2.3 pg/ml in healthy subjects, 19.8 ± 2.6 pg/ml in patients with cerebral infarction and 11.8 ± 2.5 pg/ml in those with cerebral bleeding (Fig. 1). The mean concentration was significantly (P < 0.01) higher in the patients with cerebral infarction than in either the control group or
DISCUSSION The objective of the present study was to examine angiotensin II content of platelets in relation to the presence of stroke. Recent studies have demonstrated the presence of angiotensin II immuno-reactivity in the cytosol' and, following the incubation of human platelets with angiotensin I, a peptide capable of splitting off the leucine residue to produce a nonapeptide, des-leu-angiotensin I, which acts like angiotensin II, has been detected. Although the physiological significance of this peptide is unclear, the formation of angiotensin II may be regulated by the
291
30 , . . . - - - - - - P
t
, . . . - - - - - - NS - - - - - - - ,
C.
:::: 20
I
-=----:-----:-'-:--:-:--
--l.-_:-Cerebral bleeding (n = 14)
OL-_ _L-
Control (n = 12)
Cerebral infarction (n = 16)
Mean (± SD) platelet angiotensin 11 concentrations in patients with cerebral bleeding or cerebral infaraction compared with control healthy subiects.
30 -----.-- Captopril ______ Enalapril _______ Delapril hydrochloride
c -iii c Q)
"§ 0> C
ctl
Q) Ql
1**
10
(;i
a:: O~-'-------------'---------'---------'----
o
4
8
12
Time (weeks)
Effect of oral administration of 75 mg/day captopril, 5 mg/day enalapril and 30 mg/day delapril hydrochloride with a washout period of 4 weeks between treatments given for 12 weeks on mean (± SD) platelet angiotensin 11 concentrations in 20 hypertensive patients: *p < 0.05 and **p < 0.01 compared with time O.
292
modulation of renin or by ACE activity. Platelets interact with the vascular endothelium during such local processes as haemostasis and inflammation. It is hypothesized that the platelet mitogens released at the sites of the endothelial denudation account for the smooth muscle cell profileration found in the vessels with arteriosclerotic and atherosclerotic changes." It has been suggested that angiotensin II may playa direct role in the development of both hyperplastic and hypertrophic changes in chronic vascular disease. 11 Other studies have shown the presence of angiotensin II in human platelets and have demonstrated that the aggregation of platelets induced by adenosine diphosphate or thrombin leads to the release of angiotensin II.1.7 This phenomenon may be of importance in the study of mechanisms that regulate local vascular tone and platelet-mediated vascular lesions, since angiotensin II can induce endothelial lesions and cause proliferation of vascular smooth muscle cells. n . ! 2 These data have considerable theoretical importance and suggest a further mechanism for the formation of a platelet-dependent vascular lesion. The local release of a peptide such as angiotensin II could damage the endothelium and lead to the proliferation of vascular smooth muscle calls.":" Although the factors that produce the
atherosclerosis and arteriosclerotic lesions are not fully understood, it is possible that it occurs where the endothelium has been damaged. 15 . 1 It is speculated that a similar effect occurs in small vessels. The data presented here show that platelet angiotensin II is elevated in patients with cerebral infarction suspected of having arteriosclerosis of the intracerebral artery, further supporting this concept. From the finding that the more the platelet aggregability is enhanced the more platelet angiotensin II is released, it would be necessary to diminish the release of angiotensin II and reduce the angiotensin II content when platelets are activated." The mechanisms that would result in the three agents producing differing effects on platelet angiotensin II are unclear; however, the drugs differ in their fat solubility with delapril having the greatest solubility. Another difference between the three drugs is the presence of the sulphydryl group. The angiotensin IIconcentration of platelets was decreased significantly with delapril hydrochloride compared with captopril and enalapril. The findings of the present studies, therefore, suggest that delapril hydrochloride may be of interest in treating patients with arteriosclerotic disorders since it decreases the platelet angiotensin II content. It may thus inhibit the tendency towards atherosclerotic changes. !;
REFERENCES 1 Prach MJ: Renin - angiotensin system: biochemistry and mechanism of action. Physio1 Rev 1977; 57: 313 - 370. 2 Cadwell PRB, Seegal BC, Hsu KC, et 01: Angiotensin-converting enzyme: vascular
endothelial localization. Science 1976; 191: 1050 - 1051.
3 Oshima G, Geese A, Erdos EG: Angiotensin I converting enzyme of the kidney cortex. Biochim Biophys Acta 1974; 350: 26 - 37.
293
4 Ward PE, Sheridan MA, Hammon KJ, et a1: Angiotensin I converting enzyme (kininase II) of the brush border of human and swine intestine. Biochem Pharmaco1 1980; 29: 1525 - 1529. 5 Yang HYT, Neff NH: Distribution and properties of angiotensin converting enzyme of rat brain. J Neurochem 1972; 19: 2443 - 2450. 6 Friedland J. Setton C, Silverstein E: Induction of angiotensin converting enzyme in human monocytes in culture. Biochem Biophys Res Commun 1978; 83: 843 - 849. 7 De Leeuw PW, De Bos R, Van Es PN, et a1: Blood platelets and angiotensin II. J Hypertens 1984; 2(suppl 3): 225 - 226. 8 Ferri C, Angelis CD, Porto MAD, et a1: Blood platelets and angiotensin II: angiotensin II release after platelet aggregation. Circulation 1988; 6(suppl 1): 69 - 71. 9 Preibisz Jl. Sealey JE, Laragh JH, et a1: Plasma and platelet vasopressin in essential hypertension and in congestive heart failure. Hypertension 1983; 5(suppl 1): 1129 - 1138. 10 Leonetti Luperini R, Ferri C, Del Porto MA, et a1: Vasoactive substances in human platelets: identification of angiotensin II. Cardio1ogia 1987; 32: 581 - 584. 11 Campbell-Boswell M, Lazzarini-Robertson A Jr: Effect of angiotensin II and vasopressin on human smooth muscle cells in vitro.
Exp Mol Patho11981; 35: 265 - 276. 12 Nilsson J: Growth factors and the pathogenesis of atherosclerosis. Atherosclerosis 1986; 62: 185 - 199. 13 Ferri C, Angelis DC, Del Porto MA, et al: Effect of nicardipine on angiotensin II platelet content. J Hypertens 1988; 6: 117 - 119. 14 Yoshida N, Weksler B, Nachman R: A calcium-dependent protease on human platelets. J BioI Chem 1983; 285: 7168 7174. 15 Schwartz SM, Cambell GR, Cambell JH: Replication of smooth muscle cells in vascular disease. Circ Res 1986; 58: 427444. 16 Vanhoutte PM, Cohen RA: The elusory role of serotonin in vascular function and disease. Biochem Pharmacol 1983; 32: 3671 - 3674. 17 Santucci A, Ferri C, Leonetti Luperini R, et a1: Effect of angiotensin converting enzyme inhibition on platelet angiotensin II content. Am J Med 1988; 84(suppl 3A): 119 -121.
MHayakawa Platelet Angiotensin II in Cerebrovascular Accident and the Effect of Angiotensin-converting Enzyme Inhibitors The [ourual of Intcrnotionol Medical Research 1992: 20: 289 - 294 Received for publication 5 March 1992 Accepted 11 March 1992 © Copyright 1992 Cambridge Medical Puhl icat ions Ltd
Address for correspondence DR M HAYAKAWA Nagoya Quarantine Station, Nagoya Airport Branch Office, The Ministry of Health and Welfare, Toyoba, Toyoyama-cho, Nichikasugai-Gun, Aichi Prefecture 480-02, Japan.
294
HAYAKAWA
Department of Geriatrics, Nagoya University School of Medicine, Nagoya City, Japan
Platelet angiotensin II concentrations were significantly (P < 0.01) elevated in 16 patients with a history of cerebral infarction, compared with 12 control subjects. The angiotensin-converting enzyme inhibitors, captopril, enalapril and delapril hydrochloride, were evaluated in 20 hypertensive patients with a history of cerebral infarction. Each agent was administered orally each day for 12 weeks using an open randomized crossover design. After 4 weeks' treatment, 75 mg/kg captopril significantly (P < 0.01) increased platelet angiotensin II concentrations and the increase was maintained for a further 8 weeks. Treatment with 5 mg/day enalapril resulted in no significant change in angiotensin II. Treatment with 30 mg/day delapril hydrochloride significantly (P < 0.05) decreased platelet angiotensin II concentrations at 4 weeks and the change persisted for 12 weeks (P < 0.01). During delapril hydrochloride treatment platelet angiotensin II concentrations approached normal values. It is concluded that delapril hydrochloride may be used to treat patients with arteriosclerosis disorders and may inhibit the tendency for atherosclerotic changes and thrombosis. KEY WORDS: ENALAPRIL; CAPTOPRIL; DELAPRIL; CEREBRAL INFARCTION; PLATELET ANGIOTENSIN
II
289
INTRODUCTION verified by computerized tomography of the brain 3 months before the study. None of the subjects had received any medication in the 2 weeks before the study.
Angiotensin II, a vasoactive peptide, plays an important role in the maintenance of fluid homeostasis and blood pressure, and in the regulation of blood flow in various vascular beds.' Angiotensin-converting enzyme (ACE) is localized in the endothelial cells of many mammalian tissues, 2 as well as in the kidney," intestine! brain,' cultured human monocytes" and platelets.' The platelets interact with the vascular endothelium during local processes such as haemostasis and inflammation, but the precise role of platelet angiotensin II in this interaction is unclear. In the present studies the role of platelet angiotensin II in patients with thrombotic disorders was examined and evaluation was made of the effects of three different ACE inhibitors administered orally on the angiotensin II content of platelets: captopril (1- [(2 S)-3-mercapto-2 -methyl propionyl]-Lproline); enalapril ([N-[(S)-l-ethoxycarbonyl3-phenylpropyl]-L-alanyl]-L-proline maleate); and delapril hydrochloride (N-[N-[N-[(S)-lethoxycarbonyl-3-phenyl propyll-t-alany1] -N(indan-2-yl)]glycine hydrochloride) were studied.
EFFECTS OF ACE INHIBITORS. A total of 20 hypertensive patients with cerebral infarction and no other medication history before or during treatment with ACE inhibitors were studied. Patients were defined as hypertensive if systolic blood pressure was greater than 160 mmHg and/or diastolic blood pressure was greater than 95 mmHg measured twice in resting position prior to enrolment. Selection was made according to the criteria used in patients in whom platelet angiotensin II concentrations were determined.
STUDY DESIGNS DETERMINA nON OF ANGIOTENSIN II. Blood for measurement of angiotensin II concentrations was drawn from an antecubital vein of supine subjects into tubes containing 3.18% sodium citrate as the anticoagulant. In patients with a history of previous cerebrovascular accident, blood samples were obtained 12 weeks after the event. Platelet angiotensin II was measured using a modification of the method of Ferri et al" A 1 ml blood sample was centrifuged for 13 min at 130 g to obtain platelet-rich plasma. This was further centrifuged for 10 min at 900 g and washed three times with Tris buffer (0.5 mM, pH 7.4) to obtain platelet pellets. The pellets obtained from 1 ml blood were resuspended in Tris buffer and the count confirmed as 431000 ± 31 OOO/mm" by the method of Preibisz et aI.'I This suspension was sonicated to obtain platelet lysate and centrifuged, and the supernatant was used for the radio-immunoassay of angiotensin II. W The concentration of angiotensin II is given in
PATIENTS AND METHODS PATIENTS All subjects provided written informed consent before enrollment. DETERMINA TION OF ANGIOTENSIN II. Subjects were evaluated in three groups: 12 healthy controls (mean age 73.2 ± 2.3 years), 16 patients with a prior (more than 3 months before the study) cerebral infarction (mean age 74.1 ± 3.1 years) and 14 patients with cerebral bleeding (mean age 73.8 ± 2.9 years). Patients with cerebrovascular accidents all had a history of typical onset, course, signs and symptom of stroke that had also been
290
patients with cerebral bleeding. Mean blood pressure in the healthy patients was 138 ± 6/ 72 ± 4 mmHg compared with 136 ± 5/78 ± 2 and 140 ± 4/80 ± 6 mmHg, respectively, in patients with cerebral infarction and cerebral bleeding. There was no significant correlation between platelet angiotensin II concentration and blood pressure in any group.
pg/ml of platelet suspension (platelet count of 431 OOO/mm'). EFFECTS OF ACE INHIBITORS. In an open, randomized crossover manner the 20 hypertensive patients each received 75 mg/day captopril, 5 mg/day enalapril and 30 mg/day delapril hydrochloride taken orally for 12 weeks with a 4-week washout period between treatments. Blood was sampled immediately before therapy and again after 4, 8 and 12 weeks of drug administration, and platelet angiotensin II concentrations were determined. The sodium intake of the patients was maintained at 120 mmol/day.
EFFECT OF ACE INHIBITORS The mean blood pressure of the patients included in this study was 176 ± 8.6/98 ± 2.4 mmHg. In the 20 patients given captopril in the randomized crossover study, the mean platelet angiotensin II concentration was significantly (P < 0.05) increased from pretreatment concentrations after 4 weeks and remained elevated (P < 0.01) throughout the 12-week study period (Fig. 2). With the administration of delapril hydrochloride, the mean platelet angiotensin II concentration was significantly (P < 0.01) decreased at 4 weeks and remained so for 12 weeks. The administration of enalapril produced no significant effect on platelet angiotensin II concentrations. During the washout periods, platelet angiotensin II concentrations returned to pretreatment values.
STATISTICAL METHODS Data are expressed as means (± SD). Student's t-test was applied to determine the significance of differences between groups; the level of significance was set at P < 0.05.
RESULTS PLATELET ANGIOTENSIN II CONCENTRA TIONS A total of 16 patients with cerebral infarction had an occlusion of the middle cerebral artery and showed no electrocardiographic abnormalities. Blood chemistry and blood coagulation parameters were within normal limits. Examination of the carotid artery by Xrays revealed no atheromatous lesions; thus, in most patients, the stroke diagnosis was thrombosis of the middle cerebral artery due to arteriosclerosis. The mean platelet angiotensin II concentration was 11.2 ± 2.3 pg/ml in healthy subjects, 19.8 ± 2.6 pg/ml in patients with cerebral infarction and 11.8 ± 2.5 pg/ml in those with cerebral bleeding (Fig. 1). The mean concentration was significantly (P < 0.01) higher in the patients with cerebral infarction than in either the control group or
DISCUSSION The objective of the present study was to examine angiotensin II content of platelets in relation to the presence of stroke. Recent studies have demonstrated the presence of angiotensin II immuno-reactivity in the cytosol' and, following the incubation of human platelets with angiotensin I, a peptide capable of splitting off the leucine residue to produce a nonapeptide, des-leu-angiotensin I, which acts like angiotensin II, has been detected. Although the physiological significance of this peptide is unclear, the formation of angiotensin II may be regulated by the
291
30 , . . . - - - - - - P
t
, . . . - - - - - - NS - - - - - - - ,
C.
:::: 20
I
-=----:-----:-'-:--:-:--
--l.-_:-Cerebral bleeding (n = 14)
OL-_ _L-
Control (n = 12)
Cerebral infarction (n = 16)
Mean (± SD) platelet angiotensin 11 concentrations in patients with cerebral bleeding or cerebral infaraction compared with control healthy subiects.
30 -----.-- Captopril ______ Enalapril _______ Delapril hydrochloride
c -iii c Q)
"§ 0> C
ctl
Q) Ql
1**
10
(;i
a:: O~-'-------------'---------'---------'----
o
4
8
12
Time (weeks)
Effect of oral administration of 75 mg/day captopril, 5 mg/day enalapril and 30 mg/day delapril hydrochloride with a washout period of 4 weeks between treatments given for 12 weeks on mean (± SD) platelet angiotensin 11 concentrations in 20 hypertensive patients: *p < 0.05 and **p < 0.01 compared with time O.
292
modulation of renin or by ACE activity. Platelets interact with the vascular endothelium during such local processes as haemostasis and inflammation. It is hypothesized that the platelet mitogens released at the sites of the endothelial denudation account for the smooth muscle cell profileration found in the vessels with arteriosclerotic and atherosclerotic changes." It has been suggested that angiotensin II may playa direct role in the development of both hyperplastic and hypertrophic changes in chronic vascular disease. 11 Other studies have shown the presence of angiotensin II in human platelets and have demonstrated that the aggregation of platelets induced by adenosine diphosphate or thrombin leads to the release of angiotensin II.1.7 This phenomenon may be of importance in the study of mechanisms that regulate local vascular tone and platelet-mediated vascular lesions, since angiotensin II can induce endothelial lesions and cause proliferation of vascular smooth muscle cells. n . ! 2 These data have considerable theoretical importance and suggest a further mechanism for the formation of a platelet-dependent vascular lesion. The local release of a peptide such as angiotensin II could damage the endothelium and lead to the proliferation of vascular smooth muscle calls.":" Although the factors that produce the
atherosclerosis and arteriosclerotic lesions are not fully understood, it is possible that it occurs where the endothelium has been damaged. 15 . 1 It is speculated that a similar effect occurs in small vessels. The data presented here show that platelet angiotensin II is elevated in patients with cerebral infarction suspected of having arteriosclerosis of the intracerebral artery, further supporting this concept. From the finding that the more the platelet aggregability is enhanced the more platelet angiotensin II is released, it would be necessary to diminish the release of angiotensin II and reduce the angiotensin II content when platelets are activated." The mechanisms that would result in the three agents producing differing effects on platelet angiotensin II are unclear; however, the drugs differ in their fat solubility with delapril having the greatest solubility. Another difference between the three drugs is the presence of the sulphydryl group. The angiotensin IIconcentration of platelets was decreased significantly with delapril hydrochloride compared with captopril and enalapril. The findings of the present studies, therefore, suggest that delapril hydrochloride may be of interest in treating patients with arteriosclerotic disorders since it decreases the platelet angiotensin II content. It may thus inhibit the tendency towards atherosclerotic changes. !;
REFERENCES 1 Prach MJ: Renin - angiotensin system: biochemistry and mechanism of action. Physio1 Rev 1977; 57: 313 - 370. 2 Cadwell PRB, Seegal BC, Hsu KC, et 01: Angiotensin-converting enzyme: vascular
endothelial localization. Science 1976; 191: 1050 - 1051.
3 Oshima G, Geese A, Erdos EG: Angiotensin I converting enzyme of the kidney cortex. Biochim Biophys Acta 1974; 350: 26 - 37.
293
4 Ward PE, Sheridan MA, Hammon KJ, et a1: Angiotensin I converting enzyme (kininase II) of the brush border of human and swine intestine. Biochem Pharmaco1 1980; 29: 1525 - 1529. 5 Yang HYT, Neff NH: Distribution and properties of angiotensin converting enzyme of rat brain. J Neurochem 1972; 19: 2443 - 2450. 6 Friedland J. Setton C, Silverstein E: Induction of angiotensin converting enzyme in human monocytes in culture. Biochem Biophys Res Commun 1978; 83: 843 - 849. 7 De Leeuw PW, De Bos R, Van Es PN, et a1: Blood platelets and angiotensin II. J Hypertens 1984; 2(suppl 3): 225 - 226. 8 Ferri C, Angelis CD, Porto MAD, et a1: Blood platelets and angiotensin II: angiotensin II release after platelet aggregation. Circulation 1988; 6(suppl 1): 69 - 71. 9 Preibisz Jl. Sealey JE, Laragh JH, et a1: Plasma and platelet vasopressin in essential hypertension and in congestive heart failure. Hypertension 1983; 5(suppl 1): 1129 - 1138. 10 Leonetti Luperini R, Ferri C, Del Porto MA, et a1: Vasoactive substances in human platelets: identification of angiotensin II. Cardio1ogia 1987; 32: 581 - 584. 11 Campbell-Boswell M, Lazzarini-Robertson A Jr: Effect of angiotensin II and vasopressin on human smooth muscle cells in vitro.
Exp Mol Patho11981; 35: 265 - 276. 12 Nilsson J: Growth factors and the pathogenesis of atherosclerosis. Atherosclerosis 1986; 62: 185 - 199. 13 Ferri C, Angelis DC, Del Porto MA, et al: Effect of nicardipine on angiotensin II platelet content. J Hypertens 1988; 6: 117 - 119. 14 Yoshida N, Weksler B, Nachman R: A calcium-dependent protease on human platelets. J BioI Chem 1983; 285: 7168 7174. 15 Schwartz SM, Cambell GR, Cambell JH: Replication of smooth muscle cells in vascular disease. Circ Res 1986; 58: 427444. 16 Vanhoutte PM, Cohen RA: The elusory role of serotonin in vascular function and disease. Biochem Pharmacol 1983; 32: 3671 - 3674. 17 Santucci A, Ferri C, Leonetti Luperini R, et a1: Effect of angiotensin converting enzyme inhibition on platelet angiotensin II content. Am J Med 1988; 84(suppl 3A): 119 -121.
MHayakawa Platelet Angiotensin II in Cerebrovascular Accident and the Effect of Angiotensin-converting Enzyme Inhibitors The [ourual of Intcrnotionol Medical Research 1992: 20: 289 - 294 Received for publication 5 March 1992 Accepted 11 March 1992 © Copyright 1992 Cambridge Medical Puhl icat ions Ltd
Address for correspondence DR M HAYAKAWA Nagoya Quarantine Station, Nagoya Airport Branch Office, The Ministry of Health and Welfare, Toyoba, Toyoyama-cho, Nichikasugai-Gun, Aichi Prefecture 480-02, Japan.
294
