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Blood Vessels 1991;28:231-235
Role of the Local Renin-Angiotensin System in the Autoregulation of the Cerebral Circulation O.B. Paulson, G. Waldemar Department of Neurology, Rigshospitalet, Copenhagen, Denmark
Key Words. Angiotensin II • Angiotensin-converting enzyme • Autoregulation • Cerebral circulation • Cerebral blood flow • Renin-angiotensin system Abstract. Inhibition of angiotensin-converting enzyme (ACE) shifts the limits of cerebral blood flow autoregulation toward lower blood pressure values. This effect seems to be mediated by blocking the formation of angiotensin II on the luminal side of the larger cerebral resistance vessels. Baseline cerebral blood flow (the flow within the autoregulatory limits) is not changed by acute or chronic ACE inhibition. An interaction between the vascular reninangiotensin and the sympathetic nervous system is present. Activation of the latter inhibits the downwards shift of the upper limit of autoregulation following ACE inhibition.
Autoregulation of cerebral blood flow (CBF) ensures a constant CBF despite varia tions in the arterial blood pressure within wide limits. The limits of autoregulation are not completely fixed, but may vary under dynamic physiological control as well as adapt to chronic changes in the level of the arterial blood pressure. The present report gives a short review of the cerebral autoregulation with special re gard to the role of the local renin-angiotensin system. Blocking of this system has been shown to reset autoregulation to lower pres sure levels, but still with possibilities for interaction with the sympathetic nervous system.
Autoregulation of CBF CBF autoregulation is defined as the pro cess which maintains CBF at a rather con stant level despite changes in arterial perfu sion pressure within wide limits [1, 2]. The mechanism is mediated by dilation or con striction of predominantly the smaller cere bral resistance vessels, the arterioles. As the arterial perfusion pressure decreases these vessels dilate. The lower limit of CBF auto regulation is reached when the dilation be comes insufficient to maintain CBF, which then falls with further decreases in the perfu sion pressure. During increases in the perfu sion pressure the resistance vessels constrict. The upper limit of CBF autoregulation is reached when the arterial perfusion pressure
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Introduction
Paulson/Waldemar
232
of a cerebral vasodilation superimposed on the autoregulatory response. Vasodilators with no direct pharmacological action on ce rebrovascular smooth muscle, e.g. diazoxide, do not change the limits or plateau of auto regulation. As discussed below, inhibitors of the angiotensin-converting enzyme (ACE) af fect CBF autoregulation in a unique way.
ACE Inhibition and CBF
Fig. 1. Autoregulation of CBF after captopril, 10 mg kg- i.v. (•----- • - lower limit studied by con trolled hemorrhage; ■----- ■ = upper limit studied by norepinephrine infusion), and during a control study (o—— o) in spontaneously hypertensive rats. Capto pril shifts the autoregulation curve toward lower blood pressure levels. MAP = Mean arterial blood pressure. Redrawn from Barry et al. [9].
causes a forceful dilation of the constricted resistance vessels with an increase in CBF (breakthrough of autoregulation). CBF autoregulation is influenced by sev eral factors. The sympathetic nerves exert a protective effect against breakthrough of au toregulation of CBF during acute hyperten sion as sympathetic activation shifts the lim its to higher blood pressure levels [3]. In chronic arterial hypertension, the autoregulatory curve is shifted permanently to higher blood pressure levels, leaving the brain less tolerant to acute reductions of the arterial blood pressure. This shift is, however, part ly reversed by long-term antihypertensive treatment [4-6]. Vasodilators with a direct pharmacological action on cerebrovascular smooth muscle, e.g. dihydralazine, may cause CBF autoregulation to be lost, because
Effect on Baseline CBF The results of experimental investigations of the effect of acute or prolonged ACE inhi bition on baseline CBF have to some extent been controversial [7-10]. Most of these studies, however, demonstrate that ACE in hibitors have little if any influence on base line CBF as long as the arterial blood pres sure is maintained within physiological lim its. Clinical studies both of single doses and of prolonged administration of ACE inhibi tors all show that baseline CBF remains un changed even though blood pressure is re duced by 10-15% [11-15], Effect on CBF Autoregulation
The mechanism by which ACE inhibi tors, in contrast to direct vasodilators, could maintain cerebral perfusion has not been fully elucidated, but may be understood by analyzing the effect on CBF autoregulation. Following acute ACE inhibition with capto pril in normotensive and in spontaneously hypertensive rats (fig. 1), the lower and up per limits of autoregulation are shifted to lower blood pressure levels, and the autoreg ulatory plateau shortened [9], Under these conditions, the tolerance of the brain to acute blood pressure lowering is improved,
Downloaded by: King's College London 137.73.144.138 - 1/11/2018 3:14:11 PM
MAP, mm Hg
CBF Autoregulation and the Renin-Angiotensin System
Inhibition of Vascular Wall ACE in Cerebral Arteries: A Possible Mechanism of Action The influence of ACE inhibitors on the cerebral circulation cannot be mediated through the brain parenchyma renin-angio tensin system. Thus, intraventricular appli cation of captopril to rats, resulting in a pharmacological concentration in the brain parenchyma, did not influence the limits of CBF autoregulation, in contrast to the effect of intravenous application (fig. 2) [ 18]. Hence, it can be hypothesized that ACE inhi bition prevents angiotensin II formation on the luminal side of the large arteries, leading to a dilation of the large arteries and a com pensatory constriction of the small arteries/ arterioles. Under these conditions, CBF would be unchanged at resting arterial blood
Fig. 2. Autoregulation of CBF after intraventricu lar application of captopril (•----- •) and during a con trol study (o----- o) in Wistar-Kyoto rats. Autoregula tion remains unchanged. MAP = Mean arterial blood pressure. From Jarden et al. [18].
pressure, but during a blood pressure de crease the smaller vessels would have a larger dilatory capacity - explaining the decrease in the lower limit of CBF autoregulation [2, 9. 17-19]. This hypothesis is supported by studies demonstrating that captopril dilates larger cerebral arteries in vitro [20, 21], and by a clinical study, using pulsed Doppler methods, showing that captopril caused an increase in the diameter of the common ca rotid artery [22],
Interaction between the Renin-Angiotensin System and the Sympathetic Nervous System The effect of captopril on CBF autoregu lation is also present in rats subjected to sympathetic denervation [23]. Therefore, the
Downloaded by: King's College London 137.73.144.138 - 1/11/2018 3:14:11 PM
but the tolerance to acute hypertension is reduced; however, this may be counteracted by the sympathetic nervous system as dis cussed below. Fosinopril, a new ACE inhibi tor of the phosphinic acid class, appears to reduce primarily the lower limit of autoregu lation [16, 17], Recent studies from our lab oratory show that the ACE inhibitor ceranopril also reduces the limits of autoregula tion. The effect of a single oral dose of captopril (25-50 mg) on CBF autoregulation was recently investigated in patients with chronic arterial hypertension as well as in normotensive volunteers [13], Compared to the experimental studies, the clinical effect on CBF autoregulation was less pronounced, probably as a consequence of a lower sympa thetic tonus induced by the blood-pressure lowering technique in the human studies.
233
234
Paulson/Waldemar
Concluding Remarks 300 -i
The local cerebrovascular renin-angioten sin system has an important role in the regu lation of CBF. Thus, blocking of the reninangiotensin system shifts the limits of CBF autoregulation toward lower pressures, an effect which is counteracted by activation of the sympathetic nervous system. These phys iological findings support the clinical use of blockade of the renin-angiotensin system in the treatment of arterial hypertension. MAP, mm Hg
Fig. 3. Electric stimulation of the cervical sympa thetic trunk abolishes the effect of captopril given acutely intravenously on the upper limit of autoregu lation of CBF in spontaneously hypertensive rats. Following captopril, the upper limit of autoregulation was lowered, and norepinephrine, intravenously, caused a marked rise in CBF (■----- ■). This was almost completely prevented by concomitant sympa thetic stimulation (•----- •). The third group is a con trol group of nonstimulated noncaptopril-treated spontaneous hypertensive rats (o------o). * p < 0.05; **p < 0.01. MAP = Mean arterial blood pressure. From Waldemar et al. [24].
effect of ACE inhibition on the limits of autoregulation cannot be explained by an influence on the tonus of the cerebral peri vascular sympathetic nerves. Concomitant stimulation of the cervical sympathetic nerves attenuates the effect of captopril on the upper limit of CBF autoregulation (fig. 3) [24]. This effect may be of major significance as endogenous blood pressure increase is ac companied by activation of the sympathetic nervous system. The brain may therefore still be protected by CBF autoregulation af ter ACE inhibition.
1 Strandgaard S. Paulson OB: Hypertensive disease and the cerebral circulation; in Laragh JH. Bren ner BM (eds); Pathophysiology, Diagnosis and Management. New York, Raven Press. 1990: pp 399-416. 2 Paulson OB, Strandgaard S, Edvinsson L; Cere bral autoregulation. Cerebrovasc Brain Metab Rev, in press. 3 Edvinsson L, Owman C. Siesjö B: Physiological role of cerebrovascular sympathetic nerves in the autoregulation of cerebral blood flow. Brain Res 1976;117:519-523. 4 Strandgaard S: Autoregulation of cerebral circula tion in hypertension. Acta Neurol Scand 1978; 57(suppl 66); 1-82. 5 Barry DI, Strandgaard S, Graham DI, Braendstrup O. Svendsen UG, Vorstrup S, et al: Cerebral blood flow in rats with renal and spontaneous hypertension: Resetting of the lower limit of au toregulation. J Cereb Blood Flow Metab 1982;2: 347-353. 6 Vorstrup S, Barry DI, Jarden JO, Svendsen UG, Braendstrup O, Graham DI. et al: Chronic antihy pertensive treatment in the rat reverses hyperten sion-induced changes in cerebral blood flow au toregulation. Stroke 1984:15:312-318. 7 Gavras H, Liang C. Brunner HR: Redistribution of regional blood flow after inhibition of the an giotensin converting enzyme. Circ Res 1978; 43(suppl I):59—63. 8 Takeyama K, Minato H. Nakatsuji K. Suzuku H.
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References
CBF Autoregulation and the Renin-Angiotensin System
10
11
12
13
14
15
16
17
18 Jarden JO, Barry DI, Juhler M, Graham DI, Strandgaard S, Paulson OB: Cerebrovascular as pects of converting-enzyme inhibition II: Bloodbrain barrier permeability and effect of intracerebroventricular administration of captopril. J Hy pertens 1984;2:599-604. 19 Postiglione A, Bobkiewicz T, Vinholdt-Pedersen E, Lassen NA, Paulson OB. Barry DI: Cerebrovas cular effects of angiotensin converting enzyme in hibition: Indirect evidence for large artery dilata tion. Submitted. 20 Whalley ET, Wahl M: The effect of kininase II inhibitors on the response of feline cerebral arter ies to bradykinin and angiotensin. Pflügers Arch 1983;398:175-177. 21 Whalley ET, Wahl M: Cerebrovascular reactivity to angiotensin and angiotensin-converting en zyme activity in cerebrospinal fluid. Brain Res 1988;438:1-7. 22 Bouthier JD, Safar ME. Benetos A, Simon AC, Levenson JA, Hugues CM: Haemodynamic ef fects of vasodilating drugs on the common carotid and brachial circulations of patients with essential hypertension. Br J Clin Pharmacol 1986;21:137— 142. 23 Waldemar G: Acute sympathetic denervation does not eliminate the effect of angiotensin con verting enzyme inhibition on CBF autoregulation in spontaneously hypertensive rats. J Cereb Blood Flow Metab 1990;10:43-47. 24 Waldemar G. Paulson OB. Barry DI, Knudsen GM: Angiotensin converting enzyme inhibition and the upper limit of cerebral blood flow auto regulation: Effect of sympathetic stimulation. Circ Res 1989;64:1197-1204.
Olaf B. Paulson Department of Neurology Rigshospitalet Blegdamsvej DK-2100 Copenhagen (Denmark) Downloaded by: King's College London 137.73.144.138 - 1/11/2018 3:14:11 PM
9
Nose I, Oka M, et al: Effect of the novel orally active angiotensin convening enzyme inhibitor alacepril on cardiovascular system in experimen tal animals. Arzneimittelforschung 1986;36:6973. Barry DI, Jarden JO, Paulson OB, Graham DI, Strandgaard S: Cerebrovascular effects of convert ing enzyme inhibition. I. Effects of intravenous captopril in spontaneously hypertensive and normotensive rats. J Hypertens 1984;2:589-597. Richer C, Doussau M, Giudicelli J: Systemic and regional hemodynamic profile of five angiotensin I converting enzyme inhibitors in the sponta neously hypertensive rat. Am J Cardiol 1987;59: 12D-17D. Frei A, Müller-Brand J: Cerebral blood flow and antihypertensive treatment with enalapril. J Hy pertens 1986;4:365-367. Minematsu K, Yamaguchi T, Tsuchiya M, Ito K. Ikeda M, Omae T: Effect of angiotensin convert ing enzyme inhibitor (captopril) on cerebral blood flow in hypertensive patients without a history of stroke. Clin Exp Hypertens 1987;A9:551—557. Waldemar G, Schmidt JF, Andersen AR, Vorstrup S, Paulson OB: Angiotensin converting en zyme inhibition and cerebral blood flow autoregu lation in normotensive and hypertensive man. J Hypertens 1989;7:229-235. Waldemar G, Vorstrup S, Andersen AR, Pedersen H, Paulson OB: Angiotensin-converting enzyme inhibition and regional cerebral blood flow in acute stroke. J Cardiovasc Pharmacol 1989; 14: 722-729. Waldemar G, Ibsen H, Strandgaard S, Paulson OB, Andersen AR, Rasmussen S: The effect of fosinopril sodium on cerebral blood flow in mod erate essential hypertension. Am J Hypertens, in press. Waldemar G, Pedersen EV, Barry DI: Cerebral blood flow autoregulation during angiotensin con verting enzyme inhibition. J Cereb Blood Flow Metab 1987;7(suppl 1):S283. Paulson OB. Waldemar G, Andersen AR, Barry DI, Pedersen EV, Schmidt JF, et al: Role of angio tensin in autoregulation of cerebral blood flow. Circulation 1988;77(suppl I):55—58.
235
Blood Vessels 1991;28:231-235
Role of the Local Renin-Angiotensin System in the Autoregulation of the Cerebral Circulation O.B. Paulson, G. Waldemar Department of Neurology, Rigshospitalet, Copenhagen, Denmark
Key Words. Angiotensin II • Angiotensin-converting enzyme • Autoregulation • Cerebral circulation • Cerebral blood flow • Renin-angiotensin system Abstract. Inhibition of angiotensin-converting enzyme (ACE) shifts the limits of cerebral blood flow autoregulation toward lower blood pressure values. This effect seems to be mediated by blocking the formation of angiotensin II on the luminal side of the larger cerebral resistance vessels. Baseline cerebral blood flow (the flow within the autoregulatory limits) is not changed by acute or chronic ACE inhibition. An interaction between the vascular reninangiotensin and the sympathetic nervous system is present. Activation of the latter inhibits the downwards shift of the upper limit of autoregulation following ACE inhibition.
Autoregulation of cerebral blood flow (CBF) ensures a constant CBF despite varia tions in the arterial blood pressure within wide limits. The limits of autoregulation are not completely fixed, but may vary under dynamic physiological control as well as adapt to chronic changes in the level of the arterial blood pressure. The present report gives a short review of the cerebral autoregulation with special re gard to the role of the local renin-angiotensin system. Blocking of this system has been shown to reset autoregulation to lower pres sure levels, but still with possibilities for interaction with the sympathetic nervous system.
Autoregulation of CBF CBF autoregulation is defined as the pro cess which maintains CBF at a rather con stant level despite changes in arterial perfu sion pressure within wide limits [1, 2]. The mechanism is mediated by dilation or con striction of predominantly the smaller cere bral resistance vessels, the arterioles. As the arterial perfusion pressure decreases these vessels dilate. The lower limit of CBF auto regulation is reached when the dilation be comes insufficient to maintain CBF, which then falls with further decreases in the perfu sion pressure. During increases in the perfu sion pressure the resistance vessels constrict. The upper limit of CBF autoregulation is reached when the arterial perfusion pressure
Downloaded by: King's College London 137.73.144.138 - 1/11/2018 3:14:11 PM
Introduction
Paulson/Waldemar
232
of a cerebral vasodilation superimposed on the autoregulatory response. Vasodilators with no direct pharmacological action on ce rebrovascular smooth muscle, e.g. diazoxide, do not change the limits or plateau of auto regulation. As discussed below, inhibitors of the angiotensin-converting enzyme (ACE) af fect CBF autoregulation in a unique way.
ACE Inhibition and CBF
Fig. 1. Autoregulation of CBF after captopril, 10 mg kg- i.v. (•----- • - lower limit studied by con trolled hemorrhage; ■----- ■ = upper limit studied by norepinephrine infusion), and during a control study (o—— o) in spontaneously hypertensive rats. Capto pril shifts the autoregulation curve toward lower blood pressure levels. MAP = Mean arterial blood pressure. Redrawn from Barry et al. [9].
causes a forceful dilation of the constricted resistance vessels with an increase in CBF (breakthrough of autoregulation). CBF autoregulation is influenced by sev eral factors. The sympathetic nerves exert a protective effect against breakthrough of au toregulation of CBF during acute hyperten sion as sympathetic activation shifts the lim its to higher blood pressure levels [3]. In chronic arterial hypertension, the autoregulatory curve is shifted permanently to higher blood pressure levels, leaving the brain less tolerant to acute reductions of the arterial blood pressure. This shift is, however, part ly reversed by long-term antihypertensive treatment [4-6]. Vasodilators with a direct pharmacological action on cerebrovascular smooth muscle, e.g. dihydralazine, may cause CBF autoregulation to be lost, because
Effect on Baseline CBF The results of experimental investigations of the effect of acute or prolonged ACE inhi bition on baseline CBF have to some extent been controversial [7-10]. Most of these studies, however, demonstrate that ACE in hibitors have little if any influence on base line CBF as long as the arterial blood pres sure is maintained within physiological lim its. Clinical studies both of single doses and of prolonged administration of ACE inhibi tors all show that baseline CBF remains un changed even though blood pressure is re duced by 10-15% [11-15], Effect on CBF Autoregulation
The mechanism by which ACE inhibi tors, in contrast to direct vasodilators, could maintain cerebral perfusion has not been fully elucidated, but may be understood by analyzing the effect on CBF autoregulation. Following acute ACE inhibition with capto pril in normotensive and in spontaneously hypertensive rats (fig. 1), the lower and up per limits of autoregulation are shifted to lower blood pressure levels, and the autoreg ulatory plateau shortened [9], Under these conditions, the tolerance of the brain to acute blood pressure lowering is improved,
Downloaded by: King's College London 137.73.144.138 - 1/11/2018 3:14:11 PM
MAP, mm Hg
CBF Autoregulation and the Renin-Angiotensin System
Inhibition of Vascular Wall ACE in Cerebral Arteries: A Possible Mechanism of Action The influence of ACE inhibitors on the cerebral circulation cannot be mediated through the brain parenchyma renin-angio tensin system. Thus, intraventricular appli cation of captopril to rats, resulting in a pharmacological concentration in the brain parenchyma, did not influence the limits of CBF autoregulation, in contrast to the effect of intravenous application (fig. 2) [ 18]. Hence, it can be hypothesized that ACE inhi bition prevents angiotensin II formation on the luminal side of the large arteries, leading to a dilation of the large arteries and a com pensatory constriction of the small arteries/ arterioles. Under these conditions, CBF would be unchanged at resting arterial blood
Fig. 2. Autoregulation of CBF after intraventricu lar application of captopril (•----- •) and during a con trol study (o----- o) in Wistar-Kyoto rats. Autoregula tion remains unchanged. MAP = Mean arterial blood pressure. From Jarden et al. [18].
pressure, but during a blood pressure de crease the smaller vessels would have a larger dilatory capacity - explaining the decrease in the lower limit of CBF autoregulation [2, 9. 17-19]. This hypothesis is supported by studies demonstrating that captopril dilates larger cerebral arteries in vitro [20, 21], and by a clinical study, using pulsed Doppler methods, showing that captopril caused an increase in the diameter of the common ca rotid artery [22],
Interaction between the Renin-Angiotensin System and the Sympathetic Nervous System The effect of captopril on CBF autoregu lation is also present in rats subjected to sympathetic denervation [23]. Therefore, the
Downloaded by: King's College London 137.73.144.138 - 1/11/2018 3:14:11 PM
but the tolerance to acute hypertension is reduced; however, this may be counteracted by the sympathetic nervous system as dis cussed below. Fosinopril, a new ACE inhibi tor of the phosphinic acid class, appears to reduce primarily the lower limit of autoregu lation [16, 17], Recent studies from our lab oratory show that the ACE inhibitor ceranopril also reduces the limits of autoregula tion. The effect of a single oral dose of captopril (25-50 mg) on CBF autoregulation was recently investigated in patients with chronic arterial hypertension as well as in normotensive volunteers [13], Compared to the experimental studies, the clinical effect on CBF autoregulation was less pronounced, probably as a consequence of a lower sympa thetic tonus induced by the blood-pressure lowering technique in the human studies.
233
234
Paulson/Waldemar
Concluding Remarks 300 -i
The local cerebrovascular renin-angioten sin system has an important role in the regu lation of CBF. Thus, blocking of the reninangiotensin system shifts the limits of CBF autoregulation toward lower pressures, an effect which is counteracted by activation of the sympathetic nervous system. These phys iological findings support the clinical use of blockade of the renin-angiotensin system in the treatment of arterial hypertension. MAP, mm Hg
Fig. 3. Electric stimulation of the cervical sympa thetic trunk abolishes the effect of captopril given acutely intravenously on the upper limit of autoregu lation of CBF in spontaneously hypertensive rats. Following captopril, the upper limit of autoregulation was lowered, and norepinephrine, intravenously, caused a marked rise in CBF (■----- ■). This was almost completely prevented by concomitant sympa thetic stimulation (•----- •). The third group is a con trol group of nonstimulated noncaptopril-treated spontaneous hypertensive rats (o------o). * p < 0.05; **p < 0.01. MAP = Mean arterial blood pressure. From Waldemar et al. [24].
effect of ACE inhibition on the limits of autoregulation cannot be explained by an influence on the tonus of the cerebral peri vascular sympathetic nerves. Concomitant stimulation of the cervical sympathetic nerves attenuates the effect of captopril on the upper limit of CBF autoregulation (fig. 3) [24]. This effect may be of major significance as endogenous blood pressure increase is ac companied by activation of the sympathetic nervous system. The brain may therefore still be protected by CBF autoregulation af ter ACE inhibition.
1 Strandgaard S. Paulson OB: Hypertensive disease and the cerebral circulation; in Laragh JH. Bren ner BM (eds); Pathophysiology, Diagnosis and Management. New York, Raven Press. 1990: pp 399-416. 2 Paulson OB, Strandgaard S, Edvinsson L; Cere bral autoregulation. Cerebrovasc Brain Metab Rev, in press. 3 Edvinsson L, Owman C. Siesjö B: Physiological role of cerebrovascular sympathetic nerves in the autoregulation of cerebral blood flow. Brain Res 1976;117:519-523. 4 Strandgaard S: Autoregulation of cerebral circula tion in hypertension. Acta Neurol Scand 1978; 57(suppl 66); 1-82. 5 Barry DI, Strandgaard S, Graham DI, Braendstrup O. Svendsen UG, Vorstrup S, et al: Cerebral blood flow in rats with renal and spontaneous hypertension: Resetting of the lower limit of au toregulation. J Cereb Blood Flow Metab 1982;2: 347-353. 6 Vorstrup S, Barry DI, Jarden JO, Svendsen UG, Braendstrup O, Graham DI. et al: Chronic antihy pertensive treatment in the rat reverses hyperten sion-induced changes in cerebral blood flow au toregulation. Stroke 1984:15:312-318. 7 Gavras H, Liang C. Brunner HR: Redistribution of regional blood flow after inhibition of the an giotensin converting enzyme. Circ Res 1978; 43(suppl I):59—63. 8 Takeyama K, Minato H. Nakatsuji K. Suzuku H.
Downloaded by: King's College London 137.73.144.138 - 1/11/2018 3:14:11 PM
References
CBF Autoregulation and the Renin-Angiotensin System
10
11
12
13
14
15
16
17
18 Jarden JO, Barry DI, Juhler M, Graham DI, Strandgaard S, Paulson OB: Cerebrovascular as pects of converting-enzyme inhibition II: Bloodbrain barrier permeability and effect of intracerebroventricular administration of captopril. J Hy pertens 1984;2:599-604. 19 Postiglione A, Bobkiewicz T, Vinholdt-Pedersen E, Lassen NA, Paulson OB. Barry DI: Cerebrovas cular effects of angiotensin converting enzyme in hibition: Indirect evidence for large artery dilata tion. Submitted. 20 Whalley ET, Wahl M: The effect of kininase II inhibitors on the response of feline cerebral arter ies to bradykinin and angiotensin. Pflügers Arch 1983;398:175-177. 21 Whalley ET, Wahl M: Cerebrovascular reactivity to angiotensin and angiotensin-converting en zyme activity in cerebrospinal fluid. Brain Res 1988;438:1-7. 22 Bouthier JD, Safar ME. Benetos A, Simon AC, Levenson JA, Hugues CM: Haemodynamic ef fects of vasodilating drugs on the common carotid and brachial circulations of patients with essential hypertension. Br J Clin Pharmacol 1986;21:137— 142. 23 Waldemar G: Acute sympathetic denervation does not eliminate the effect of angiotensin con verting enzyme inhibition on CBF autoregulation in spontaneously hypertensive rats. J Cereb Blood Flow Metab 1990;10:43-47. 24 Waldemar G. Paulson OB. Barry DI, Knudsen GM: Angiotensin converting enzyme inhibition and the upper limit of cerebral blood flow auto regulation: Effect of sympathetic stimulation. Circ Res 1989;64:1197-1204.
Olaf B. Paulson Department of Neurology Rigshospitalet Blegdamsvej DK-2100 Copenhagen (Denmark) Downloaded by: King's College London 137.73.144.138 - 1/11/2018 3:14:11 PM
9
Nose I, Oka M, et al: Effect of the novel orally active angiotensin convening enzyme inhibitor alacepril on cardiovascular system in experimen tal animals. Arzneimittelforschung 1986;36:6973. Barry DI, Jarden JO, Paulson OB, Graham DI, Strandgaard S: Cerebrovascular effects of convert ing enzyme inhibition. I. Effects of intravenous captopril in spontaneously hypertensive and normotensive rats. J Hypertens 1984;2:589-597. Richer C, Doussau M, Giudicelli J: Systemic and regional hemodynamic profile of five angiotensin I converting enzyme inhibitors in the sponta neously hypertensive rat. Am J Cardiol 1987;59: 12D-17D. Frei A, Müller-Brand J: Cerebral blood flow and antihypertensive treatment with enalapril. J Hy pertens 1986;4:365-367. Minematsu K, Yamaguchi T, Tsuchiya M, Ito K. Ikeda M, Omae T: Effect of angiotensin convert ing enzyme inhibitor (captopril) on cerebral blood flow in hypertensive patients without a history of stroke. Clin Exp Hypertens 1987;A9:551—557. Waldemar G, Schmidt JF, Andersen AR, Vorstrup S, Paulson OB: Angiotensin converting en zyme inhibition and cerebral blood flow autoregu lation in normotensive and hypertensive man. J Hypertens 1989;7:229-235. Waldemar G, Vorstrup S, Andersen AR, Pedersen H, Paulson OB: Angiotensin-converting enzyme inhibition and regional cerebral blood flow in acute stroke. J Cardiovasc Pharmacol 1989; 14: 722-729. Waldemar G, Ibsen H, Strandgaard S, Paulson OB, Andersen AR, Rasmussen S: The effect of fosinopril sodium on cerebral blood flow in mod erate essential hypertension. Am J Hypertens, in press. Waldemar G, Pedersen EV, Barry DI: Cerebral blood flow autoregulation during angiotensin con verting enzyme inhibition. J Cereb Blood Flow Metab 1987;7(suppl 1):S283. Paulson OB. Waldemar G, Andersen AR, Barry DI, Pedersen EV, Schmidt JF, et al: Role of angio tensin in autoregulation of cerebral blood flow. Circulation 1988;77(suppl I):55—58.
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