Angiotensin II AT2 receptor stimulation increases cerebrovascular resistance during hemorrhagic hypotension in rats

ELSEVIER

Regulatory Peptides 52 (1994)21-29

Angiotensin II AT 2 receptor stimulation increases cerebrovascular resistance during hemorrhagic hypotension in rats Liisa N~iveri 1, Christer Str0mberg, Juan M. Saavedra* Section on Pharmacology, Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892. USA

(Received 22 November 1993; revised version received 12 March 1994; accepted 23 March 1994)

Abstract

The effects of the angiotensin II (ANG II) AT 2 ligand PD 123319 and the AT~ antagonist losartan on cerebral blood flow (CBF) were studied during hemorrhagic hypotension in anesthetized rats using laser-Doppler flowmetry. In the control group CBF remained stable when mean arterial blood pressure (MABP) was lowered from 84 mmHg (baseline) to 45 mmHg, whereafter there was a pressure dependent decrease in CBF indicating inadequacy of autoregulation. Cerebrovascular resistance (CVR) was reduced until MABP 40 mmHg, where a maximum dilation was reached. PD 123319 dosedependently (3-30 mg/kg i.v.) increased CVR through all blood pressures. Losartan 3 mg/kg i.v. bad an effect similar to PD 123319. Selective stimulation of AT E receptors with intravenous A N G II infusion, in the presence of AT, receptor blockade by losartan, also increased CVR. As a result, reduced CBF was seen in the treatment groups. The effects of A N G II and PD 123319 30 mg/kg were antagonized by the nonselective A N G II antagonist Sar~,Ile8-ANG II (4 #g/kg/min i.v.). None of the treatments affected baseline CBF. The results confirm that A N G II contributes to cerebrovascular resistance and participates in the regulation of CBF apparently through AT E receptors. K e y words: PD 123319; Losartan; Laser-Doppler flowmetry; Cerebral blood flow; Sar~,IleS-ANG II

1. Introduction

Angiotensin II ( A N G II) regulates c a r d i o v a s c u l a r function via receptors located in the periphery and in the central nervous system [ 1 ]. A t least two sub* Corresponding author. Fax: + 1 (301) 4020337. x Present address: Department of Pharmacology and Toxicology, University of Helsinki, Helsinki, Finland. Elsevier Science B.V. SSDI 0 1 6 7 - 0 1 1 5 ( 9 4 ) 0 0 0 2 6 - T

types o f A N G II receptors, A T 1 and A T 2, have been characterized [2]. M o s t o f the k n o w n physiological effects o f A N G II, including peripheral v a s o c o n striction, are m e d i a t e d by A T 1 receptors ' [3]. H o w ever, A T 2 receptors were found in cerebral arteries o f the rat [4] and recent findings indicate that A T 2 receptors m a y play a role in the regulation o f cerebral b l o o d flow ( C B F ) [ 5 - 7 ] . In addition to circulating A N G II, the peptide can

22

L. N6veri et al. / Regulatoo' Peptides 52 (1994) 21-29

be formed locally in the arterial wall [8,9] and it has been proposed that cerebrovascular tone is maintained by locally produced A N G II [10]. We have recently shown that both losartan, an AT 1 antagonist, and PD 123319 and CGP 42112 which are AT 2 agonists in this model, shift the autoregulatory limits of CBF towards higher blood pressures during acutely induced hypertension [6,7]. The present study was designed to examine the effect of A N G II receptor ligands on the regulation of CBF during hemorrhagic hypotension.

2. Materials and methods

97 male Sprague-Dawley rats (Zivic-Miller, Zelienople, PA), weighing 270-410 g were anesthetized with a mixture of ketamine (150 mg/kg) and acepromazine (15 mg/kg) i.m. and additional doses were given i,p. as needed to maintain adequate anesthesia. Arterial blood pressure was measured with a Spectramed P23XL transducer (Spectramed, Inc., Oxnard, CA) connected to a cannula inserted in the left femoral artery. The right femoral artery was cannulated for blood withdrawal to lower blood pressure, and to measure blood gases. Experimental drugs were administered in the femoral veins. Cerebrocortical blood flow was measured using laser-Doppler flowmetry (LDF) [ 11,12]. After placing the animals in a stereotaxic frame, the skull was exposed and a small (3 × 3 mm) hole was drilled in the parietal bone leaving the dura mater intact. During drilling, the exposed skull was flushed with saline to prevent thermal injury. A L D F probe (BPM 2, Vasamedics, Inc., St. Paul, MN) was fixed in a position close ( < 1 mm) to the dural surface. Care was taken to avoid any large vessels in the vicinity of the probe tip. The blood pressure and L D F signals were recorded simultaneously using a Grass model 79 polygraph (Grass Instrument Co., Quincy, MA). Rectal temperature was maintained at 36.5-37.5 °C with a heating pad. After starting the drug infusions, blood pressure

was lowered at a rate of approximately 5 mmHg/ min. Arterial blood for blood gas analyses was drawn at baseline, immediately before hemorrhage (5 min post-drug), and when mean arterial blood pressure (MABP) was 50 mmHg and 25 mmHg. The samples were immediately analyzed with a Stat Profile 3 (Nova Biomedical, Waltham, MA) analyzer. The drugs used were the AT 2 selective ligand PD 123319 (1-[ [4-(dimethylamino)-3-methylphenyl]methyl ] - 5 - (diphenylacetyl) - 4,5,6,7 - tetrahydro - 1H imidazo[4,5-c]pyridine-6-carboxylic acid) (ParkeDavis), the AT 1 selective antagonist losartan potassium (Du Pont Merck), the nonselective A N G II antagonist Sarl,IleS-ANG II and human angiotensin II (Peninsula). The experimental groups were (a) saline (n = 7), (b) PD 123319 3 mg/kg (n = 8), 10 mg/kg (n = 8) and 30 mg/kg (n = 6), (c) PD 123319 3 mg/kg + 0.36 mg/ kg/min infusion (n = 8), (d) losartan 1 mg/kg (n = 8) and 3 mg/kg (n = 8), (e) losartan 1 mg/kg + A N G II infusion (n = 7), (f) losartan 1 mg/kg+ A N G II infusion + PD 123319 30 mg/kg (n = 6), (g) Sart,Ile 8A N G II 4 #g/kg/min + PD 123319 30 mg/kg (n = 6), (h) SarI,IleS-ANG II 4 gg/kg/min + A N G I! infusion (n--6). In groups a, b and d, the drugs were given as i.v. injections via the femoral vein, 5 min before starting the hemorrhage, in volumes of 1 ml/ kg. In group c, the injection was followed by continuous i.v. infusion throughout the experiment to examine whether infusion of PD 123319 would be more effective than one bolus injection. In group e, the losartan injection was followed by A N G II infusion. The infusion rate was slowly increased to find the highest dose that did not raise MABP. The mean A N G II dose thus attained was 41 (range 8-152) ng/kg/min. The purpose of this group was to selectively stimulate AT 2 receptors with A N G II. In group f, losartan and A N G II were given as in group e and PD 123319 was injected to examine the possible interaction of PD 123319 and A N G II at the AT, receptors. In groups g and h, Sarl,IleS-ANG II was infused for 5 min, whereafter PD 123319 was injected or A N G II infusion was started. In group

23

L. N~lveri et al. / Regulatory Peptides 52 (1994) 21-29

g, the dose of A N G II was 50 ng/min (130-170 ng/kg/min). To examine whether the experimental drugs affected baseline C B F and M A B P we conducted a time course study. In this study the additional experimental groups were (i) saline 10 #l/min infusion ( n = 7 ) , (j) P D 123319 3 m g / k g + 0 . 3 6 mg/kg/min infusion (n = 6), and (k) losartan 3 mg/kg (n = 6). M A B P and C B F were recorded continuously for 60 min after/during the drug treatment. The experiments were carried out in accordance with the National Institutes of Health guidelines for experimental animal research. The statistical treatment o f the C B F / M A B P curves, the time course experiments and blood gas values included a two-way repeated measures analysis o f variance (drug*MAB P or drug*time). Baseline M A B P s between treatment groups, and within group changes in blood gas values were c o m p a r e d with Tukey's H S D test. Pre-hemorrhage drug effects (baseline vs. 5 min post-drug) on M A B P and C B F were c o m p a r e d with paired t-test [13].

Table 1 MABP at baseline (MABPo) and 5 min after the indicated treatments (MABP~) and % change from baseline CBF at 5 min (CBFs)

Saline PD 123319 3 mg/kg 10 mg/kg 30 mg/kg 3 mg/kg + 0.36 mg/kg/min Losartan I mg/kg 3 mg/kg Losartan 1 mg/kg +ANG II +ANG II+PD 123319 30 mg/kg Sar I +, IIeS-ANG II +PD 123319 30 mg/kg +ANG II

MABPo (mmHG)

MABP5 (mmHg)

CBF 5 (Fo)

84 + 2

84 + 1

83 + 2 82_+3 81-+1 79 + 3

84 +_3 3+ 7 90_+4*** 10+6 79+2 -5-+4 78 -+3 1 _+2

83 _+1 83 _+2

83 _+2 68 _+2**

14 _+7 0 +_4

80-+3 83_+3

81-+4 70_+4*

7-+8 -2_+4

80_+2 81_+2

62_+2*** - 1 _+3 71_+4" 5_+8

7+3

Values are mean + S.E.M. *P<0.05; **P<0.01; *** P<0.001 vs. MABP0 (paired t-test).

3. R e s u l t s

In the 60-min time course experiment (data not shown) there were no differences in baseline M A B P s between the experimental groups. After losartan 3 mg/kg, M A B P acutely decreased, but returned close to baseline within 10 min. Saline or P D 123319 had no effect on M A B P . N o n e of the treatments affected CBF. In the hypotension study drug effects on baseline M A B P and C B F were assessed before hemorrhage, and are given in Table 1. P D 123319 10 mg/kg slightly increased M A B P , and losartan 3 mg/kg, losartan 1 mg/kg + A N G II + P D 123319 30 mg/kg and both Sarl,Ile8-ANG II combinations lowered M A B P . There were no changes in C B F in any of the experimental groups. The overall analysis of the C B F / M A B P curves showed a statistically significant drug effect

( P < 0.05). In the control group C B F remained stable during hemorrhage until M A B P was 40 m m H g below baseline, whereafter C B F decreased steeply and pressure dependently indicating inadequacy of autoregulation. After P D 123319 C B F was reduced through a wide range o f M A B P s (Figs. 1 and 2). T w o - w a y analysis o f variance of the C B F / M A B P curves showed that all P D 123319 doses were different from the saline group (F(1,35) = 8.9, P < 0.01). Figs. 1 and 2 show that the P D 123319 effect was dose dependent. Infusion of the drug did not differ from a similar dose given as a bolus injection (Fig. 2). Comparison of the losartan treatments (groups d and e) gave a marginally significant result ( P < 0.1). However, further comparison indicated that losartan 3 mg/kg and losartan i mg/kg + A N G II infusion were different from saline and losartan 1 mg/kg

24

L. N~iveri eta/. / Regulatory Peptides 52 (1994) 21-29 120

120

~" .c loo

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~

80

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~

60

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100

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3 mg/kg

,

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,

-50 -40 -30 -20 -10 change in MABP (mmHg)

change in NABP (mmHg)

I

0

Fig. 1. Effect of PD 123319, 3 and 30 mg/kg, on CBF during hemorrhagic hypotension. Each curve represents the means + S.E.M. plotted against the change in MABP (in 5 mmHg decrements). All curves start at 0 mmHg and 100~ (baseline). The dashed line shows the drug effect before hemorrhage (Table 1). The solid line indicates CBF during hemorrhage.

Fig. 3. Effect of losartan on CBF during hemorrhagic hypotension. Each curve represents the means + S.E.M. plotted against the change in MABP (in 5 mmHg decrements). All curves start at 0 mmHg and 100 ~o (baseline). The dashed line shows the drug effect before hemorrhage (Table 1). The solid line indicates CBF during hemorrhage.

(F(1,28) 8.3, P<0.01). Thus, losartan had a similar effect to PD 123319 (Fig. 3). Selective stimulation of AT 2 receptors by A N G II in the presence of

AT 1 blockade by losartan 1 mg/kg shifted the curve even further (Fig. 4). The combination oflosartan +

=

120 120 "~ _c

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Fig, 2. Effect of PD 10 mg/kg and 3 mg/kg + 0.36 mg/kg/min on CBF during hemorrhagic hypotension. Each curve represents the means _+S.E.M. plotted against the change in MABP (in 5 mmHg decrements). All curves start at 0 mmHg and 100~o (baseline). The dashed line shows the drug effect before hemorrhage (Table 1). The solid line indicates CBF during hemorrhage.

,/~

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Fig. 4. Effect of AT 2 receptor stimulation by ANG II infusion in the presence of AT~ blockade by losartan 1 mg/kg on CBF during hemorrhagic hypotension. Each curve represents the means +_S.E.M. plotted against the change in MABP (in 5 mmHg decrements). All curves start at 0 mmHg and 100~o (baseline). The dashed line shows the drug effect before hemorrhage (Table 1). The solid line indicates CBF during hemorrhage.

25

L. Naveri et al. / Regulatory Peptides 52 (1994) 21-29 120

120

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ANG II+PD 123319 was not different from losartan + A N G II, but was significantly different from saline ( P < 0.05). Thus, the effects of A N G II a n d P D 123319 were not additive, n o r did P D 123319 antagonize A N G II (Fig. 5). Sarl,IleS-ANG II antagonized both A N G II (Fig. 6) a n d P D 123319 (Fig. 7), since neither c o m b i n a t i o n differed significantly from saline. To determine whether the lowered C B F was due to increased cerebrovascular resistance (CVR), some of the treatments were plotted with CVR against absolute M A B P using the formula CVR = (MABPx/ MABPb)/(CBFx/CBFb), where MABPx and M A B P b are arterial blood pressures at any given pressure and at baseline, respectively. C B F x and C B F b are corresponding C B F values. Since this was only a t r a n s f o r m a t i o n of the data, no additional statistical analysis was done. However, it can be seen that P D 123319 (Fig. 8), and losartan 3 mg/kg and losartan + A N G II (Fig. 9) increased CVR at all M A B P s indicating that this was the probable reason for the reduced CBF.

° S?:'A:~ HAINnGfu:[o4 ug/kg/rnin

I , I , I , I I i , I , -60 -50 -40 -30 -20 -I0

I

0

Fig. 5. Interaction of PD 123319 30 mg/kg and ANG II on CBF during hemorrhagic hypotension in the presence of AT~ blockade by losartan 1 mg/kg. Each curve represents the means + S.E.M. plotted against the change in MABP (in 5 mmHg decrements). All curves start at 0 mmHg and 100% (baseline).The dashed line shows the drug effect before hemorrhage (Table 1). The solid line indicates CBF during hemorrhage.

/

40 I 0

change in MABP (mm Hg)

Fig. 6. Effectof Sarl,lleS-ANOII 4 #g/kg/min + ANG II on CBF during hemorrhagic hypotension. Both curves represents the means + S.E.M. plotted against the change in MABP (in 5 mmHg decrements). Both curves start at 0 mmHg and 100% (baseline). The dashed line shows the drug effect before hemorrhage (Table 1). The solid line indicates CBF during hemorrhage.

Table 2 shows the arterial blood gas values during the experiment. At n o time of analysis were there

120

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change in MABP (mm Hg) Fig. 7. Sarl,lle8-ANG II 4 gg/kg/min antagonizes the effect of PD 123319 30 mg/kg on CBF during hemorrhagic hypotension. Each curve represents the means + S.E.M. Iplotted against the change in MABP (in 5 mmHg decrements). All curves start at 0 mmHg and 100% (baseline). The dashed line shows the drug effect before hemorrhage (Table 1). The solid line indicates CBF during hemorrhage.

26

L. Niiveri et al. I Regulatory Peptides 52 (1994) 21-29

•

c

o pD ,233z9 lo ~,g/k~

:'~U] 100

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123319

T/

30 rng/kg

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100

80

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80 '

Fig. 8. Effect of PD 123319, 10 and 30 mg/kg, on CVR during hemorrhagic hypotension. CVR was calculated as described in Results. Each curve represents the means_+ S.E.M. plotted against absolute MABP (in 5 mmHg decrements).

any differences between the experimental groups. At the MABP 25 mmHg the animals had hypocapnia and a slightly elevated Po_,, which still remained

I

I

.

,

I

40 60 MABP (mm Hg)

80

Fig. 9. Effect oflosartan, 1 and 3 mg/kg and losartan 1 mg/kg+ ANG II on CVR during hemorrhagic hypotension. CVR was calculated as described in Results. Each curve represents the means-+ S.E.M. plotted against absolute MABP (in 5 mmHg decrements).

within the normal range. Arterial pH did not change during the experiment.

Table 2 Arterial blood gas values in the experimental groups Baseline CO, Saline PD 123319 3 10 30 3+inf Losartan 1 3 I+ANGII I+ANGII+

02

pH

5 min post-drug

50 mmHg

CO,

CO-,

02

pH

02

38-+1 87-+2 7.37-+0.00 41_+2 86_+2

7.38-+0.01 39_+1

37_+1 38_+2 39-+1 38_+1

87_+2 92-+4 87+3 85_+3

7.38_+0.01 7.38_+0.01 7.37_+0.01 7.37_+0.01

40_+1 40_+1 41_+1 39_+1

86_+1 90-+4 87-+2 86_+2

7.38-+0.01 37+1 96+2"* 7.38_.+0.01 39-+2 100-+3 7.37_+0.01 40_+2 92+2 7.37_+0.01 37_+1 92_+4

38_+1 40_+1 39_+1 39_+2

87_+2 88_+1 88_+2 89_+2

7.38-+0.01 7.38_+0.01 7.38_+0.01 7.40+0.01

41_+1 42_+2 41_+2 38_+2

87-+2 88_+2 86_+3 89+3

7.38_+0.01 7.39_+0.01 7.39_+0.01 7.39_+0.01

40_+2 41_+2 35+3 38_+2

PD 123319 Sar L, IIeSANG II + P D 123319 36_+1 88_+1 7.40_+0.01 38_+1 94_+1" 7.39_+0.00 39_+1 +ENGII 38_+1 85_+2 7.40-+0.01 38-+1 89_+2 7.40_+0.01 38+1

93 -+ 3

25 mmHg pH

CO 2

O2

pH

7.38 -+0.00 29 _+2*** 108 _+4

7.40 -+0.02

7.40+0.00 7.39-+0.01 7.48_+0.01 7.38_+0.01

28+2"** 30-+2* 30-+2* 25_+2***

110+2"** 115_+3"** 108+1"** 110_+2"**

7.41-+0.01 7.41_+0.01 7.40_+0.01 7.40_+0.01

96_+2 7.40_+0.01 30_+3* 93+3 7.39_+0.01 31_+2"* 98 -+ 2* 7.41 -+ 0.01 25 + 3*** 95_+3 7.39-+0.01 32+1"**

113_+3'** 113+_5"** 108 _+2*** 106_+2"**

7.43-+0.01 7.42+0.01 7.43 _+0.02 7,4t_+0.01

95_+2* 7.38_+0.01 31_+2"** 107+3'** 7.41_+0.01 91 + 2** 7.41 + 0.01 32 -+2*** 103 -+ 2*** 7,41 -+ 0.02

Values are mean -+ S.E.M.; *P<0.05, **P<0.01, ***P<0.001 vs. Baseline (Turkey's test).

L. Nilveri et al. / Regulatory Peptides 52 (1994) 21-29

4. Discussion We previously demonstrated that in the rat both peptide and nonpeptide A N G II ligands extend the upper limit of CBF autoregulation and that AT 2 receptors appear to mediate this effect [6,7]. The present results offer further evidence for AT 2 mediated cerebrovascular regulation by demonstrating that AT 2 receptor stimulation increases CVR during hemorrhage. A N G II induces contraction in cerebral arteries, both in vivo [14-16] and in vitro [17,18]. ACE inhibition prevents A N G II formation and A N G I induced contractions in large cerebral arteries [17,19]. A hypothesis forwarded by Paulson and co-workers [ 10] suggests that locally produced A N G II contributes to cerebrovascular resistance, and thus plays a role in the autoregulation of CBF. Our earlier finding that A N G II shifted the upper limit of CBF autoregulation towards higher blood pressures [6] agrees with such hypothesis. In the present experiment, PD 123319 increased CVR and reduced CBF, effects that are seemingly opposite to that seen previously after ACE inhibition [20,21 ]. This is in agreement with PD 123319 being an AT 2 receptor agonist as we suggested earlier [6], in contrast to previous studies where PD 123319 acts as an antagonist [22-25]. We also recently found that C G P 42112, another AT2 selective agonist [23,25] caused a similar effect on CBF as PD 123319 [7]. The effects of both these compounds were blocked, like the effects of PD 123319 and A N G II in the present experiment, by the nonselective A N G II antagonist Sar~,IleS-ANG II. Further, the selective stimulation of AT 2 receptors (present results) with A N G II in the presence of the AT~ receptor blocker losartan also increased CVR. These data are consistent with A N G II mediated constriction, through AT 2 receptor stimulation, of cerebral arteries. Since the effects of PD 123319 and A N G II were not additive, it appears that these drugs have a common mechanism of action. The slight, but nonsignificant attenuation of the A N G II effect by PD

27

123319 may indicate that PD 123319 is a partial agonist, which could also explain why both antagonist [22-25] and agonist (Ref. 7; present results) effects have been observed with this compound [26]. It should, however, be emphasized that there are difficulties in interpreting the results from experiments where losartan and PD 123319 were coadministered, since these drugs may interact with each other. In the present study, losartan + PD 123319 reduced MABP, whereas the same doses of the drugs given alone had no hypotensive effects. A possible explanation is displacement oflosartan from plasma protein binding by PD 123319, as has been shown for the related compound PD 123177 by Wong et al. [27]. In the present experiments, losartan 1 mg/kg + PD 123319 reduced MABP similarly to losartan 3 mg/kg. We have previously speculated on a role of AT 1 receptors on CBF autoregulation [6]. This was based on the observation that the AT Lselective losartan had a similar effect to the AT 2 selective PD 123319. Since both compounds are highly selective for their receptor subtypes [3,28], it is unlikely that they would have interacted with the other subtype in the doses used. However, in the present study, the lower dose of losartan (1 mg/kg) had no effect on CBF or CVR, although this dose has been shown to readily block AT1 mediated responses in rats [29]. Losartan could cause its CBF effects by acting on a brain structure located inside the blood-brain barrier, but this is unlikely since chronically administered losartan does not readily cross the blood-brain barrier [30]. Also, the brain renin-angiotensin system does not contribute to the modulation of CBF by captopril [31]. Therefore, it is questionable whether AT 1 receptors play a direct role in the regulation of CBF. The effect of losartan 3 mg/kg could have been either indirect or nonspecific. The inability of Sar~,IIe8-ANG II to block the effect oflosartan on CBF [7], may indicate that its effect is independent of A N G II. There are also reports demonstrating a dilating effect of A N G II on rat and rabbit brain arterioles

28

L. NOveri et al. / Regulatoo" Peptides 52 (19941 21-29

by an endothelium-dependent mechanism [32,33]. This dilatory effect has been p r o p o s e d to be due to A N G I I ( 3 - 8 ) , a natural d e g r a d a t i o n p r o d u c t o f A N G II [33], for which a distinct binding site was recently discovered [34]. This new site is found in different cell types and in a variety o f tissues and species and is not recognized by k n o w n A T j or A T 2 selective ligands, including losartan a n d P D 123177 [34]. Therefore, it is unlikely that our earlier [ 5 - 7 ] or present results on A N G II effects on C B F involve the A N G I I ( 3 - 8 ) binding site. W e have also recently found that A N G II is a constrictor o f the rat anterior cerebral artery in vitro (unpublished results). In conclusion, our d a t a s u p p o r t the hypothesis that A N G II contributes to c e r e b r o v a s c u l a r resistance and plays a role in regulation of C B F [ 10,35]. High levels o f circulating A N G II during hypotension m a y be detrimental and of m a j o r clinical importance. A c u t e lowering of b l o o d pressure a p p a r ently may have c a u s e d lethal cerebral hypoperfusion in patients with hyperangiotensinemic hypertension [36,37]. O n the other hand, A N G II might have a protective effect against strokes during acute hypertension [38]. O f special interest is that these effects o f A N G II seem to be m e d i a t e d by the A T z receptors. N o w it b e c o m e s possible to m o d u l a t e this system without interfering with the b l o o d pressure regulating A T t receptors. It remains to be seen whether specific A T 2 agonists, or antagonists, prove to be beneficial in the t r e a t m e n t or prevention of some c e r e b r o v a s c u l a r disorders. If so, it a p p e a r s that such treatments could be a c c o m p l i s h e d without other m a j o r c a r d i o v a s c u l a r c o n s e q u e n c e s or overt adverse effects.

Acknowledgements We thank Dr. David G. Taylor, Jr., Parke-Davis, A n n Arbor, M I , for donating P D 123319 and Dr. R o n a l d D. Smith, D u P o n t M e r c k , Wilmington, D E , for donating losartan.

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