(Hypertension. 2000;35:1105.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Effect of Lovastatin on Cerebral Circulation in Spontaneously Hypertensive Rats
From the Laboratoire de Pharmacologie Cardiovasculaire (O.R., J.A., C.C.-A., P.L., J.-M.C.), Faculté de Pharmacie, Nancy, France.
Correspondence to Jeffrey Atkinson, PhD, Laboratoire de Pharmacologie Cardiovasculaire, Faculté de Pharmacie, UHP—Nancy 1, 5, rue Albert Lebrun, BP 403, 54000 Nancy, France. E-mail atkinson{at}pharma.u-nancy.fr
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Statins, which are often given to hypertensive patients, reduce the incidence of stroke. However, their effects on the cerebral circulation have been scarcely studied, although lovastatin has been reported to reduce hypertension-induced renal arteriolar hypertrophy. We examined the structure and mechanics of cerebral arterioles and the lower limit of cerebral blood flow (CBF) autoregulation in spontaneously hypertensive rats (SHR) that were untreated (n=9) or treated for 1 month with lovastatin (n=12; 20 mg · kg-1 · d-1) and in untreated Wistar-Kyoto rats (WKY; n=8). We studied the lower limit of CBF autoregulation by repeated measurement of CBF (arbitrary units; laser Doppler) and internal arteriolar diameter (µm; cranial window) at baseline and during stepwise hypotension. Stress-strain relationships were calculated from repeated measurement of internal arteriolar diameter during stepwise hypotension and cross-sectional area (CSA) of the vessel wall in maximally dilated cerebral arterioles (EDTA, 67 mmol/L). Lovastatin slightly reduced mean arterial pressure (treated, 153±3 versus untreated, 171±5 mm Hg, P<0.05; WKY, 106±3 mm Hg) and normalized CSA (treated, 826±52 versus untreated, 1099±16 µm2, P<0.05; WKY, 774±28 µm2). Stress-strain curves show that lovastatin also attenuated the increase in passive distensibility. Lovastatin had no effect on the external diameter of cerebral arterioles or the lower limit of CBF autoregulation. Our results show that although lovastatin has substantial effects on arteriolar mechanics and wall CSA, it has little effect on internal diameter. This phenomenon may explain its lack of effect on CBF autoregulation.
Key Words: hypertrophy • remodeling • inhibitors, HMG-CoA reductase • autoregulation
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patients with high cholesterol are treated with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins); at least one third of these patients also suffer from hypertension.1 Meta-analysis of clinical trials reveals that statins reduce the incidence of ischemic stroke,1 2 and the data have been interpreted as evidence of a cholesterol-independent effect of statins on cerebrovascular disease.1 Lovastatin can reduce renal arteriolar-wall hypertrophy in spontaneously hypertensive rats (SHR).3 However, at the present time, little is known about the effects of statins on cerebral arteriolar structure and mechanics in hypertensive rats and how such effects may modify cerebral blood flow (CBF) autoregulation.
The first goal of the present study was to examine the effects of chronic treatment (1 month) with lovastatin on cerebral arteriolar structure and passive distensibility in SHR. The second goal was to determine whether modification of the structure and passive distensibility has any effect on the lower limit of CBF autoregulation in SHR.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animal Preparation
Experiments were performed on male Wistar-Kyoto rats (WKY) and male SHR (Iffa-Credo, l’Arbresle, France). At 10 weeks of age, SHR were divided into 2 groups: a group that received lovastatin in the drinking water (20 mg · kg-1 · d-1; n=12) and a group that received vehicle (n=9). A group of WKY that drank vehicle served as normotensive controls (n=8).
Lovastatin was prepared twice weekly by dissolving the base in warm (55°C) ethanol (95° vol/vol; 2 mL per 100 mg of lovastatin) plus NaOH 0.6N (1 mL per 100 mg of lovastatin) dissolved in demineralized water (22 mL per 100 mg of lovastatin) as previously described.4 After 30 minutes at 22°C to complete the conversion of lovastatin to the sodium salt, the final lovastatin solution (4 mg/mL) was adjusted to pH 8.0 with HCl. This solution was then diluted 20 times with demineralized water such that rats received 20 mg · kg-1 · d-1 of lovastatin. Water consumption and body weight were determined twice per week. Control animals received a solution prepared in the same way, except that lovastatin was omitted. Animals were allowed free access to food and drinking fluid and housed at 24°C. Experiments were performed in accordance with the guidelines of the European Union and the French Ministry of Agriculture (permits Nos. 54-4 and 03575).
After 1 month of treatment, we examined the cerebral circulation and the structure and mechanics of cerebral arterioles. Animals were anesthetized with sodium pentobarbital (60 mg · kg-1 IP). A polyethylene cannula (Merck Biotrol) was introduced into the left femoral artery and connected to a low-volume strain-gauge transducer (Baxter; Bentley Laboratories) for measurement of blood pressure and heart rate. A polyethylene cannula (Merck Biotrol) was introduced into the right femoral artery to withdraw blood for measurement of arterial blood gases and production of hypotension. A silicone catheter (Sigma Medical) was introduced into a femoral vein and connected to a pump (Bioblock Scientific) for infusion of sodium pentobarbital (0.25 mL · h-1; 20 mg · kg-1 · h-1) throughout the experiment to maintain anesthesia. Animals were intubated and mechanically ventilated with room air (60 strokes · min-1; 10 mL · kg-1). Paralysis of skeletal muscles was obtained with an injection of gallamine triethiodide (20 mg · kg-1 IV) repeated every hour. Rectal temperature was maintained at 37°C with a heating pad. Because the animals were paralyzed, the depth of anesthesia was periodically evaluated by application of pressure to the tail and confirmation of the absence of changes to heart rate and blood pressure.
Measurement of Arteriolar Inner Diameter
We measured internal diameter in first-order arterioles of the
cerebrum5 through an open-skull
preparation.6 7 The head was placed in an adjustable head
holder. A 1-cm incision was made in the skin to expose the skull. Ports
were placed for inflow and outflow of artificial cerebrospinal fluid
(CSF). Craniotomy was performed over the left parietal
cortex, and the dura was incised to expose cerebral vessels. The
exposed brain was continuously suffused with artificial CSF warmed to
37°C to 38°C and equilibrated with a gas mixture of 5%
CO2/95% N2. The
composition of the CSF was (in mmol/L) KCl 3.0,
MgCl2 0.6, CaCl2 1.5, NaCl
131.9, NaHCO3 24.6, urea 6.7, and glucose
3.7.6 7
Arterioles were monitored through a microscope (Stemi 200-C, Carl Zeiss Jena GMBH) connected to a closed-circuit video system with a final magnification of x400. Images of arterioles were digitized using a video-frame grabber. Arteriolar inner diameter was measured from the digitized images by use of image-analysis software (Saisam, Microvision Instruments); the precision of this system is 0.5 µm or 0.4% to 1.2%, depending on measured diameter.
Measurement of CBF
CBF was measured by laser Doppler flowmetry with a
BLF 21 system (Transonic Systems Inc) equipped with a 1.2-mm-diameter
needle probe.8 The probe was placed through the cranial
window into the CSF above the surface of the brain stem. CBF was
expressed in arbitrary units or as percentage of baseline changes in
CBF during stepwise hypotension.
Experimental Protocol
Thirty minutes after completion of surgery, cerebral arteriolar
inner diameter was measured at baseline. Stepwise hypotension (10
mm Hg per step) decreasing to 20 to 30 mm Hg was induced by
controlled withdrawal of blood. At each step, systemic pressure,
arteriolar inner diameter, CBF, and blood gases were measured 1 minute
after the decrease in blood pressure. Ventilation (volume and rate) was
adjusted as a function of blood gases such that pH,
PaO2, and
PaCO2 were maintained within the
physiological range. After the final stepwise fall
in blood pressure, blood was reinjected and blood pressure returned to
prehemorrhage values.
Vascular smooth muscle was fully relaxed by suffusion of cerebral vessels with artificial CSF that contained the calcium chelator EDTA (67 mmol/L), which produces complete deactivation of smooth muscle in cerebral arterioles.9 Pressure–internal diameter relationships were obtained in deactivated cerebral arterioles from a mean arterial pressure of 130 to 20 mm Hg by use of hemorrhage to reduce pressure (steps of 10 mm Hg). At each pressure step, arteriolar diameter reached steady state within 15 seconds, and inner diameter was measured 30 seconds later. After the final step, blood was reinjected to restore blood pressure. Arterioles, maximally dilated by EDTA, were fixed at their physiological pressure in vivo by suffusion with glutaraldehyde (2.25% vol/vol 0.10 mol/L cacodylate buffer). Arterioles were considered to be fixed adequately when blood flow ceased. After the animal was euthanatized, the arteriolar segment was removed and embedded in paraffin.
The cross-sectional area (CSA) of the arteriolar wall was determined on 7-µm sections by use of the video image analyzing system described above. Luminal and total (lumen plus vessel wall) CSA of the arteriole were measured by tracing the luminal and outer edges of the vessel wall. CSA of the vessel wall was calculated by subtraction of luminal CSA from total CSA.
Calculations of CBF Autoregulation Characteristics
Cerebral arteriolar inner diameter and blood flow values are
reported as absolute values or as percentage change from baseline. For
each group, CBF (absolute values and percentage of baseline), internal
diameter (absolute values), arterial pressure, heart rate,
and blood gas values were presented in the form used by Barry
et al.10 Values were pooled and grouped by categories over
mean arterial pressure ranges of 10 mm Hg. One-way
ANOVA within these different mean arterial pressure ranges
was performed for each treatment group. The lower limit of CBF
autoregulation was defined as the lower limit of the lowest mean
arterial blood pressure range in which CBF was not
significantly less than baseline CBF. The security margin (percentage),
which indicates the degree to which mean arterial pressure
may fall before CBF starts to decrease, was calculated as [(baseline
mean arterial blood pressure-lower limit of CBF
autoregulation)x100]/baseline mean arterial blood
pressure.11
Calculation of Mechanical Characteristics
The assumptions on which we based the calculations of
circumferential stress and strain and tangential elastic modulus have
been described in detail previously.9 12 However, note
that in the present experiments, systemic arterial
pressure was used and not pial arteriolar pressure as previously
described. The rationale for this approach is based on published
data13 14 that show a linear relationships between
systemic pressure (x) and pial arteriolar pressure
(y) in cats. Furthermore, similar linear relationships were
also found in SHR:
[y=(0.61±0.02)x-(10.9±2.2)]
and WKY [y=(0.61±
0.01)x-(8.0±0.9)] (G.L. Baumbach, MD, personal
communication, 1999). Finally, the stress-strain curves that we
obtained in the present experiments were similar to those obtained
with pial arteriolar pressure measurements.15 16
Circumferential stress 
at each pressure step was calculated from
systemic arterial pressure P, inner diameter of
cerebral arterioles Di, and wall thickness
WT:
=(PxDi)/(2WT).
Systemic arterial pressure was converted from millimeters
of Hg to newtons per meter squared (1.334x102).
On the basis of the assumption that the volume of the vessel wall does
not change with changes in vessel diameter and
pressure17 and on the previous finding that changes
in vessel length during reductions in pressure are
small,18 wall thickness was calculated from CSA of the
vessel wall and cerebral arteriolar internal diameter:
WT=[(4CSA/
+Di2)1/2-Di]/2.
External diameter De was calculated as
De=Di+2WT.
Histological determinations of CSA were used in all
calculations of wall thickness and circumferential stress.
Circumferential strain 
was calculated as
=(Di-Do)/Do,
where Do is internal diameter at 20
mm Hg of pressure.
To obtain the tangential elastic modulus, the stress-strain data from
each animal were fitted to an exponential equation
(y=aebx)
by use of least-squares analysis:
=oeße,
where o is stress at the pressure step of
20 to 29 mm Hg and ß defines the rate of increase of the
stress-strain curve. Tangential elastic modulus
ET was calculated as
ET=d/d=ßoebe.
.
Substances Used
Gallamine triethiodide was purchased from Sigma Chemical Co,
N2 from Air Liquide, sodium pentobarbital from
Sanofi Santé Animale, and KCl, MgCl2,
CaCl2, NaCl, NaHCO3, urea,
and glucose from Merck KGaA. Lovastatin was a gift from MSD
Research Laboratories (Paris, France).
Statistical Analysis
Results are expressed as mean±SEM. The experimental protocol
was designed to use 1-way ANOVA with the variable "group" (WKY,
SHR untreated, and SHR treated with lovastatin).
Significant differences between means were determined with the
Bonferroni test. One-way ANOVA with the variable "mean
arterial blood pressure range" was performed separately
for each treatment group for the analysis of values obtained
after hypotensive hemorrhage. The probability level chosen was
P
0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Baseline Values
Lovastatin significantly decreased mean arterial blood pressure in SHR (11±4%), but pressure remained higher than in WKY. Heart rate, pH, and blood gases were similar in all groups. Lovastatin significantly increased internal diameter of cerebral arterioles before deactivation (21±8%), but diameter remained smaller than in WKY. Lovastatin increased internal diameter of cerebral arterioles after deactivation to a level that was not significantly different to that observed in WKY and also normalized CSA (see Table).
|
Vascular Mechanics
After arterioles were deactivated, external
diameter was significantly less in treated and untreated SHR than in
WKY at mean arterial pressures of 130 to 20 mm Hg
(Figure 1).
|
; n=8) and SHR that were untreated (
; n=9) or
treated with lovastatin (
; n=12). Values are mean±SEM.
*PThe stress-strain curve in cerebral arterioles of untreated SHR was shifted to the right of the WKY curve (Figure 2), and the slope of tangential elastic modulus versus stress was significantly less in untreated SHR than in WKY (Table). Thus, passive distensibility was increased in cerebral arterioles of SHR, despite hypertrophic inward remodeling of the vessel wall. Lovastatin attenuated the rightward shift of the stress-strain curve (Figure 2) and the decrease in the slope of tangential elastic modulus versus stress (Table).
|
Lower Limit of CBF, Security Margin, and Dilatation of
Cerebral Arterioles
After hypotensive hemorrhage in WKY, CBF remained constant
until the 50 to 59 mm Hg pressure range and then significantly
decreased; the lower limit of CBF autoregulation was 50 mm Hg,
and the security margin, which indicates the degree to which mean
arterial pressure may fall before CBF starts to decrease,
was 53% (Figure 3).The
lower limit of CBF autoregulation was shifted to the higher mean
arterial blood pressure values of 90 mm Hg in
untreated SHR and 80 mm Hg in treated SHR, but the security
margin remained constant (47% and 48%, respectively) (Figure 3).
|
In WKY, cerebral arterioles dilated significantly at pressures <50 mm Hg; maximal dilatation (38±3%) was observed at 20 to 29 mm Hg. In SHR, cerebral arterioles dilated significantly at pressures <70 mm Hg and maximal dilatation (40±4%) was observed at 40 to 49 mm Hg. In SHR treated with lovastatin, cerebral arterioles dilated significantly at pressures <60 mm Hg and maximal dilatation (36±4%) was observed at 30 to 39 mm Hg. In SHR, the internal diameter was significantly less than in WKY at each pressure step (Figure 4).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Chronic hypertension modifies the responses of cerebral blood vessels to acute decreases in pressure,19 which shifts the lower limit of CBF autoregulation toward higher levels of blood pressure.20 21 Such altered vascular responsiveness may be due in part to hypertrophic inward remodeling of the vessel wall, which encroaches on the vascular lumen and reduces internal diameter.22 23 24 The reduction in internal diameter is also due to eutrophic inward remodeling, defined as a decrease in external diameter with no reduction in vascular passive distensibility.25 Inward remodeling allows the cerebral circulation to adapt to the higher blood pressure level and protects the brain against stroke. After treatment of hypertension, if the reduction in blood pressure is not accompanied by an increase in maximal vasodilation capacity, the risk of cerebral ischemia will increase.26 In the present study, lovastatin decreased hypertrophic inward remodeling of the vessel wall and attenuated the increase in passive distensibility in SHR but had no effect on eutrophic inward remodeling or CBF autoregulation.
Remodeling
Although pressure is an important determinant of hypertrophic
inward remodeling,18 27 in the present study,
lovastatin reduced hypertrophic inward remodeling but had
little effect on systemic blood pressure. At least 3 hypotheses could
explain this apparent discrepancy. First, although a close correlation
exists between systemic and arteriolar pressures in normotensive and
hypertensive models (see Methods), this may not be the case after
treatment. We cannot rule out the possibility that
lovastatin, even if it has a small but significant effect
on systemic pressure, does not normalize mean or pulse pial arteriolar
pressure. Previous work showed that a minor fall in pulse arteriolar
blood pressure was accompanied by a major change in CBF
autoregulation28 and in wall
hypertrophy.12 Second, HMG-CoA reductase
inhibitors such as lovastatin inhibit
isoprenoid synthesis and prenylation of key cellular proliferation
proteins such as members of the ras and rho
families.29 30 31 Thus, they may modify CSA of the vessel
wall independent of any change in blood pressure. Finally, HMG-CoA
reductase inhibitors enhance eNOS activity.32
We have previously reported that NO may reduce hypertrophic inward
remodeling in cerebral arterioles in hypertensive rats.7
Cerebral arterioles in SHR also undergo eutrophic inward remodeling; ie, a reduction in external diameter that cannot be attributed to a decrease in passive distensibility.33 Lovastatin did not significantly alter external diameter in SHR.
The prevention by lovastatin of hypertrophic inward remodeling and the nonsignificant effect on external diameter may be responsible for the small but significant increase in internal diameter that we observed before deactivation of cerebral arterioles in SHR treated with lovastatin.
During chronic hypertension in SHR, structural alterations of cerebral arterioles impair maximal diameter in deactivated arterioles and contribute to the increase in the lower limit of CBF autoregulation. A previous report found that hypertrophic inward remodeling accounts for only 25% of encroachment on the lumen, the remaining 75% being due to eutrophic inward remodeling.25 Thus, in the present experiment, although it prevented hypertrophic inward remodeling, lovastatin failed to decrease the lower limit of CBF autoregulation, because the treatment did not attenuate eutrophic inward remodeling.
Vascular Distensibility
Passive distensibility of cerebral arterioles increases in SHR,
despite hypertrophic inward remodeling.33 This may be due
to a reduction in the proportion of stiff (collagen and basement
membrane) to compliant (smooth muscle, elastin, and
endothelium) components.9 18 33 34
Therefore, lovastatin may attenuate the increase in passive
distensibility by decreasing the proportion of smooth muscle cells and
thus may modify diameter measured after deactivation. A small
(nonsignificant) effect was observed that could be linked to the effect
of lovastatin on isoprenoid synthesis. However, the change
in passive distensibility does not lead to any change in the lower
limit of CBF autoregulation; this may not be the case for the upper
limit of CBF autoregulation, which remains to be investigated.
Conclusions and Implications
Treatment with lovastatin in SHR prevented
hypertrophic inward remodeling of the cerebral arteriole vessel wall
and attenuated increases in passive distensibility but had no effect on
cerebral arteriolar eutrophic inward remodeling. Given that eutrophic
inward remodeling is the main determinant of cerebral vasodilatation,
the lower limit of CBF autoregulation was not modified by
lovastatin, and despite marked reduction in hypertrophic
inward remodeling, the cerebral circulation of SHR treated with
lovastatin remained well adapted to the high level of blood
pressure.
The benefit of the treatment with lovastatin is that although it prevented arteriolar wall hypertrophy, it did not modify the way in which the cerebral circulation adapts to high blood pressure. This effect is probably due to its lack of effect on eutrophic inward remodeling. Furthermore, at the present time, we have no information on the effects of longer treatment with lovastatin, on the effects of an association lovastatin plus an antihypertensive drug, or on the effect of lovastatin on carotid artery distensibility and its subsequent effect on the cerebral circulation.
|
Acknowledgments |
|---|
The present study was funded by grants from the French Ministry of Education and Research (EA/JE2166, Paris, France), the Regional Development Committee (Metz, France), the Greater Nancy Urban Council (Nancy, France), and the Henri Poincaré University (Nancy, France). The authors thank Merck Research Laboratories (Paris, France) for the gift of lovastatin.
Received September 23, 1999; first decision October 25, 1999; accepted January 6, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Blauw GJ, Lagaay AM, Smelt AHM, Westendorp RGJ.
Stroke, statins, and cholesterol: a meta-analysis
of randomized, placebo-controlled, double-blind trials with HMG-CoA
reductase inhibitors. Stroke. 1997;28:946–950.
[Abstract/Free Full Text] - Crouse JR, Byington RP, Furberg CD. HMG-CoA reductase inhibitor therapy and stroke risk reduction: an analysis of clinical trials data. Atherosclerosis. 1998;138:11–24.[Medline] [Order article via Infotrieve]
-
Jiang J, Roman RJ. Lovastatin prevents
development of hypertension in spontaneously hypertensive rats.
Hypertension. 1997;30:968–974.
[Abstract/Free Full Text] - Kita T, Brown MS, Goldstein JL. Feedback regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in livers of mice treated with mevinolin, a competitive inhibitor of the reductase. J Clin Invest. 1980;66:1094–1100.
-
Harper SL, Bohlen HG. Microvascular adaptation in the
cerebral cortex of adult spontaneously hypertensive rats.
Hypertension. 1984;6:408–419.
[Abstract/Free Full Text] -
Chillon JM, Heistad DD, Baumbach GL. Effects of
endothelin receptor inhibition on cerebral arterioles in hypertensive
rats. Hypertension. 1996;27:794–798.
[Abstract/Free Full Text] -
Chillon JM, Ghoneim S, Baumbach GL. Effects of chronic
nitric oxide synthase inhibition on cerebral arterioles in rats.
Hypertension. 1997;30:1097–1104.
[Abstract/Free Full Text] -
Fuji K, Heistad DD, Faraci FM. Role of the basilar
artery in the regulation of blood flow to the brain stem in the rats.
Stroke. 1991;22:763–767.
[Abstract/Free Full Text] - Baumbach GL, Walmsley JG, Hart MN. Composition and mechanics of cerebral arterioles in hypertensive rats. Am J Pathol. 1988;133:464–471.[Abstract]
- Barry DI, Strandgaard S, Graham DI, Braendstrup O, Svendsen UG, Vorstrup S, Hemmingsen R, Bolwig TG. Cerebral blood flow in rats with renal and spontaneous hypertension: resetting of the lower limit of autoregulation. J Cereb Blood Flow Metab. 1982;2:347–353.[Medline] [Order article via Infotrieve]
- Lartaud I, Bray-des-Boscs L, Chillon JM, Atkinson J, Capdeville-Atkinson C. In vivo cerebrovascular reactivity in Wistar and Fischer 344 rat strains during aging. Am J Physiol. 1993;264(Heart Circ Physiol 26):H851–H858.
- Baumbach GL, Heistad DD. Adaptive changes in cerebral blood vessels during chronic hypertension. J Hypertens. 1991;9:987–991.[Medline] [Order article via Infotrieve]
- Kontos HA, Wei EP, Navari RM, Levasseur JE, Rosenblum WI, Patterson JLJ. Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am J Physiol. 1978;234:371–383.
-
Stromberg DD, Fox J. Pressures in the pial
arterial microcirculation of the cat during changes in
systemic arterial blood pressure. Circ Res. 1972;31:229–239.
[Abstract/Free Full Text] - Chillon JM, Baumbach GL. Functional and structural alterations of cerebral arterioles in chronic hypertension induced by nitric oxide synthesis inhibition. Br J Pharmacol. 1995;114:127P. Abstract.
- Baumbach GL, Heistad DD. Mechanics of cerebral arterioles in chronic hypertension. In: Halpern W, Pegram BL, Brayden J, MacKay K, McLaughlin M, Osol G, eds. Second International Symposium on Resistance Arteries. Ithaca, NY: Perinatology Press,; 1988;355–361.
- Dobrin PB, Rovick AA. Influence of vascular smooth muscle on contractile mechanics and elasticity of arteries. Am J Physiol. 1969;217:1644–1651.
-
Baumbach GL, Siems JE, Heistad DD. Effects of local
reduction in pressure on distensibility and composition of cerebral
arterioles. Circ Res. 1991;68:338–351.
[Abstract/Free Full Text] -
Jones JV, Fitch W, McKenzie ET, Strandgaard S, Harper
AM. Lower limit of cerebral blood flow autoregulation in experimental
renovascular hypertension in the baboon. Circ Res. 1976;39:555–557.
[Abstract/Free Full Text] - Barry DI, Lassen NA. Cerebral blood autoregulation in hypertension and effects of hypertensive drugs. J Hypertens. 1984;2:S519–S526.
- Barry DI. Cerebral blood flow in hypertension. J Cardiovasc Pharmacol. 1985;7:S94–S98.
- Folkow B, Grimby G, Thulesius O. Adaptive structural changes of the vascular walls in hypertension and their relation to the control of the peripheral resistance. Acta Physiol Scand. 1958;44:255–272.[Medline] [Order article via Infotrieve]
- Folkow B. The fourth Volhard lecture: cardiovascular structural adaptation: its role in the initiation and maintenance of primary hypertension. Clin Sci Mol Med Suppl. 1978;4:3s–22s.[Medline] [Order article via Infotrieve]
- Folkow B, Hallbäck M, Lundgren Y, Sivertsson R, Weiss L. Importance of adaptive changes in vascular design for establishment of primary hypertension, studied in man and in spontaneously hypertensive rats. Circ Res. 1973;32:I-2–I-16.
-
Baumbach GL, Heistad DD. Remodeling of cerebral
arterioles in chronic hypertension. Hypertension. 1989;13:968–972.
[Abstract/Free Full Text] - Paulson OB, Strandgaard S. Antihypertensive treatment and the cerebral circulation. J Cardiovasc Pharmacol. 1987;10:S104–S107.
-
Baumbach GL. Effects of increased pulse pressure on
cerebral arterioles. Hypertension. 1996;27:159–167.
[Abstract/Free Full Text] -
Lartaud I, Makki T, Bray-des-Boscs L, Niederhoffer N,
Atkinson J, Corman B, Capdeville-Atkinson C. Effect of chronic ANG
I-converting enzyme inhibition on aging processes, IV: cerebral blood
flow autoregulation. Am J Physiol. 1994;267:R687–R694.
[Abstract/Free Full Text] - Hughes AD. The role of isoprenoids in vascular smooth muscle: potential benefits of statins unrelated to cholesterol lowering. J Hum Hypertens. 1996;10:387–390.[Medline] [Order article via Infotrieve]
- Nègre-Aminou P, van Vliet AK, van Erck M, van Thiel GCF, van Leeuwen REW, Cohen LH. Inhibition of proliferation of human smooth muscle cells by various HMG-CoA reductase inhibitors; comparison with other human cell types. Biochim Biophys Acta. 1997;1345:259–268.[Medline] [Order article via Infotrieve]
- Munro E, Patel M, Chan P, Betteridge L, Clunn G, Gallagher K, Hughes A, Schachter M, Wolfe J, Sever P. Inhibition of human vascular smooth muscle cell proliferation by lovastatin: the role of isoprenoid intermediates of cholesterol synthesis. Eur J Clin Invest. 1994;24:766–772.[Medline] [Order article via Infotrieve]
-
Endres M, Laufs U, Huang Z, Nakamura T, Huang P,
Moskowitz MA, Liao JK. Stroke protection by 3-hydroxy-3-methylglutaryl
(HMG)-CoA reductase inhibitors mediated by
endothelial nitric oxide synthase. Proc Natl Acad
Sci U S A. 1998;95:8880–8885.
[Abstract/Free Full Text] -
Baumbach GL, Hadju MA. Mechanics and composition of
cerebral arterioles in renal and spontaneously hypertensive rats.
Hypertension. 1993;21:816–826.
[Abstract/Free Full Text] -
Baumbach GL, Heistad DD, Siems JE. Effect of
sympathetic nerves on composition and distensibility of cerebral
arterioles in rats. J Physiol. 1989;416:123–140.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  S. Delbosc, J.-P. Cristol, B. Descomps, A. Mimran, and B. Jover Simvastatin Prevents Angiotensin II-Induced Cardiac Alteration and Oxidative Stress Hypertension, August 1, 2002; 40(2): 142 - 147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M Lefer, R. Scalia, and D. J Lefer Vascular effects of HMG CoA-reductase inhibitors (statins) unrelated to cholesterol lowering: new concepts for cardiovascular disease Cardiovasc Res, February 1, 2001; 49(2): 281 - 287. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||