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20.
21.
22.
23.
24.
STROKE
effect of bilateral carotid artery ligation and the morphometry of the
main communicating circuit in normotensive and spontaneously
hypertensive rats. Acta Physiol Scand 121: 241-247, 1984
Green EC: The anatomy of the rat. Hafner Publ Co, New York,
1959
Furuyama M: Histometrical investigations of arteries in reference
to arterial hypertension. Tohoku J Exp Med 76: 388-414, 1962
Folkow B, Neil E: Circulation, P. 46. Oxford University Press,
1971
Folkow B: Description of the myogenic hypothesis. Circ Res 1415 Suppl I: 279-287, 1964
Nordborg C, Ivarsson H, Johansson BB, Stage L: Morphometric
study of mesenteric and renal arteries in spontaneously hyperten-
VOL
16,
No
2,
MARCH-APRIL
1985
sive rats. J Hypertension 1: 333-338, 1983
25. Nordborg J, Johansson BB: Cerebral arterial morphometry in
young and adult stroke-prone spontaneously hypertensive rats. In:
Hypertensive Mechanisms, pp 165-168. Rascher W, Clough D,
Ganten D (eds). Schattauer Verlag, Stuttgart 1981
26. Brayden JE, Halpem W, Brann LR: Biochemical and mechanical
properties of resistance arteries from normotensive and hypertensive rats. Hypertension 5: 17-25, 1983
27. Johansson BB, Auer LM, Hodde KC, Nordborg C: Cerebral resistance vessel morphometry in normotensive and hypertensive rats.
Progress in Applied Microcirculation, in press 1985
28. Wolinsky H, Glagow S: A lamellar unit of aortic medial structure
and function in mammals. Circ Res 20: 99-111, 1967
Reaction of Pial Arteries and Veins to Hypercapnia in
Hypertensive and Normotensive Rats
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BARBRO B. JOHANSSON, M . D . ,
LUDWIG M.
AUER, M . D . ,
AND ICHIRO S A Y A M A ,
M.D.
SUMMARY The lumen diameters of the main cortical surface arteries were continuously monitored
through a closed cranial window in spontaneously hypertensive rats (SHR) and normotensive VVistar Kyoto
rats (WKY). The arterial diameter was significantly smaller in SHR (55 ± 1 fjcrn) than in WKY (87 ± 1 /am)
during resting conditions as well as during hypercapnic dilatation (87 ± 2 /xm compared to 117 ± 5 /urn).
The per cent increase in diameter induced by hypercapnia was larger in SHR (54%) than in WKY (36%),
presumably a consequence of the altered vascular wall to lumen ratio. Alpha-adrenoreceptor blockade with
yohimbine and phenoxybenzamine had no significant effect on arterial diameter during hypercapnia. The
diameters of the largest pial surface veins increased to the same extent in SHR and WKY during hypercapnia (about 10%).
Stroke Vol 16, No 2, 1985
MORPHOMETRIC STUDIES on cerebral arteries ex
vivo have demonstrated an increased media thickness
and vessel wall to lumen ratio with or without a concomitant reduction of the internal radius in hypertensive man'- 2 as well as in spontaneously hypertensive
rats. M The increase of resistance induced by vascular
smooth muscle shortening is augmented by a heightened media to radius ratio — for every degree of
smooth muscle shortening a larger muscle mass has to
be pulled into the lumen — resulting in a steeper resistance curve and a higher maximal contractile strength.7
The arterial wall tension increases with the radius and
decreases with the wall thickness, hence the altered
vascular geometry would enable the resistance vessels
of hypertensive rats to withstand a higher intraluminal
pressure than corresponding vessels in normotensive
rats when relaxed as well as at any degree of vascular
tone. Studies on the blood-brain barrier and cerebral
blood flow support this hypothesis. 8 "" However, intraFrom the Department of Neurology, University of Lund, Sweden;
and the Research Department of Neurosurgery, University of Graz,
Austria.
This study was supported by the Osterreichischer Fonds zur Forderung der wissenschaftlichen Forschung, the Swedish Medical Research
Council (project 14X-4968), the Swedish Association against Heart and
Chest Diseases, and the Edit Jacobson Donation Fund.
Address correspondence to: Barbro B. Johansson, M.D., Department
of Neurology University of Lund, Lund Hospital, S-221 85 Lund,
Sweden.
Received July 11, 1983; revision # 2 accepted September 26, 1984.
vital microscopy of cremasteric and mesenteric arteries indicate that, in vivo, the diameters of small arteries may be the same or even larger in hypertensive than
normotensive rats. l2 - l3 A decrease in number of arteries per unit tissue rather than a change in arterial diameter could account for the increased peripheral resistance in hypertension.14 This situation would,
however, not explain the increased capacity to autoregulate and the protection of the blood-brain barrier in
hypertensive rats mentioned above.
To determine whether there is an in vivo difference
in pial arterial diameter between normotensive and
hypertensive rats in the resting state and/or when dilated, we have measured the diameter of the main parasagittal cortical surface arteries through a closed cranial window during resting conditions as well as during
hypercapnic vasodilatation. The diameter of cortical
surface veins was also measured since functional or
structural alterations may occur also in veins in hypertensive animals. Data for arteries have been briefly
presented earlier.15
Materials and Methods
Six spontaneously hypertensive rats (SHR)16 and six
Wistar-Kyoto rats (WKY), six months of age, were
anesthetized with pentobarbital (30 mg/kg i.p.), tracheotomized and mechanically ventilated with air.
Catheters were inserted into the aorta from a femoral
artery for continuous recording of mean arterial pres-
PIAL ARTERIES AND VEINS IN HYPERTENSION/Jo/ia/uson et al
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sure (MAP) and for sampling of blood for blood gas
analyses and into a femoral vein for injection of drugs.
Body temperature was controlled by a Philips rectal
thermosensor unit and maintained between 37 and
38°C with the aid of an electric heating pad. After
placing the animal in the prone position the head was
fixed in a stereotactic headholder and a closed cranial
window was inserted in the parasagittal parietal region
on the left side.17 A TKX 29 Philips video camera was
attached to a Leitz intravital microscope and the caliber
of the cortical arteries and veins continuously monitored by the aid of a multichannel video angiometer
device.18 With this device three different portions
could be simultaneously and continuously measured
by analysis of gray value changes along single TV
lines. Data of inner vessel diameter, i.e. the red cell
column seen on the tele-screen, arereproducedas analogue signals and recorded on a penwriter. The maximum in vivo measurement error of the method is 2 per
cent.l8 The single experiments wererecordedon videotape, thus multiple replay allowed the analyses of the
whole vasculature visible under the microscope at 50fold magnification. The main cortical surface arteries
were measured at specified sites (fig. 1). The pial veins
showed a more irregular pattern than arteries and the
measurements could not be standardized. The largest
vein in each cranial window was measured. After recording the resting values, hypercapnia was induced
stepwise until no further dilatation was observed.
Thereafter, yohimbine, an alpha2-receptor antagonist,
was given i.v. (5 mg/kg) followed by phenoxybenzamine (1 mg/kg) to evaluate a possible sympatho-adrenergic influence on vessel tone during hypercapnia. Statistical differences were calculated with Student's
t-test. Values are given as mean ± SE.
Results
Table 1 shows the initial MAP and the blood pressure response during the various experimental steps.
Initial PaO2 was 110 ± 6 mm Hg in SHR and 100 ± 7
mm Hg in WKY and did not vary significantly during
321
TABLE 1 Mean Arterial Pressure (MAP) during the Various Experimental Steps
Initial MAP (mm Hg)
Hypercapnia
Hypercapnia + Yohimbine
Hypercapnia + Phenoxybenzamine
WKY
SHR
1O3±5
127±7
125±1O
106±12
172±9
183±9
180±9
147±17
Mean ± SEM. n = 6 in each group.
the experiments. There was no difference in PaCO2
between the groups at the various steps of hypercapnia.
For the sake of simplicity the values are given in the
figures as 30,40, 50, 60 and 70 mm Hg; the true values
for SHR were 29.4 ± 0.7, 38.4 ± 0.4, 49.0 ± 0.8,
59.9 ± 0.4 and 69.2 ± 1.3; the corresponding values
for WKY were 30.2 ± 0.6,39.0 ± 0.7,50.3 ± 0.6,
58.8 ± 0.7 and 69.6 ± 1.0 mm Hg. There was no
significant further dilatation above PaCO2 70 mm Hg.
Seven to 10 vessel portions from the main cortical
arterial surface branches were determined in each rat.
Mean resting diameter was 55 ± 1 /un (n = 53) in
SHR and 87 ± 1 /urn (n = 53) in WKY (p < 0.001).
The absolute increase in diameter in the two groups
during hypercapnia and alpha-adrenoceptor blockade
is shown in Fig. 2a and the per cent increase in diameter in Fig 2b. In spite of the larger per cent increase, the
diameter of the dilated arteries remained significantly
smaller in SHR (84 ± 2 /urn compared to 117 ± 5 /urn
in WKY; p < 0.001). No significant further dilatation was seen in either group after adrenoreceptor
blockade. However, in three WKY and in five SHR
the arteries showed a slight dilatation after phenoxybenzamine.
The diameter of the main pial veins varied considerably. Mean value of the largest veins in the parietal
windows of SHR was 71.6 ± 3.7 jum (n = 50) compared to 103.2 ± 10.4 jtitn for WKY (n = 34) during
normocapnia. At PaCO2 70 mm Hg the corresponding
value was 76.0 ± 4.6 /im (A 10.4 ± 2%) in SHR and
112.8 ± 11.2/im in WKY (A 10.1 ± 1.8%). No or
FIGURE 1A AND B. A main cortical surface artery in the left parasagittal region in a normotensive (A) and spontaneously
hypertensive (B) rat as seen on the TW screen during resting conditions.
322
STROKE
0A1
%
SHR
DIL.
50
WKY
30
40 50 60 70
PaC0 2
mmHg
Y0H
PB
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FIGURE 2. The resting arterial diameter (0A) of the main
cortical surface branches in the left parasagittal region in WKY
and SHR and the absolute increase in diameter during graded
hypercapnia, as well as after i.v. administration of 5 mglkg
yohimbine (YOH) and 1.5 mglkg phenoxybenzamine. At all
levels the difference between WKY and SHR is statistically significant (p < 0.001; Student's t-test).
minor reaction was seen after yohimbine and phenoxybenzamine (fig. 2 and 3).
Discussion
The main arterial cortical surface branches had
smaller lumen diameter in SHR than in WKY under
resting conditions, most likely an autoregulatory vasoconstriction in response to the increased intraluminal
pressure. Even in the absence of the structural alterations discussed in the introduction, the smaller resting
diameter of cortical surface arteries in SHR would
enable these arteries to withstand higher pressure than
corresponding arteries in WKY. Studies on the bloodbrain barrier after an acute rise in blood pressure at
various levels of cerebrovascular tone in normotensive
animals have demonstrated this point.19-20 The smaller
vascular resting diameter in pial arteries in SHR contrasts to what has been observed in vivo in mesenteric
arteries and cremasteric muscle arteries. l2 ' l3 This illus-
0A
100
VOL
16, No
2, MARCH-APRIL
1985
trates that vascular beds differ as to hemodynamic and
morphometric consequences of hypertension.7
Adrenoceptor blockade during hypercapnia did not
significantly increase the arterial diameter in SHR or
WKY. In an earlier study a significant further dilatation was observed after phenoxybenzamine in SHR but
not in WKY when vasodilatation was induced by dihydralazine,21 a drug known to enhance sympathetic activity. The alpha2-adrenoceptor antagonist yohimbine
was given before phenoxybenzamine because blockade of presynaptic alpha2-receptors may unmask an
effect of post-synaptic receptors22 and because there
may also be post-synaptic alpha2-receptors in the cerebral arteries.23 The results gave no evidence for pre- or
postsynaptic alphaadrenergic activation in cerebral
surface arteries during pronounced hypercapnia in
SHR or WKY. This is in agreement with a study on
cats,24 whereas one study on cats during more moderate hypercapnia indicated a neurogenic vasoconstriction in arteries > 100 /am but not in smaller arteries.25
The finding of smaller internal radius of pial arteries
in SHR than in WKY during hypercapnic vasodilatation is in agreement with an in vivo study on pharmacological vasodilatation2' as well as with morphometric
measurement of pial arteries of corresponding size ex
vivo'' and measurements on vascular casts (Hodde,
Nordborg and Johansson, unpublished observations).
It cannot be guaranteed that the pial arteries are fully
relaxed under hypercapnia or pharmacologically induced vasodilatation, nor that the "dilated state" in
histological preparations or on vascular casts corresponds to in vivo conditions. Nevertheless, the consistency between the results obtained with the various
methods, together with the observation that the total
cerebrovascular resistance is higher in hypertensive
than in normotensive rats during vasodilatation induced by hypercapnia or by epileptic seizures26'27 suggests a real difference between the dilated cerebrovascular bed in SHR and WKY in vivo. There is a close
correlation between the hemodynamic and the structural alterations in SHR.5 The increased vulnerability
observed in these rats during conditions predisposing
for ischemia may therefore at least partly be explained
by structural alterations in the arterial resistance
vessels.6
Acknowledgments
The skilled technical assistance by Silvia Schreiner and Klaus Leber
is gratefully acknowledged.
References
50
30
40
50 60
mmHg
70
YOH PB
FIGURE 3. The same data as in figure 2, but given as percent
increase in diameter from resting levels. At PaCC>2 60 mm Hg
and above as well as during the sympatho-adrenergic blockade
the percent dilatation is significantly larger in SHR than in WKY
(p < 0.01).
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measurement of pial microvessels. Acta Neurol Scand 60 Suppl 72:
208-209, 1979
19. Auer LM, Sayama I, Johansson BB: Cerebrovascular effects of
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20. Linder J: Cerebral and ocular blood flow during a2-blockade: evidence for a modulated sympathetic response. Acta Physiol Scand
113: 511-517, 1981
21. Skarby T, Andersson K-E, Edvinsson L: Characterization of the
postsynaptic a-adrenoceptor in isolated feline cerebral arteries.
Acta Physiol Scand 112: 105-107, 1981
22. Haggendal E, Johansson B: On the pathophysiology of the increased cerebrovascular permeability in acute arterial hypertension
in cats. Acta Neurol Scand 48: 265-270, 1972
23. Johansson B: Brain barrier pathology in acute arterial hypertension.
Adv Exp Med Biol 69: 517-527, 1976
24. Auer LM, Trummer UG, Johansson BB: Alpha-adrenoreceptor
antagonists and pial vessel diameter during hypercapnia and hemorrhagic hypotension in the cat. Stroke 12: 847-851, 1981
25. Wei EP, Kontos HA, Patterson JL: Dependence of pial arteriolar
response to hypercapnia on vessel size. Am J Physiol 238: H697H703, 1980
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against stroke in stroke-prone spontaneously hypertensive rats. Am
J Physiol 244: H406-412, 1983
A 1-4 Year Follow-Up Study of 306 Cases of Stroke
QINGTANG CHEN, M . D . , * AND RUIZHU LING, M . D . t
SUMMARY To study the long-term prognosis of stroke, we performed annual follow-up examinations on
306 patients who had survived cerebrovascular accidents. All patients had been admitted to the Neurology
Service, First Teaching Hospital, Beijing Medical College from January 1,1976, to December 31,1978, and
were followed up for 1 to 4 years. The series included 217 cases of cerebral thrombosis, 54 of cerebral
hemorrhage, and 35 of TIA. The life-table method was used to determine the cumulative survival rate
(CSR), cumulative marked improvement rate (CMIR), and cumulative recurrence rate (CRR), for each of
these three types of stroke. The main results were the following: 1. The prognosis was not significantly
influenced by sex, BP level on admission, or type of cerebrovascular accident. 2. Age was an important
prognostic factor. The survival rate decreased significantly in each successive age group. However, age was
not a risk factor for recurrence or poor improvement. 3. The cumulative survival rate, cumulative marked
improvement rate, and cumulative recurrence rate did not differ significantly among cerebral thrombosis,
cerebral hemorrhage, and TIA.
Stroke Vol 16, No 2, 1985
THE SHORT-TERM OUTCOME of cerebrovascular
accidents has been widely reported. We studied the
long-term prognosis in cerebral thrombosis, cerebral
hemorrhage, and TIA, and used the life-table method
to determine the cumulative survival rate (CSR), the
cumulative marked improvement rate (CMIR), and the
cumulative recurrence rate (CRR) in these diseases. 1 ' 2
From The Department of Neurology, First Teaching Hospital,* and
The Institute of Clinical Research,t Beijing Medical College, Beijing,
China.
Address correspondence to: Qingtang Chen, M.D., Department of
Neurology, First Teaching Hospital, Beijing Medical College, Beijing,
China.
Received April 19, 1984; revision #1 accepted September 5, 1984.
Materials and Methods
Selection of Cases
There were about 150 admissions for stroke per year
to the Neurology Service, First Teaching Hospital,
Beijing Medical College between 1976 and 1979.
Each stroke was classified by type as either cerebral
thrombosis, cerebral hemorrhage, cerebral embolism,
subarachnoid hemorrhage, TIA or other. Most of the
patients had lumbar puncture, EEG, and skull radiographs. Cerebral arteriography and isotope brain scan
were performed in some of our patients. CT scan was
not available during that time. The diagnosis and differential diagnosis were based on clinical history, neurological symptoms and signs, and the examinations
Reaction of pial arteries and veins to hypercapnia in hypertensive and normotensive rats.
B B Johansson, L M Auer and I Sayama
Stroke. 1985;16:320-323
doi: 10.1161/01.STR.16.2.320
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Copyright © 1985 American Heart Association, Inc. All rights reserved.
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