© 1995 American Heart Association, Inc.
Articles |
Role of Extracellular and Intracellular Acidosis for Hypercapnia-Induced Inhibition of Tension of Isolated Rat Cerebral Arteries
From the Department of Pharmacology, University of Aarhus (Denmark), and the Department of Clinical Physiology (N.A.L.), Bispebjerg Hospital, Copenhagen, Denmark.
Correspondence to Dr Christian Aalkjær, Department of Pharmacology, University of Aarhus, 8000 Aarhus C, Denmark.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract The importance of smooth muscle cell pHi and pHo for the hypercapnic vasodilation of rat cerebral arteries was evaluated in vitro. Vessel segments were mounted in a myograph for isometric tension recording; pHi was measured by loading the smooth muscle cells with the fluorescent dye BCECF, and pHo was measured with a glass electrode. In all studies, Ca2+-dependent basal tension (in the absence of any agonist) and tension in the presence of arginine vasopressin were investigated. Control solution was physiological saline bubbled with 5% CO2 and containing 25 mmol/L HCO3- (pH 7.45 to 7.50). Induction of hypercapnic acidosis (10% CO2) or normocapnic acidosis (15 mmol/L HCO3-) caused significant inhibition of smooth muscle tension, and both conditions reduced pHi as well as pHo. N-Nitro-L-arginine significantly inhibited the relaxation to hypercapnic acidosis but had no significant effect on relaxation to normocapnic acidosis. Predominant extracellular acidosis, induced by reducing [HCO3-] from 25 to 9 mmol/L and CO2 from 5% to 2.5%, also caused inhibition of tension in steady state. By contrast, predominant intracellular acidosis, induced by increasing [HCO3-] from 25 to 65 mmol/L and CO2 from 5% to 15%, induced a small increase of basal tension and a small decrease of tension in the presence of arginine vasopressin. The responses to predominant intracellular or extracellular acidosis were qualitatively similar in the presence and absence of endothelium and in the presence and absence of N-nitro-L-arginine. It is concluded that the extracellular acidosis and not smooth muscle intracellular acidosis is responsible for the relaxation to hypercapnic acidosis.
Key Words: cerebral arteries • pH • hypercapnia • nitric oxide
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
It is well known that hypercapnic acidosis dilates cerebral vessels through a direct effect on the vessels.1 2 3 It has further been documented that the decrease of pH is necessary for the relaxation of the smooth muscles.4 5 6 7 However, whether the relaxation is mediated through reduction of pHo or pHi has never been clarified.8 9 10 For vascular smooth muscle in general, the role of pHi is controversial. It has been suggested by a number of investigators that reduction of pHi may be of importance for vasodilation,3 11 12 13 14 15 but it has also been suggested that pHo may be the dominant mechanism responsible for relaxation.1 2 3 16 Interestingly, in several vascular beds an acute intracellular acidification with a maintained pHo leads to force development,17 18 19 which is caused by an increase in [Ca2+]i.18 Whether, in steady state, reduction of pHi also causes force development has not been investigated. Part of the reason that this question has not been clarified is because it has not previously been possible to measure pHi in vascular smooth muscles, and much of the confusion alluded to above reflects the fact that the discussion has been based on assumptions concerning changes in pHi. However, with the ability to measure pHi and force simultaneously in small arteries,20 it has become possible to address this problem in a more direct way and provide new information.
In the present study, we have investigated the effect of changes in pHi and pHo on both basal isometric tension (tension seen in the absence of any agonist and dependent on [Ca2+]i) and isometric tension induced by arginine vasopressin (AVP). The reason for studying both types of tension was that pH might have different effects on different types of tension.
Since it has recently been demonstrated that N-nitro-L-arginine (l-NNA), an inhibitor of nitric oxide (NO) synthase, causes a significant attenuation of the cerebrovasodilation induced by hypercapnia in vivo,21 22 we found it important also to evaluate the effect of the endothelium and of l-NNA for the responses to changes in pHi and pHo.
The results of the present study indicate that the reduction of pHo can explain the vasodilation to hypercapnic acidosis, whereas the concomitant reduction of smooth muscle pHi is of little or no importance for the effect.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Preparation
Male Wistar rats (12 to 16 weeks old) were killed with CO2. The brain was taken out, and a branch of the middle cerebral artery (internal diameter,
250 µm) was dissected out.
Setup
The arteries were mounted as ring preparations in a myograph for
isometric force development by threading them on two stainless steel
wires.23 The internal diameter was set to an internal
circumference on the basis of the passive tension–length curve, which
was equal to 0.9 times L100, where L100 is the
circumference the vessel would have when exposed to a transmural
pressure of 100 mm Hg in vivo.
pHi was measured with BCECF, as described
previously.20 Vessels mounted on the myograph were loaded
at 37°C with 5 µmol/L BCECF-AM (the membrane-permeable
acetoxymethylester form of BCECF) for 60 minutes. The vessels were then
excited alternately with light at 450 and 495 nm provided by a 75-W
xenon lamp, which fed into a monochromator. The emission from the
preparation passed through a bandpass filter (515 to 560 nm) and a
<720-nm cutoff filter and was, via the photomultiplier, fed into the
computer, where the ratio of emission at the two different excitation
wavelengths was calculated after subtraction of background
fluorescence. A ratio measurement was obtained every 30 seconds in
these experiments. The ratio was calibrated in terms of pHi
with nigericin.20 24 When the vessels are loaded with
BCECF-AM in this way, removal of the endothelium does not affect the
amount of fluorescence. In 14 experiments, the fluorescence in
arbitrary units was 0.59±0.03 before and 0.56±0.05 after removal of
the endothelium with excitation at 450 nm and 3.04±0.27 before and
3.43±0.40 after removal of the endothelium with excitation at 495 nm
(functional removal was achieved [Table 1
] by rubbing
the luminal surface with a human hair25 ). None of these
differences were statistically significant. Furthermore, with confocal
microscopy, a uniform loading of the smooth muscle cells is seen,
whereas no fluorescence from endothelial cells can be detected (G. Daly
and I. McGrath, Glasgow, Scotland, personal communication), indicating
that the fluorescence is reflecting pHi of the smooth
muscle cells. pHo in the bath was measured continuously
with a pH microelectrode (Ingold).
|
To assess the relation between basal isometric tension and
[Ca2+]i in the cerebral small arteries,
[Ca2+]i was measured in three experiments as
described previously with fura 2,26 27 and the fluorescent
signal was calibrated as described by Grynkiewicz et
al28 by using a Kd for the fura
2–Ca2+ complex of 342 nmol/L.29 As seen in
Fig 1, the basal tension of the cerebral arteries was
dependent on the presence of extracellular Ca2+, and
omission of extracellular Ca2+ caused a reduction of
[Ca2+]i and a concomitant reduction of
tension. When AVP was added, both [Ca2+]i and
tension increased. In the experiment shown, l-NNA was present, but
the same pattern was seen in the absence of l-NNA.
|
Protocol
The protocol used in all experiments in which pHi
was measured is outlined in Fig 2, where tracings of
pHi, pHo, and force are shown in response to
different solutions and substances. In all experiments, the vessel
segments were activated with AVP (1 or 2 U/L). The importance of
pHi and pHo for the tension was studied in five
different solutions: a control physiological saline solution (PSS) and
test solutions A, B, C, and D.
|
PSS had the following composition (mmol/L): NaCl 119, KCl 4.7, KH2PO4 1.18, MgSO4 1.17, NaHCO3 25, CaCl2 2.5, EDTA 0.026, HEPES 5, and D-glucose 5.5. The pH of this solution was 7.45 to 7.50 when gassed with 5% CO2/95% O2. In the Ca2+-free PSS, CaCl2 was omitted and 0.1 mmol/L EGTA was added.
Solutions A through D were as follows: solution A, hypercapnic acidosis
(PSS, 10% CO2, pH 7.25); solution B, normocapnic
acidosis (PSS containing 15 mmol/L HCO3-, 5%
CO2, pH 7.25); solution C, extracellular acidosis (PSS
containing 9 mmol/L HCO3-, 2.5%
CO2, pH 7.35); and solution D, intracellular acidosis
(PSS containing 65 mmol/L HCO3-, 15%
CO2, pH 7.45). In solutions C and D, chloride was added
or removed to keep the sum of chloride and bicarbonate concentrations
constant.
The purpose of changing CO2 and
[HCO3-] in the test solutions was to obtain
different levels of pHi and pHo in steady
state. The pH values obtained in the experiments are given in Figs 3 and 4. These pH values refer to values
in the absence of AVP. Addition of AVP did not significantly affect
these values. Fig 3 shows values for pHi and
pHo in control solution and in solutions A and B. Both
solutions are seen to induce significant reductions in pHo
as well as pHi. pHo was reduced to a similar
extent in the two solutions, but pHi was reduced
significantly more in solution A (0.15±0.02 pH units) than in solution
B (0.10±0.02 pH units, n=8, P=.002). Fig 4 shows values for
the reductions of pHi and pHo in solutions C
and D. Solution C is seen to induce a predominant extracellular
acidosis, whereas solution D is seen to induce a predominant
intracellular acidosis. In solution C, pHo is significantly
more reduced than pHi; in solution D, pHi is
significantly more reduced than pHo.
|
|
The tension development at the different values for pHi and pHo were studied in the following six series of experiments: (1) control versus solution A and control versus solution B, (2) as in series 1, but in the presence of l-NNA (10-5 and 10-4 mol/L for solution A and 10-5 mol/L for solution B), (3) control versus solution C and control versus solution D, (4) as in series 3, with subsequent repeat of the experiments after removal of the endothelium, (5) as in series 3, with subsequent repeat of the experiments after removal of the endothelium and in the presence of 10-6 mol/L sodium nitroprusside (SNP), and (6) as in series 3, with subsequent repeat of the experiments in the presence of 10-5 mol/L l-NNA. The sequence of application of test solutions was randomized.
To evaluate the importance of endothelial function for the vasodilator
responses to acidification, the effect of endothelial removal, l-NNA,
and SNP were assessed as detailed above. The influence of applying
these drugs or procedures on the basal characteristics of the vessels
is summarized in Table 1
. Table 1 shows that pHo and
pHi in the control solution were unaffected by removal of
the endothelium. The increase in basal tension did not reach
statistical significance, but the bradykinin (BRK)-induced relaxation
(both transient and sustained; see Fig 2) was abolished. Table 2 shows the effect of l-NNA in the control solution.
pHo and pHi were not affected, but the basal
tension was increased, and the relaxant response to 10-6
mol/L BRK was decreased. The values for BRK-induced relaxation refer to
the sustained relaxation. The transient BRK-induced relaxation was
unaffected by l-NNA. Table 2 also shows that the relaxation to SNP is
significantly increased by l-NNA. pHi and pHo
were not significantly affected by the presence of SNP in control
solution or in solutions C and D (data not shown).
|
Chemicals
Other chemicals used were BCECF-AM (Molecular Probes); SNP,
bradykinin, nigericin, and l-NNA (Sigma Chemical Co); and AVP (Sandoz).
Data Analysis
In the text, values are mean±SEM. To assess the effect of the
four different test solutions, the tension in test solution was
compared with the mean tension in control solution immediately before
and after the test (see Fig 2). Unless otherwise stated, mean values
were compared with a paired two-tailed t test. A value of
P<.05 was considered significant. The numbers in
parentheses indicate the number of arteries, one artery per rat. In
figures, force development is shown as tension development. Tension
development is the tension (force divided by two times segment length)
at a specified time during the experiment minus the minimal tension
recorded during the experiment (after setting the internal
circumference of the vessels to 0.9 · L100).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Effect of Hypercapnic and Normocapnic pH Reduction on Vessel Tension
Fig 5
shows the result of the first series of
experiments, in which the effects of solution A (hypercapnic acidosis)
and solution B (normocapnic acidosis) were studied as outlined in Fig 2. The basal tension was not reduced significantly by either of the two
acidification procedures, but the tension in the presence of 2 U/L AVP
was significantly reduced by solution A as well as solution B. Both
solutions also reduced the tension in the presence of 10-5
mol/L l-NNA. For solution A, this reduction (9±1%) was significantly
smaller than the reduction produced by solution A when l-NNA was absent
(24±4%). For solution B, there was no significant difference between
reductions observed in the presence (29±5%) and absence (33±4%) of
l-NNA. To assess whether further inhibition of the vasodilatory
response to acidification could be obtained with a higher concentration
of l-NNA, the effect of 10-5 and 10-4 mol/L
l-NNA was compared in a separate series of seven experiments. The basal
tension in control solution was 0.59±0.15 N/m in the presence of
10-5 mol/L l-NNA and 0.50±0.13 N/m in the presence of
10-4 mol/L l-NNA. This difference was not significantly
different. Furthermore, the reduction of tension (with 1 U/L AVP) in
solution A was 30±5% and 44±4% with 10-5 and
10-4 mol/L l-NNA, respectively, and this difference was
not significantly different.
|
Effect of Reductions of pHo or pHi on
Vessel Tension
Fig 6, top left, shows that with predominant
reduction of pHo (solution C), both the basal tension and
the tension development with 1 and 2 U/L AVP were significantly
reduced. In contrast, when pHi was decreased (solution D),
the basal tension was slightly but significantly increased, whereas
there was no significant change in tension development in the presence
of 2 U/L AVP and a small although significant reduction with 1 U/L AVP.
In addition, the attenuation of tension development to both 1 and 2 U/L
AVP was significantly greater in solution C compared with solution D.
|
To assess whether the reduction of tension seen with solution C
(extracellular acidosis) and the generally small effect of solution D
(intracellular acidosis) were reflecting characteristics of the smooth
muscles, the experiments with solutions C and D were repeated in the
absence of a functional endothelium (Fig 6, top right). Extracellular
acidosis (solution C) was associated with a reduction of both basal
tension and tension in the presence of 1 U/L AVP. Although the
reduction in tension tended to be smaller in the absence of the
endothelium compared with the endothelium-intact
preparation (25±5% and 32±5%, respectively), this difference did
not reach statistical significance. With intracellular acidosis
(solution D), a small but significant increase in basal tension was
seen, whereas the small reduction in tension in the presence of 1 U/L
AVP did not reach statistical significance. These responses to solution
D were qualitatively similar to the responses in the
endothelium-intact preparation.
In the next series of experiments (Fig 6, bottom left), the responses
to solutions C and D were assessed after removal of the endothelium but
in the presence of a constant source of NO provided by SNP. In eight
experiments, the responses to solutions C and D were first obtained in
intact vessels, after which the endothelium was removed,
10-6 mol/L SNP was added, and new responses to solutions C
and D were obtained. In the absence of endothelium but presence of SNP,
extracellular acidosis (solution C) again caused a significant
reduction of both basal tension and tension in the presence of 1 U/L
AVP, whereas intracellular acidosis (solution D) caused a small
increase of basal tension and a small reduction of tension in the
presence of AVP, although neither response achieved statistical
significance. The reduction in tension in solution C (13±4%) was not
significantly different from the relaxation in the presence of
endothelium (20±4%).
In the last series of experiments, the effect of 10-5 mol/L l-NNA was assessed. Selective reduction of pHi (solution D) did not significantly affect tension in the presence of 2 U/L AVP (1.53±0.20 and 1.47±0.20 N/m for the control solution and solution D, respectively; P=NS, n=5) or basal tension (0.44±0.15 and 0.48±0.12 N/m for control solution and solution D, respectively; P=NS, n=5), whereas selective reduction of pHo (solution C) significantly reduced tension development in the presence of 2 U/L AVP (1.55±0.21 and 1.47±0.20 N/m for control solution and solution C, respectively; P=.04, n=5) as well as basal tension (0.43±0.14 and 0.34±0.15 N/m for control solution and solution C, respectively; P=.03, n=5).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In the present study, the aim was to evaluate the relative importance of pHo and smooth muscle pHi for tension in small cerebral arteries. We investigated the cerebral small arteries because this is a vascular bed, where pH is known to play an important physiological role in the control of blood flow.16 To achieve this, we measured pHo, pHi of the smooth muscles, and force simultaneously in isolated cerebral small arteries under conditions in which PCO2 and [HCO3-] were changed.
It is probable that the effect of pHi and pHo may depend on the type of tension that is present. For that reason, we studied the effect of pHi and pHo on both the AVP-induced tension and the tension that is present in the absence of any agonist, which we showed to be dependent on extracellular Ca2+ through an effect on [Ca2+]i and therefore to be a spontaneous active tone. Although the importance of vascular smooth muscle pHi for vascular tone is an old question, the problem has not previously been approached on the basis of direct measurements of steady state changes in vascular smooth muscle pHi.
Hypercapnic and Normocapnic Reductions of pH
As expected, hypercapnic acidosis (solution A) was associated with
attenuated tension development to AVP, confirming several previous
reports showing that high PCO2 induces
cerebrovasodilation through a direct effect on the vascular
wall.1 2 3 Furthermore, reduction of
[HCO3-] to 15 mmol/L with a maintained
PCO2 (solution B), which decreased
pHo to the same extent as the high
PCO2, also reduced tension development in the
presence of AVP. This observation is consistent with the idea that
reduction of pH is of importance for the vasodilation induced by
hypercapnia,1 2 3 16 although it obviously does not exclude
the possibility that a direct effect of molecular CO2 adds
to the vasodilation (eg, see Reference 33 ). On the other hand, the small
effect on tension of solution D, which was gassed with 15%
CO2 gives further support to the notion that molecular
CO2 per se probably has little effect on cerebral vascular
tone. It is likely that NO plays a role in the response to hypercapnic
acidosis, since both 10-4 and 10-5 mol/L
l-NNA reduced this response, although without abolishing it. l-NNA also
enhanced basal tension (as previously reported30 31 ) and
inhibited the relaxation to BRK, confirming an important role of NO for
the function of cerebral arteries. To substantiate this conclusion, the
specificity of l-NNA was assessed by evaluating the effect of l-NNA on
the response to SNP. Interestingly, the relaxing effect of SNP was
enhanced in the presence of l-NNA (Table 2), in contrast to the
reduction of the relaxation to hypercapnic acidosis and to BRK. This
shows that l-NNA does not cause an unspecific inhibition of the ability
of the vessels to relax. The enhanced relaxant effect of SNP induced by
l-NNA may suggest that under control conditions the level of NO and
cGMP is so high that the addition of an NO donor (SNP) has only a small
effect on tension (11% reduction of tension, Table 2), which is
enhanced (28% reduction of tension, Table 2) after inhibition of
endogenous NO production.
The fact that the inhibitory effect of l-NNA on the response to hypercapnic acidosis in AVP-activated vessels was only partial is consistent with recent in vivo data suggesting that NO is partly responsible for the increase of cerebral blood flow during hypercapnia.21 22 The finding is further consistent with the suggestion21 22 that a significant part of the response to hypercapnic acidosis is NO independent. Furthermore, normocapnic acidosis induced the same relaxations in the presence and absence of l-NNA, suggesting that normocapnic acidosis also induces relaxation that is NO independent.
Predominant Reductions of pHo or pHi
Both the increase of PCO2 in solution A
and the decrease of [HCO3-] in solution B
were associated with a reduction of pHi, although the
reduction was slightly but significantly more pronounced when
PCO2 was increased than when
[HCO3-] was decreased. Previously, the
vasodilation caused by reduction of [HCO3-]
with maintained PCO2 was taken as evidence for
a minor role of pHi for the vasodilation, because it was
assumed32 that the membrane was impermeable to protons and
HCO3- and that pHi therefore was
not affected by the reduction of [HCO3-].
However, the finding of the present experiments, ie, that a
reduction of [HCO3-] also reduces
pHi, questions this argument. Thus, it is difficult to
evaluate the relative importance of pHo and pHi
by comparing the vasodilator effect of hypercapnic and normocapnic
acidosis. On the other hand, the differential effect of a normocapnic
and a hypercapnic acidosis on pHi suggested that a
combination of low PCO2 and
[HCO3-] might result in a decreased
pHo with a maintained pHi and that high
PCO2 and [HCO3-]
might result in a decreased pHi with a maintained
pHo in steady state.
Although this was not entirely achieved, near-selective
reductions of pHo or pHi in steady state were
achieved for the combinations of PCO2 and
[HCO3-] in solutions C and D. Furthermore,
the 0.11–pH unit reduction of pHo in solution C and the
0.06–pH unit reduction of pHi in solution D are what might
be expected for pHo and pHi during a moderate
hypercapnic acidosis (C. Aalkjær, unpublished observation; compare
also with the 0.25–pH unit reduction of pHo and the
0.15–pH unit reduction of pHi in the more severe
hypercapnic acidosis of solution A). With solutions C and D, we have
therefore isolated these changes in pHo and
pHi, respectively, which gave us the opportunity to
evaluate their relative importance. When pHo was reduced
(with minimal changes in pHi), it was a consistent finding
that both basal tension and tension in the presence of AVP were
reduced. This observation suggests that a reduction of pHo
can account for the attenuation of tension during hypercapnia and also
suggests that the pHo-induced reduction of tension is a
generalized phenomenon not only confined to agonist-induced tension.
This was also the case after inhibition of NO production by either
removal of the endothelium or by l-NNA, strongly suggesting that
reduction of pHo reduces tension by a direct effect on the
smooth muscles. This conclusion regarding the importance of
pHo in cerebral vascular tone agrees with the conclusion
reached by West et al,9 who used a completely different
approach. In voltage-clamped vascular smooth muscle cells isolated from
the cerebral arteries, these authors found that reduction of
pHo (with pHi maintained by having 10 mmol/L
HEPES in the patch pipette) caused a reduction of Ca2+
current, and this could account for the vasodilation we demonstrated.
The conclusion was further substantiated by our experiments with SNP. These experiments were made to assess the possibility that the differential response to solutions C and D could be obtained under conditions of a constant supply of NO. The results were consistent with the interpretation of the previous experiments and suggest that extracellular acidosis can cause relaxation via a direct effect on the smooth muscle cells under conditions with a constant supply of NO. Thus, the role of endothelium-derived NO could be permissive and may not necessarily increase during extracellular acidosis. This possibility would be consistent with recent data showing that cGMP in the isolated rat basilar artery is not increased by hypercapnic acidosis.33
In contrast to the consistent reduction of tension with
extracellular acidosis, reduction of pHi, with an only
minimal reduction of pHo (solution D), had only a small
effect on tension, and the effect seemed different for basal tension
and tension in the presence of AVP. In the four series of experiments
with intracellular acidification (solution D), the basal tension was
always enhanced relative to the control value, although this did only
reach statistical significance in the presence of endothelium (Fig 6,
top left) and in the absence of endothelium without SNP (Fig 6, top
right). In the experiments with l-NNA and with SNP, the apparent
increase in basal tension just failed to reach statistical
significance. This may suggest that a steady state intracellular
acidosis induces a small enhancement of basal tension in these
arteries. This interpretation is consistent with the observation that
an acute decrease of pHi in several vascular beds
(including cerebral small arteries [C. Aalkjær, unpublished
observation]) is associated with force
development.17 18 19 34 It is also consistent with another
recent observation indicating that the metabolically produced acid
during hypoxia does not contribute to the inhibition of tension during
hypoxia in cerebral small arteries.27 Whether the increase
of steady state tension reflects a change in the buffering of
intracellular Ca2+ by the increased proton concentration,
as has been suggested for the acute effect of intracellular
acidification,18 remains to be seen. In contrast to the
effect of intracellular acidification on basal tension, the tension in
the presence of AVP may be slightly reduced by intracellular
acidification. Although this was only significant in the presence of
endothelium, the trend was seen both in the absence of endothelium and
in the presence of l-NNA. Therefore, it cannot be excluded that
intracellular acidification may inhibit one or more steps in the
excitation-contraction coupling for AVP, and this may counteract the
potentiating effect of acidification on basal tension with a resultant
small relaxation.
Conclusion
In summary, we made simultaneous measurements of smooth muscle
pHi, pHo and both basal tension and tension in
the presence of AVP in isolated cerebral arteries. These were made to
obtain new information on the relative importance of pHi
and pHo for the steady state vasodilation seen during
hypercapnic acidosis. The results point to a dominant direct effect of
pHo on both basal tension and tension in the presence of
AVP, whereas reduction of smooth muscle pHi may only be of
minor importance for the relaxation. Indeed, a reduction of
pHi seemed to increase basal tension, whereas the effect in
the presence of AVP was possibly a small decrease, suggesting that the
effect of pHi may depend on the type of tension
present. In addition, the results are consistent with the
possibility that part of vasodilation to hypercapnic acidosis is
dependent on NO released from the vascular wall, probably from the
endothelium, although the mechanism responsible for this effect of NO
is unknown.
|
Acknowledgments |
|---|
This study was supported by the Danish Medical Research Council and the Danish Heart Foundation.
Received February 16, 1994; accepted October 7, 1994.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Lassen NA. Brain extracellular pH: the main factor controlling cerebral blood flow. Scand J Clin Lab Invest. 1968;22:247-251. [Medline] [Order article via Infotrieve]
2.
Kontos HA, Wei EP, Raper AJ, Patterson JL. Local mechanism of
CO2 action on cat pial arterioles. Stroke. 1977;8:226-229.
3.
Toda N, Hatano Y, Mori K. Mechanisms underlying response to
hypercapnia and bicarbonate of isolated dog cerebral arteries.
Am J Physiol. 1989;257:H141-H146.
4. Wahl M, Deetjen P, Thuray K, Ingvar DH, Lassen NA. Micropuncture evaluation of the importance of perivascular pH for the arteriolar diameter on the brain surface. Pflugers Arch. 1970;316:152-163. [Medline] [Order article via Infotrieve]
5. Panniers JL, Weyne J, Demeester G, Leusen I. Influence of changes in the acid-base composition of the ventricular system on cerebral blood flow in cats. Pflugers Arch. 1972;333:337-351. [Medline] [Order article via Infotrieve]
6. Edvinsson L, Sercombe R. Influence of pH and pCO2 on alpha-receptor mediated contraction in brain vessels. Acta Physiol Scand. 1976;97:325-331. [Medline] [Order article via Infotrieve]
7.
Kontos HA, Raper AJ, Patterson JL. Analysis of vasoactivity
of local pH, PCO2 and bicarbonate on pial vessels.
Stroke. 1977;8:358-360.
8. Harder DR, Madden JA. Cellular mechanism of force development in cat middle cerebral artery by reduced PCO2. Pflugers Arch. 1985;403:402-404. [Medline] [Order article via Infotrieve]
9.
West GA, Leppla DC, Simard JM. Effects of external pH on
ionic currents in smooth muscle cells from the basilar artery of the
guinea pig. Circ Res. 1992;71:201-209.
10. Madden JA. The effect of carbon dioxide on cerebral arteries. Pharmacol Ther. 1993;59:229-250. [Medline] [Order article via Infotrieve]
11. Gotoh F, Tazaki Y, Meyer JS. Transport of gases through brain and their extravascular vasomotor action. Exp Neurol. 1961;4:48-58. [Medline] [Order article via Infotrieve]
12. Harder DR. Effect of H+ and elevated PCO2 on membrane electrical properties of rat cerebral arteries. Pflugers Arch. 1982;394:182-185. [Medline] [Order article via Infotrieve]
13.
Tomlinson FH, Anderson RE, Meyer FB. Effect of
superhypercapnia on cortical pHi and cortical blood flow.
Am J Physiol. 1993;265:R974-R981.
14.
Wray S, Austin C. Extracellular pH signals affect rat vascular
tension by rapid transduction into intracellular pH changes. J
Physiol (Lond). 1993;466:1-8.
15.
Tsukioka M, Iino M, Endo M. pH dependence of inositol
1.4.5-triphosphate-induced Ca2+ release in permeabilized
smooth muscle cells of the guinea pig. J Physiol (Lond). 1994;475:369-375.
16. Kontos HA. Regulation of the cerebral circulation. Annu Rev Physiol. 1981;43:397-407. [Medline] [Order article via Infotrieve]
17. Ighoroje AD, Spurway NC. Procedures to acidify cytoplasm raise the tone of isolated (rabbit ear) blood vessels. J Physiol (Lond). 1984;357:105P.
18.
Jensen PE, Hughes A, Boonen HCM, Aalkjær C. Force, membrane
potential, and [Ca2+]i during activation
of
rat mesenteric small arteries with norepinephrine, potassium, aluminum
fluoride, and phorbol ester: effects of changes in pHi.
Circ Res. 1993;73:314-324.
19. Matthews JG, Graves JE, Poston L. Relationships between pHi and tension in isolated rat mesenteric resistance arteries. J Vasc Res. 1992;29:330-340. [Medline] [Order article via Infotrieve]
20.
Aalkjær C, Cragoe EJ Jr. Intracellular pH regulation in
resting and contracting segments of rat mesenteric resistance vessels.
J Physiol (Lond). 1988;402:391-410.
21. Wang Q, Paulson OB, Lassen NA. Effect of nitric oxide blockade by NG-nitro-L-arginine on cerebral blood flow response to changes in carbon dioxide tension. J Cereb Blood Flow Metab. 1992;12:947-953. [Medline] [Order article via Infotrieve]
22.
Iadecola C. Does nitric oxide mediate the increases in
cerebral blood flow elicited by hypercapnia. Proc Natl Acad Sci
U S A. 1992;89:3913-3916.
23.
Mulvany MJ, Halpern W. Contractile properties of small
arterial resistance vessels in spontaneously hypertensive and
normotensive rats. Circ Res. 1977;41:19-26.
24. Thomas JA, Buchsbaum RN, Zimniak A, Racker E. Intracellular pH measurements in Ehrlich ascites tumor cells utilizing spectroscopic probes generated in situ. Biochemistry. 1979;18:2210-2218. [Medline] [Order article via Infotrieve]
25. Nyborg NCB. Action of noradrenaline on isolated proximal and distal coronary arteries of rat: selective release of endothelium-derived relaxing factor in proximal arteries. Br J Pharmacol. 1990;100:552-556. [Medline] [Order article via Infotrieve]
26. Jensen PE, Mulvany MJ, Aalkjær C. Endogenous and exogenous agonist-induced changes in the coupling between [Ca2+]i and force in rat resistance arteries. Pflugers Arch. 1992;420:536-543. [Medline] [Order article via Infotrieve]
27. Aalkjær C, Lombard J. Effect of hypoxia on force, pHi and [Ca2+]i in rat cerebral and mesenteric small arteries. J Physiol (Lond). In press.
28. Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985;260:3340-3450.
29.
Jensen PE, Mulvany MJ, Aalkjær C, Nilsson H, Yamaguchi H.
Free cytosolic calcium measured with calcium-selective electrodes and
fura-2 in rat mesenteric resistance arteries. Am J Physiol. 1993;265:H741-H746.
30.
Harder DR. Pressure-dependent membrane depolarization in cat
middle cerebral artery. Circ Res. 1984;55:197-202.
31.
Kovàch AGB, Szabò C, Benyò Z,
Csàki C, Greenberg JH, Reivich M. Effects of
NG-nitro-L-arginine and L-arginine on regional cerebral
blood flow in the cat. J Physiol (Lond). 1992;449:183-196.
32.
Wallace WM, Hastings AB. The distribution of the bicarbonate
ion in mammalian muscle. J Biol Chem. 1942;144:637-649.
33. Wang Q, You P, Jansen I, Edvinsson L, Paulson OB, Lassen NA. Mechanisms underlying effect of nitric oxide inhibition on hypercapnic vasodilation in isolated basilar arteries from rats. J Cereb Blood Flow Metab. 1993;13(suppl 1):S170. Abstract.
34. Kontos HA, Richardson DW, Patterson JL. Effect of hypercapnia in human forearm blood vessels. Am J Physiol. 1967;212:1070-1080.
This article has been cited by other articles:
 |
|
 |
|
  E. Boedtkjer, J. Praetorius, and C. Aalkjaer NBCn1 (slc4a7) Mediates the Na+-Dependent Bicarbonate Transport Important for Regulation of Intracellular pH in Mouse Vascular Smooth Muscle Cells Circ. Res., March 3, 2006; 98(4): 515 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Tomura, J.-Q. Wang, M. Komachi, A. Damirin, C. Mogi, M. Tobo, J. Kon, N. Misawa, K. Sato, and F. Okajima Prostaglandin I2 Production and cAMP Accumulation in Response to Acidic Extracellular pH through OGR1 in Human Aortic Smooth Muscle Cells J. Biol. Chem., October 14, 2005; 280(41): 34458 - 34464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. L. Xu, H. M. Koenig, S. Ye, D. L. Feinstein, and D. A. Pelligrino Influence of the glia limitans on pial arteriolar relaxation in the rat Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H331 - H339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ide, M. Eliasziw, and M. J. Poulin Relationship between middle cerebral artery blood velocity and end-tidal PCO2 in the hypocapnic-hypercapnic range in humans J Appl Physiol, July 1, 2003; 95(1): 129 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. I. Rosenblum ATP-Sensitive Potassium Channels in the Cerebral Circulation Stroke, June 1, 2003; 34(6): 1547 - 1552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Santa, T. Kitazono, T. Ago, H. Ooboshi, M. Kamouchi, M. Wakisaka, S. Ibayashi, and M. Iida ATP-Sensitive Potassium Channels Mediate Dilatation of Basilar Artery in Response to Intracellular Acidification In Vivo Stroke, May 1, 2003; 34(5): 1276 - 1280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Horiuchi, H. H. Dietrich, K. Hongo, T. Goto, and R. G. Dacey Jr Role of Endothelial Nitric Oxide and Smooth Muscle Potassium Channels in Cerebral Arteriolar Dilation in Response to Acidosis Stroke, March 1, 2002; 33(3): 844 - 849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Lindauer, A. Kunz, S. Schuh-Hofer, J. Vogt, J. P. Dreier, and U. Dirnagl Nitric oxide from perivascular nerves modulates cerebral arterial pH reactivity Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1353 - H1363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. V. Smirnov, G. A. Knock, A. E. Belevych, and P. I. Aaronson Mechanism of effect of extracellular pH on L-type Ca2+ channel currents in human mesenteric arterial cells Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H76 - H85. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bayerle-Eder, M. Wolzt, E. Polska, H. Langenberger, J. Pleiner, D. Teherani, G. Rainer, K. Polak, H.-G. Eichler, and L. Schmetterer Hypercapnia-induced cerebral and ocular vasodilation is not altered by glibenclamide in humans Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2000; 278(6): R1667 - R1673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Austin and S. Wray Interactions Between Ca2+ and H+ and Functional Consequences in Vascular Smooth Muscle Circ. Res., February 18, 2000; 86(3): 355 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T Schwerte, S Holmgren, and B Pelster Vasodilation of swimbladder vessels in the european eel (Anguilla anguilla) induced by vasoactive intestinal polypeptide, nitric oxide, adenosine and protons J. Exp. Biol., January 4, 1999; 202(8): 1005 - 1013. [Abstract] [PDF]
|
|
|
|
 |
|
 G.L. Smith, C. Austin, C. Crichton, and S. Wray A review of the actions and control of intracellular pH in vascular smooth muscle Cardiovasc Res, May 1, 1998; 38(2): 316 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-L. Peng, P. E. Jensen, H. Nilsson, and C. Aalkjar Effect of acidosis on tension and [Ca2+]i in rat cerebral arteries: is there a role for membrane potential? Am J Physiol Heart Circ Physiol, February 1, 1998; 274(2): H655 - H662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kinoshita, Z. S. Katusic, and E. P. Wei Role of Potassium Channels in Relaxations of Isolated Canine Basilar Arteries to Acidosis Stroke, February 1, 1997; 28(2): 433 - 438. [Abstract] [Full Text]
|
|
|
|
|
|
T. Hirata, R. C. Koehler, T. Kawaguchi, S. W. Brusilow, and R. J. Traystman Impaired Pial Arteriolar Reactivity to Hypercapnia During Hyperammonemia Depends on Glutamine Synthesis Stroke, April 1, 1996; 27(4): 729 - 736. [Abstract] [Full Text]
|
|
|
|
|
|
H. Ishizaka and L. Kuo Acidosis-Induced Coronary Arteriolar Dilation Is Mediated by ATP-Sensitive Potassium Channels in Vascular Smooth Muscle Circ. Res., January 1, 1996; 78(1): 50 - 57. [Abstract] [Full Text]
|
|
|
|
|
|
A. C. Ngai and H. R. Winn Modulation of Cerebral Arteriolar Diameter by Intraluminal Flow and Pressure Circ. Res., October 1, 1995; 77(4): 832 - 840. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||