Vol. 273, Issue 4, H1719-H1726, October 1997
PDGF-BB decreases systolic blood pressure through an increase
in macrovascular compliance in rats
Masahiro
Ikeda1,
Chizuru
Morita1,
Makoto
Mizuno1,
Toshio
Sada1,
Hiroyuki
Koike1, and
Kiyoshi
Kurokawa2
1 Pharmacology and Molecular
Biology Research Laboratories, Sankyo, Tokyo 140; and
2 Department of Medicine, Tokai
University School of Medicine, Isehara, Kanagawa 259, Japan
 |
ABSTRACT |
The cardiovascular roles of platelet-derived
growth factor (PDGF) were examined in anesthetized rats by monitoring
blood pressure and in isolated blood vessels and heart preparations.
Intravenous injection of PDGF-BB lowered blood pressure. The decrease
in systolic pressure was greater than that in diastolic pressure, so
the pulse pressure decreased. PDGF-AA and -AB, other isoforms of PDGF,
did not have any effect on blood pressure. Pretreatment of rats with N
-nitro-L-arginine
methyl ester (L-NAME), an
inhibitor of nitric oxide (NO) synthase, shortened duration of the
hypotensive effect of PDGF-BB. The administration of
L-arginine with
L-NAME partially prevented the
effect of L-NAME. PDGF-BB
relaxed aortic rings precontracted with phenylephrine with a 50%
effective concentration of 3 ng/ml. In contrast, in isolated mesenteric
vascular preparations, the vasodilating activity of PDGF-BB was
observed only at a high concentration (>12.5 ng/ml). In isolated
heart preparations, PDGF-BB had no effect on the beat rate or
contractile activity. These results suggest a new role of PDGF-BB that
may contribute to the regulation in circulation through the increase in
macrovascular compliance mediated by NO.
nitric oxide; endothelium; macrovessel; hypotension; 
-receptor
| |
INTRODUCTION |
PLATELET-DERIVED GROWTH FACTOR (PDGF), a potent mitogen
in various cell types, is released from the cells involved in the regulation of circulation, including platelets, monocytes and macrophages, endothelial cells, and vascular smooth muscle cells (19).
Recently, Cunningham et al. (10) have shown that PDGF-BB causes
contraction in aortic rings denuded of endothelium and relaxation in
intact aortas. In addition, it has been reported that PDGF and nitric
oxide (NO) may have an interaction: PDGF, which is released from the
platelets, inhibits NO production in interleukin-1-stimulated rat
vascular smooth muscle cells in culture (11); and NO prevents the
expression of the PDGF-B chain gene in cultured human endothelial cells
(15). These data suggest that PDGF plays a role in the regulation of
vascular tone. However, the role of PDGF in circulation in vivo remains
to be elucidated. To delineate the cardiovascular action of PDGF in
vivo, we measured blood pressure when PDGF was intravenously
administered to anesthetized rats and also examined the effect of PDGF
on isolated aorta, mesenteric artery, and heart preparations.
| |
METHODS |
Animals.
Male Wistar rats (6-7 wk old) were purchased from Japan SLC
(Shizuoka, Japan) and used in all experiments. Animals were fed a
normal diet and tap water ad libitum.
In vivo experiments.
Rats were anesthetized with pentobarbital sodium (50 mg/kg ip), and two
polyethylene cannulas were placed, one in the left femoral artery for
measuring blood pressure and the other in the left femoral vein for
injecting drugs. The arterial cannula was connected to a pressure
transducer (TP-200T, Nihon Kohden, Tokyo, Japan), and blood pressure
and heart rate (HR) were continuously recorded on a thermal pen-writing
recorder (RJG-4128, Nihon Kohden). PDGF was injected intravenously
within 3 s with a volume of 0.02 ml/kg. The dose-response curve for
PDGF was obtained by repeating the administrations from a low dose to
high doses after the initial and previous dose(s) caused no further
change in blood pressure. A bolus injection (0.1 ml/kg) of 0.9%
saline,
N-nitro-L-arginine
methyl ester (L-NAME), or
L-NAME + L-arginine was given 10-16
min before the administration of PDGF. In another series of
experiments, L-NAME or
phenylephrine (PE) was infused with the use of an infusion pump
(STC-521, Terumo, Tokyo, Japan) at a rate of 0.3 m1 · kg
1 · min1
through the catheter inserted into the left femoral vein. PDGF was
injected after a stable elevation of blood pressure was obtained with
L-NAME or PE.
In vitro experiments: isolated rat aorta preparation.
Rats were stunned by a blow on the neck, and their thoracic aortas were
removed immediately after bleeding from the common carotid arteries.
The aortas were cleaned of adherent connective tissue and cut into
transverse rings 3 mm in length. The endothelium was removed from some
rings by gently rubbing the rings with a cotton swab. The
preparation was suspended with 1 g tension in an organ bath containing
20 ml Krebs-Henseleit solution (KHS) maintained at 37°C and aerated
with 5% CO2-95%
O2. KHS had the following
composition (in mM): 119.8 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4,
25.0 NaHCO3, and 11.1 glucose. The
developed tension was measured with the use of a force-displacement
transducer (TB-612T, Nihon Kohden) and recorded on the thermal
pen-writing recorder.
After an equilibration period of 120 min or longer, the rings were
contracted with a submaximal dose of PE (0.5 µM). After stable
contraction was obtained, PDGF, acetylcholine (ACh), and sodium
nitroprusside (SNP) were added to the bath in subsequent order. The
dose-response curve for PDGF was determined by administering two or
three doses of PDGF in an ascending order in one preparation to avoid a
desensitization of response (10). The dose-response curve for ACh was
obtained by adding ACh to the bath in a cumulative manner. To test the
effect of L-NAME,
L-NAME + L-arginine, methylene blue, or
carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazole-1-oxyl-3-oxide (carboxy-PTIO), we applied each drug 10 min before the addition of PDGF
(10 ng/ml). Maximum relaxation was evoked by the addition of papaverine
(100 µM) at the end of each experiment to calculate the relative
vasorelaxant activity of the test drugs.
In another series of experiments, after stabilization of the
preparation, high-K KHS (60 mM K+
substituted for Na+) was applied
to the bath to obtain a control response. PDGF-BB was then added to the
bath. PDGF-BB-induced contraction was expressed as a percentage of the
control response.
In vitro experiments: isolated rat mesenteric vascular bed
preparation.
The mesenteric vascular beds were removed and perfused by McGregor's
method (17). The isolated mesenteric vascular preparations were placed
in a 5-ml water-jacketed organ bath maintained at 37°C, and only
four main arterial branches from the superior mesentery running to the
terminal ileum were perfused with KHS by means of a pump (Miniplus 2, Gilson, Villiers le Bel, France) at a constant flow rate of 5 ml/min
and superfused with the same solution at a rate of 0.5 ml/min to
prevent drying. The perfusate was aerated with 5%
CO2-95%
O2. Changes in the perfusion
pressure were monitored with the pressure transducer. After 20 min of
equilibration, the mesenteric vascular bed was routinely perfused with
KHS containing guanethidine (5 µM) to block adrenergic
neurotransmission and methoxamine (40 µM) to induce submaximal
vasoconstriction. After the elevated perfusion pressure was allowed to
stabilize, the preparation was subjected to an infusion of drugs. PDGF
(0.75, 2.5, 7.5, and 75 ng) and ACh (10, 30, and 100 pmol), which were diluted with KHS containing methoxamine and guanethidine, were infused
directly into the perfusate proximal to the arterial cannulas by the
infusion pump for 9 s. The infused volume was 0.05 ml. Maximum
relaxation was evoked by adding papaverine (100 µM) to calculate the
relative vasorelaxant activity of the test drugs.
In vitro experiments: isolated rat heart preparation.
The heart was isolated immediately after the rat was stunned by a blow
on the neck. The right atrium and ventricular papillary muscles were
dissected and mounted in a 30-ml organ bath containing KHS aerated with
5% CO2-95%
O2 at 37°C. The right
ventricular papillary muscle was stimulated with square pulses at a
frequency of 1 Hz and 2 ms in duration using a threefold-threshold
voltage. The developed tensions of the heart preparations were measured by means of a force-displacement transducer, and the beat rate of the
right atrium was measured using a tachometer (AT-601G, Nihon Kohden).
These data were recorded on the thermal pen-writing recorder. The
initial resting tension was set at 500 mg. After a 10-min equilibration
period, PDGF-BB at a dose of 10 or 30 ng/ml was added to the bath.
Reagents.
Human recombinant PDGF-AA, -AB, and -BB were obtained from Boehringer
Mannheim (Mannheim, Germany).
L-NAME,
L-arginine hydrochloride, PE
hydrochloride, methylene blue, and SNP were from Sigma Chemical (St.
Louis, MO). ACh hydrochloride (Ovisot) was from Daiichi (Tokyo, Japan),
methoxamine hydrochloride (Mexan) was from Nihon Shinyaku (Kyoto,
Japan), papaverine hydrochloride was from Wako Pure Chemical (Osaka,
Japan), carboxy-PTIO was from Dojin (Kumamoto, Japan), and guanethidine
sulfate was from Tokyo Kasei (Tokyo, Japan).
Data analysis.
All data are expressed as means ± SE. For all experiments,
n indicates the number of rats.
Statistical mean comparison was done by Student's
t-test between two groups and by
Dunnett's method between three or more groups. The 50% effective
concentration (EC50) in the
isolated rat mesenteric vascular bed experiment was calculated by
dividing the 50% effective dose
(ED50) by the volumes of
infusate and perfusate during drug applications.
| |
RESULTS |
In vivo experiments.
When administered intravenously, PDGF-BB (0.3-3 µg/kg) gradually
decreased mean arterial blood pressure (MBP), with systolic blood
pressure (SBP) being more affected than diastolic blood pressure (DBP),
resulting in a reduction of pulse pressure (PP) (Figs.
1 and 2). This hypotension
reached a maximum within 5-7 min after PDGF-BB administration and
recovered to the pretreatment level within 12 min (Fig.
2A). HR increased slightly in
response to PDGF-BB. Figure 1A shows
the peak amplitudes of HR, SBP, DBP, and MBP plotted against a
logarithmic dose of PDGF-BB. PDGF lowered blood pressure in a
dose-dependent manner, and its threshold dose was around 0.3 µg/kg.
Figure 1B summarizes the effects of
three isoforms of PDGF when each was injected intravenously at a dose of 3 µg/kg. Among three isoforms of PDGF, only PDGF-BB caused hypotension.
View larger version (21K):
[in this window]
[in a new window]
|
Fig. 1.
Effect of platelet-derived growth factor (PDGF) on arterial blood
pressure (BP) and heart rate (HR) in anesthetized rats.
A: peak values of HR
(top) and systolic (SBP), diastolic
(DBP), and mean blood pressure (MBP;
bottom) after administration of each
dose of PDGF-BB plotted on a logarithmic scale. B: bar graph showing
maximum changes in SBP after treatment with PDGF-AA, -AB, or -BB
isoforms (3 µg/kg each; n = 5).
Basal SBP was 135.6 ± 10.0 mmHg.
*** P < 0.001 vs. basal SBP by
Dunnett's method.
|
|
View larger version (23K):
[in this window]
[in a new window]
|
Fig. 2.
Effects of
N-nitro-L-arginine
methyl ester (L-NAME) and
L-NAME + L-arginine
(L-Arg) on PDGF-BB-induced
hypotension. Vehicle (0.9% saline) as control
(A),
L-NAME
(B), or
L-NAME + L-Arg
(C) was injected as a bolus
10-16 min before administration of PDGF-BB. Arrowheads indicate
times of injection.
|
|
Next, we examined whether the response to PDGF-BB involved NO.
Intravenous bolus injection of
L-NAME (1-2 mg/kg), an
inhibitor of NO synthase (18), caused a gradual increase in blood
pressure and a decrease in HR (Fig.
2B, Table
1), which attained a maximum within
6-7 min. After the response to
L-NAME was stabilized, PDGF-BB was injected intravenously. PDGF-BB produced a transient reduction of
SBP, followed by a rapid return to the original level (Fig. 2B). In contrast, after
L-arginine (100-200 mg/kg)
was injected in combination with
L-NAME, PDGF-BB caused a gradual
reduction in SBP, which then returned to the original level as observed in the vehicle pretreatment (saline; Figs. 2,
A and
C). Figure 4A summarizes the effect of bolus
injection of L-NAME.
L-NAME shortened the PDGF
response, whereas the absolute amplitude of change in SBP induced by
PDGF-BB was greater in the rats pretreated with
L-NAME than those pretreated
with saline and L-NAME + L-arginine (Table 1). This was
probably caused by the increase in blood pressure induced by
L-NAME. To verify the action of
L-NAME on PDGF response, we
compared the effect of L-NAME on
the PDGF-induced response to that of PE (Figs.
3 and
4B, Table
2). In this experiment, both drugs were
infused by an infusion pump before injection of PDGF. The elevation of
blood pressure induced by the infusion of PE (10 µg · kg1 · min1)
was comparable to that induced by
L-NAME (0.15 mg · kg1 · min1).
The peak reduction of SBP in response to PDGF-BB in
L-NAME-pretreated rats was the
same as that in PE-pretreated rats (Table 2). However, the duration of
PDGF-induced reduction of blood pressure was shorter in the
L-NAME-treated rats than in the
PE-treated rats (Fig. 4B). It is
noteworthy that the duration of the PDGF response in the PE-treated
rats was similar to that in the rats injected with vehicle (Fig. 4).
View larger version (23K):
[in this window]
[in a new window]
|
Fig. 3.
Effects of continuously infused
L-NAME
(A) and phenylephrine (PE;
B) on PDGF-BB-induced hypotension.
PDGF was injected after stable elevations of BP were obtained.
Arrowheads and arrows indicate times of injection and infusion,
respectively.
|
|
View larger version (20K):
[in this window]
[in a new window]
|
Fig. 4.
Effects of L-NAME,
L-NAME + L-arginine
(L-Arg), and PE on
PDGF-BB-induced duration of depressor responses. Data were collected
from bolus injection (A) and
infusion experiments (B) described
in Figs. 2 and
3, respectively. Duration of
PDGF-BB-induced hypotension is expressed as time in seconds to
half-recovery (RT1/2) from
maximum decrease in SBP. Nos. in parentheses indicate no. of rats.
** P < 0.01 vs. vehicle
(A; by Dunnett's method) or PE
(B; by Student's
t-test).
|
|
Next, we tried to examine effects of methylene blue and carboxy-PTIO,
which are the inhibitors of NO action on the PDGF-induced hypotension
(2, 14). Unfortunately, we failed, because these compounds could not
induce an elevation of blood pressure and higher doses of these
compounds led to animal death. Therefore, we did not further evaluate
the involvement of NO in the PDGF-induced hypotension.
In vitro experiments: isolated rat aorta preparation.
PDGF-BB-induced relaxation was only observed in the intact aortic rings
precontracted with PE (Fig. 5,
A and
B), and its
EC50 value was ~3 ng/ml (Table
3). At the concentration at which PDGF-BB showed the maximum response (>10 ng/ml), PDGF-AB caused a slight relaxation and PDGF-AA had virtually no effect (Fig.
5B).
View larger version (22K):
[in this window]
[in a new window]
|
Fig. 5.
Effects of PDGF and acetylcholine (ACh) in rat aortic ring preparations
contracted with PE. Representative tracings
(A) show effects of addition of
PDGF-BB, ACh, sodium nitroprusside (NP; 5 nM), and papaverine (100 µM) in subsequent order with (+) or without ( ) endothelium.
B: dose-response relationships for
PDGF-BB, -AB, and -AA in intact rings and -BB in endothelium ()
rings are expressed as percentage changes of maximum relaxation evoked
by administration of 100 µM papaverine.
C: dose-response relationship for ACh
in intact aortic rings. B and
C: dotted lines indicate 50%
relaxation; nos. in parentheses represent no. of rats.
|
|
In endothelium-denuded aortic rings, a higher dose (60 ng/ml) of
PDGF-BB elicited a transient contraction (29.5 ± 8.8%, expressed as the percentage of high-K KHS-induced contraction;
n = 3). However, we did not observe
the PDGF-BB-induced contraction at a concentration <10 ng/ml.
PDGF-BB-induced relaxation (10 ng/ml) was abolished by pretreatment
with L-NAME (30 µM; 0 ± 0%, expressed as the papaverine-induced relaxation;
n = 4). This inhibitory effect of
L-NAME was partially recovered
by concomitant addition of
L-arginine (3 mM; 15.3 ± 6.9%; n = 4). A similar result was
obtained when methylene blue (10 µM), an inhibitor of guanylate
cyclase (14), was administered before the addition of PDGF-BB (0 ± 0%; n = 4). A pretreatment with
carboxy-PTIO (300 µM), a newly developed NO-scavenger (2), also
abolished the PDGF-induced vasorelaxation (2.5 ± 2.0%; n = 3).
Addition of L-NAME,
L-NAME + L-arginine, methylene blue, or
carboxy-PTIO in the presence of PE (0.5 µM)-induced contraction alone
caused little change of contraction in intact aortic rings.
To compare the potency of ACh and PDGF-BB between rat aorta and
mesenteric vascular bed, we examined the response to ACh in aortic
rings from the same batches of rats. Cumulative addition of ACh
elicited a vasorelaxation in intact aortic rings precontracted with PE,
and its EC50 was ~100 nM (Fig.
5C, Table 3).
In vitro experiments: isolated rat mesenteric vascular bed
preparation.
ACh but not PDGF-BB lowered perfusion pressure markedly in the
mesenteric vascular bed, which was contracted submaximally with
methoxamine, an 
-adrenergic agonist (Fig.
6).
View larger version (19K):
[in this window]
[in a new window]
|
Fig. 6.
Effects of PDGF and ACh in rat mesenteric vascular beds contracted with
methoxamine. Representative recordings show vasodilation induced by ACh
(B) but not PDGF-BB
(A) from same rat. Arrowheads and
arrows indicate times of injection with PDGF-BB or ACh and perfusion
with methoxamine and guanethidine or papaverine, respectively.
Dose-response relationships are shown for PDGF-BB
(C) and ACh
(D). Dotted lines indicate 50%
relaxation; n, no. of rats. Data for
C and
D were collected from experiments
similar to those represented in A and
B.
|
|
Table 3 summarizes the EC50 and
calculated EC50 values from in
vitro blood vessel experiments. ACh relaxed both the aortas and
mesenteric vascular beds in a similar dose range, whereas PDGF-BB-induced vasorelaxation is more selective to the aortas than to
the mesenteric vascular beds.
In vitro experiments: isolated rat heart preparation.
After stabilization of preparations, the beat rate in isolated right
atrium and the developed tension in isolated papillary muscle were 346 ± 35 beats/min and 188 ± 31 mg, respectively. After treatment,
no significant effects of PDGF-BB (10 ng/ml) on the beat rate and the
developed tension were detected (beat rate: 347 ± 61 beats/min;
developed tension: 179 ± 43 mg; n = 3).
| |
DISCUSSION |
PDGF-BB given intravenously caused a transient reduction in SBP as well
as in DBP in rats. Reduction in SBP was greater than that in DBP, so PP
was reduced. L-NAME markedly
reduced the duration of PDGF-BB response, and this reduction was
partially recovered by
L-arginine as observed in
hypotension induced by ACh (1, 23). This effect is not caused by a rise
in arterial blood pressure caused by
L-NAME, because the duration of
PDGF-BB-induced hypotension was not shortened during infusion of PE.
These results suggest that the duration of PDGF-BB-induced depressor
response was at least in part caused by NO derived from
L-arginine. The diminution by
L-NAME, methylene blue, and
carboxy-PTIO of PDGF-BB-induced relaxation in intact aortic rings in
vitro supported this hypothesis.
Among three isoforms of PDGF, only PDGF-BB had effects both in vivo and
in vitro. According to current knowledge (9, 16), PDGF is a dimer
protein composed of two polypeptide chains, PDGF-A and -B, and each
chain of PDGF binds with different affinities to two specific
receptors, denoted as the PDGF - and -subtypes. The PDGF
-receptor binds both A and B types of PDGF peptide with high
affinity, and the PDGF -receptor binds only the PDGF-B chain. PDGF
receptor dimerization occurs as a result of PDGF binding and appears to
be a prerequisite for exerting the biological action of PDGF.
Therefore, the effect of PDGF-BB mediated by endothelium-derived NO is
initiated by the activation of PDGF -receptor in vitro and in
vivo. This consistency in isoform-specific action of PDGF-BB both in
vivo and in vitro may also support the notion that the PDGF-BB-induced
depressor response involves NO in vivo.
The magnitude of hypotension elicited by PDGF-BB was affected little by
the pretreatment with L-NAME.
Similar observations have been reported on the effects of ACh; Aisaka
et al. (1) have observed that
NG-monomethyl-L-arginine
(L-NMMA), an inhibitor of NO
synthase, does not inhibit the amplitude of ACh-induced hypotension in
guinea pigs, and Yamazaki et al. (23) have described a similar action of L-NMMA on ACh-induced
hypotension in rats. These data do not fully support the in vitro
study, which indicates that the inhibitors of NO synthase attenuate or
abolish the amplitudes of relaxations induced by ACh and PDGF-BB (Ref.
18 and present study). The component resistant to NO synthase
inhibitors in vivo may be related to prostanoids. However, this
possibility is unlikely, because hypotension induced by ACh may not be
affected by the pretreatment with indomethacin, a cyclooxygenase
inhibitor (1). The second possibility is that the doses of
L-NAME and
L-NMMA were not sufficient to
completely inhibit NO synthase. However, this is also unlikely because
the present study demonstrated that the infusion of
L-NAME, which elevated blood
pressure more than the bolus injection, potentiated the amplitude of
hypotension induced by PDGF-BB and because pretreatment with atropine
fails to render the vasodilator response to ACh more sensitive to
L-NMMA (12). The third
possibility is that the component resistant to NO synthase inhibitors
may be mediated by endothelium-derived hyperpolarizing factor (EDHF),
which is postulated (13) to mediate the vasodilation induced by ACh in various types of blood vessels. Unfortunately, to date, EDHF has not
been identified. The fourth possibility is that PDGF may release NO or
related molecules from a preformed pool in vivo (1). Nitrosothiols are
thought to be reservoirs of NO, but as yet no definite role has been
assigned to them (8).
PDGF-BB lowered SBP more markedly than it lowered DBP, resulting in a
decrease of PP. The possible mechanisms for this include 1) a selective dilation of the
macrovessel rather than the microvessel, 2) a decrease in venous return,
3) a reduction of cardiac
contractility, and 4) an increase in
HR. It has been reported that ACh dilates both the large femoral artery
and the hindlimb resistance vessels when administered intra-arterialy
into the hindlimb vasculature of the dog (22) and lowers mean arterial
pressure when administered intravenously in the rat, accompanied with
increases in renal, mesenteric, and hindquarters vascular conductances
(12). In the present study, we showed that ACh relaxed both the aorta
and mesenteric artery at a similar dose range, whereas PDGF-BB rather selectively dilated the aorta. Although we did not examine the effect
of PDGF-BB on other vascular beds, these observations favor the
hypothesis that the reduction of PP induced by PDGF-BB is attributed to
a selective dilation of macrovessel rather than microvessel.
Mechanisms 3 and
4 as proposed above are unlikely, because no detectable changes in the beat rate of the right atrium preparations nor in the contractilities of papillary muscles were observed in response to PDGF. Further studies are needed to examine mechanism 2.
Although it was considered that PDGF-BB may act only on the endothelial
cells of the microvessels but not of the macrovessels (3, 5), recent
reports indicate that PDGF-BB may act on the endothelium of
macrovessels. Cunningham et al. (10) have demonstrated that PDGF-BB can
directly act on macrovessels, which is in good agreement with the
present study. In addition, Battegay et al. (4) have found two
phenotypes of endothelial cells from bovine aorta in culture. One is an
angiogenic endothelial cell type that responds to PDGF-BB, and the
other is a nonangiogenic endothelial cell type that is insensitive to
PDGF. These findings suggest the possible existence of PDGF-BB receptor
on endothelium of specific phenotype in macrovessels.
In isolated aorta, it has been reported (6, 7, 20) that PDGF induces
contraction in spite of the presence of endothelium. Furthermore, in
denuded aortic rings, Cunningham et al. (10) have described that
PDGF-BB initiates contractions at concentrations lower than those
required for endothelium-dependent vasorelaxations. However, we could
not observe an elevation of blood pressure when PDGF-BB was
administered intravenously in basal and PE-induced hypertensive
conditions. Thus we conclude that PDGF-BB plays an important role in
the hypotensive regulation of systemic blood pressure. However,
regional hemodynamic effects of PDGF were not elucidated in the present
study, and further evaluations are needed.
Schini and co-workers (11, 21) recently showed that PDGF-BB inhibits NO
release from interleukin-1-stimulated vascular smooth muscle cells.
The inhibitory effect of PDGF is thought to be mediated through the
inhibition of the transcriptional activation of the inducible NO
synthase gene, which requires a lag time for exerting its effect (11).
In contrast, the present study showed that the NO release from the
endothelium in response to PDGF-BB was very rapid both in vitro and in
vivo. These data suggest that there might be different mechanisms
involved in the chronic and acute phases in the regulation of vascular
tone by PDGF-BB that acts in conjunction with NO.
In summary, we have observed for the first time that PDGF-BB decreased
SBP with a reduction in PP in vivo. This hemodynamic change in response
to PDGF-BB may be attributed to an increase in aortic compliance
mediated through the NO pathway.
| |
FOOTNOTES |
Address for reprint requests: M. Ikeda, Dept. of Veterinary
Pharmacology, Faculty of Agriculture, Miyazaki Univ., 1-1
Gakuenkibanadainishi, Miyazaki 889-21, Japan.
Received 21 April 1997; accepted in final form 29 June 1997.
| |
REFERENCES |
1.
Aisaka, K.,
S. S. Gross,
O. W. Griffith,
and
R. Levi.
L-Arginine availability determines the duration of acetylcholine-induced systemic vasodilation in vivo.
Biochem. Biophys. Res. Commun.
163:
710-717,
1989[Medline].
2.
Akaike, T.,
M. Yoshida,
Y. Miyamoto,
K. Sato,
M. Kohno,
K. Sasamoto,
K. Miyazaki,
S. Ueda,
and
H. Maeda.
Antagonistic action of imidazolineoxyl N-oxides against endothelium-derived relaxing factor/NO through a radical reaction.
Biochemistry
32:
827-832,
1993[Medline].
3.
Bar, R. S.,
M. Boes,
B. A. Booth,
B. L. Dake,
S. Henley,
and
M. N. Hart.
The effects of platelet-derived growth factor in cultured microvessel endothelial cells.
Endocrinology
124:
1841-1848,
1989[Abstract/Free Full Text].
4.
Battegay, E. J.,
J. Rupp,
L. Iruela-Arispe,
E. H. Sage,
and
M. Pech.
PDGF-BB modulates endothelial proliferation and angiogenesis in vitro via PDGF -receptors.
J. Cell Biol.
125:
917-928,
1994[Abstract/Free Full Text].
5.
Beitz, J. G.,
I. S. Kim,
P. Calabresi,
and
A. R. Frackelton, Jr.
Human microvascular endothelial cells express receptors for platelet-derived growth factor.
Proc. Natl. Acad. Sci. USA
88:
2021-2025,
1991[Abstract/Free Full Text].
6.
Berk, B. C.,
R. W. Alexander,
T. A. Brock,
M. A. Gimbrone, Jr.,
and
R. C. Webb.
Vasoconstriction: a new activity for platelet-derived growth factor.
Science
232:
87-90,
1986[Abstract/Free Full Text].
7.
Block, L. H.,
L. R. Emmons,
E. Vogt,
A. Sachinidis,
W. Vetter,
and
J. Hoppe.
Ca2+-channel blockers inhibit the action of recombinant platelet-derived growth factor in vascular smooth muscle cells.
Proc. Natl. Acad. Sci. USA
86:
2388-2392,
1989[Abstract/Free Full Text].
8.
Butler, A. R.,
F. W. Flitney,
and
D. L. H. Williams.
NO, nitrosonium ions, nitroxide ions, nitrosothiols and iron-nitrosyls in biology: a chemist's perspective.
Trends Pharmacol. Sci.
16:
18-22,
1995[Medline].
9.
Claesson-Welsh, L.
Signal transduction by the PDGF receptors.
Prog. Growth Factor Res.
5:
37-54,
1994[Medline].
10.
Cunningham, L. D.,
P. Brecher,
and
R. A. Cohen.
Platelet-derived growth factor receptors on macrovascular endothelial cells mediate relaxation via nitric oxide in rat aorta.
J. Clin. Invest.
89:
878-882,
1992.
11.
Durante, W.,
V. B. Schini,
M. H. Kroll,
S. Catovsky,
T. Scott-Bruden,
J. G. White,
P. M. Vanhoutte,
and
A. I. Schafer.
Platelets inhibit the induction of nitric oxide synthesis by interleukin-1 in vascular smooth muscle cells.
Blood
83:
1831-1838,
1994[Abstract/Free Full Text].
12.
Gardiner, S. M.,
A. M. Compton,
P. A. Kemp,
and
T. Bennett.
Regional and cardiac haemodynamic responses to glyceryltrinitrate, acetylcholine, bradykinin and endothelin-1 in conscious rats: effects of NG-nitro-L-arginine methyl ester.
Br. J. Pharmacol.
101:
632-639,
1990[Medline].
13.
Garland, C. J.,
F. Plane,
B. K. Kemp,
and
T. M. Cocks.
Endothelium-dependent hyperpolarization: a role in the control of vascular tone.
Trends Pharmacol. Sci.
16:
23-30,
1995[Medline].
14.
Gruetter, C. A.,
P. J. Kadowitz,
and
L. J. Ignarro.
Methylene blue inhibits coronary arterial relaxation and guanylate cyclase activation by nitroglycerine, sodium nitrite, and amyl nitrite.
Can. J. Physiol. Pharmacol.
59:
150-156,
1981[Medline].
15.
Kourembanas, S.,
L. P. McQuillan,
G. K. Leung,
and
D. V. Faller.
Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia.
J. Clin. Invest.
92:
99-104,
1993.
16.
LaRochelle, W. J.,
N. Giese,
K. C. Robbins,
and
S. A. Aaronson.
Variant PDGF ligands and receptors-structure-function relationships.
News Physiol. Sci.
6:
56-60,
1991.[Abstract/Free Full Text]
17.
McGregor, D. D.
The effect of sympathetic nerve stimulation on vasoconstrictor responses in perfused mesenteric blood vessels of the rat.
J. Physiol. (Lond.)
177:
21-30,
1965.
18.
Moore, P. K.,
O. A. al-Swayeh,
N. W. S. Chong,
R. A. Evans,
and
A. Gibson.
L-NG-nitro arginine (L-NOARG), a novel, L-arginine-reversible inhibitor of endothelium-dependent vasodilation in vitro.
Br. J. Pharmacol.
99:
408-412,
1990[Medline].
19.
Ross, R.,
E. W. Raines,
and
D. F. Bowen-Pope.
The biology of platelet-derived growth factor.
Cell
46:
155-169,
1986[Medline].
20.
Sachinidis, A.,
R. Locher,
J. Hoppe,
and
W. Vetter.
The platelet-derived growth factor isomers, PDGF-AA, PDGF-AB and PDGF-BB, induce contraction of vascular smooth muscle cells by different intracellular mechanisms.
FEBS Lett.
275:
95-98,
1990[Medline].
21.
Schini, V. B.,
W. Durante,
E. Elizondo,
T. Scott-Bruden,
D. C. Junquero,
A. I. Schafer,
and
P. M. Vanhoutte.
The induction of nitric oxide synthase activity is inhibited by TGF-1, PDGF AB and PDGF BB in vascular smooth muscle cells.
Eur. J. Pharmacol.
216:
379-383,
1992[Medline].
22.
Sobey, C. G.,
O. L. Woodman,
and
G. J. Dusting.
Inhibition of vasodilatation by methylene blue in large and small arteries of the dog hindlimb in vivo.
Clin. Exp. Pharmacol. Physiol.
15:
401-410,
1988[Medline].
23.
Yamazaki, J.,
N. Fujita,
and
T. Nagao.
NG-monomethyl-L-arginine-induced pressor response at developmental and established stages in spontaneously hypertensive rats.
J. Pharmacol. Exp. Ther.
259:
52-57,
1991[Abstract/Free Full Text].
AJP Heart Circ Physiol 273(4):H1719-H1726
0363-6135/97 $5.00
Copyright © 1997 the American Physiological Society
Top
Abstract
Introduction
