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1 Physiologisches Institut, Justus-Liebig-Universität, D-35392 Giessen; 2 Abteilung für Pathophysiologie, Universitätsklinikum Essen, D-45122 Essen; and 3 Abteilung für Innere Medizin, Universitätsklinikum Giessen, D-35392 Giessen, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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10.1152/ajpheart.00925. 2001.
Parathyroid hormone-related peptide (PTHrP) is expressed
throughout the cardiovascular system and is able to dilate vessels.
This study investigated whether mechanical forces generated by changes
in regional perfusion influence PTHrP release from the coronary
vascular bed. Experiments were performed in vitro on saline-perfused
rat hearts or isolated coronary endothelial cells exposed to cyclic
strain and in vivo in anesthetized pigs. In vitro, PTHrP release from
saline-perfused rat hearts was strongly correlated with coronary flow
(r = 0.84). Increasing coronary flow from 5 to 10 ml/min increased PTHrP release from 442 ± 42 to 1,563 ± 167 pg/min. Increasing the viscosity of the perfusate did not change basal
PTHrP release. Increasing flow without a concomitant increase in
pressure did not lead to an increase in release rate, but reduction in
pressure under flow-constant conditions reduced PTHrP release rate.
Cyclic strain induced a strain-dependent release of PTHrP from
endothelial cells that was inhibited by the addition of a
calcium-chelating agent. In vivo, there was a net release of PTHrP in
the coronary circulation and decreases in coronary flow and pressure
decreased the PTHrP release rate. Bradykinin in the presence of
constant pressure increased PTHrP release, probably by increasing the
intracellular calcium concentration in coronary endothelial cells. In
summary, mechanical forces evoked by blood flow can trigger a constant PTHrP release.
shear stress; endothelium; nitric oxide
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CORONARY ENDOTHELIUM PRODUCES several vasoactive factors that are involved in the regulation of coronary vasodilatation, i.e., nitric oxide (NO), prostacyclin, endothelium-derived hyperpolarizing factor (EDHF), and parathyroid hormone-related peptide (PTHrP). Initially, it was demonstrated that intracoronary injection of synthetic parathyroid hormone (PTH), which shares structural similarities with PTHrP, evoked an increase in coronary flow in the canine heart (4, 5). In a subsequent study in rat hearts, PTHrP increased coronary flow and appeared to be more potent than PTH (13). This observation is of particular interest, because PTHrP is expressed in human and rat fetal and adult hearts (2, 6), especially in coronary endothelial cells (17).
The physiological function of PTHrP released from coronary endothelial cells is not yet understood. We have recently begun to investigate the mechanisms of production and release of PTHrP by coronary endothelial cells. In a model of cultured endothelial cells, PTHrP was not released under static no-flow conditions unless the cells were energy depleted (17). In contrast to the isolated cell system, PTHrP was constantly released from the coronary circulation of well-oxygenated isolated, saline-perfused rat hearts. We hypothesized, therefore, that PTHrP might be released from the coronary vessels in a mechanosensitive manner. This hypothesis was investigated in the present study in vitro and in vivo, using isolated, perfused rat hearts, isolated coronary endothelial and smooth muscle cells that were exposed to cyclic strain, and in situ hearts of anesthetized pigs. Because NO is released in a flow-dependent manner (8), we also investigated whether endogenous basal NO release interacts with PTHrP release, as shown previously for NO and EDHF (1).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Heart perfusions.
In vitro experiments were performed in isolated, saline-perfused rat
hearts as described previously (18). Hearts from 200- to
250-g male Wistar rats were mounted on a Langendorff perfusion system
in a temperature-controlled chamber (37°C). The chamber was filled
with humidified air during perfusion of hearts at 37°C and a flow
rate of 5 ml/min for an initial stabilizing period of 5 min. Hearts
were perfused with an oxygenated saline medium [composition of the
perfusate (in mmol/l): 120.0 NaCl, 24.0 NaHCO3, 27 KCl, 0.4 NaH2PO4, 1.0 MgCl2, 1.8 CaCl2, and 5.0 glucose, gassed with 95% O2-5%
CO2, pH 7.4]. The hearts were perfused under constant-flow conditions, and coronary flow was varied between 1.25 and 10 ml/min. The effluent was collected, and the PTHrP concentration was measured. In a subgroup of experiments, the endothelial cell compartment was
carefully denuded by a 5-s perfusion with standard buffer containing
Triton X-100 (0.5% vol/vol). In another subgroup of experiments, the
viscosity of the perfusion buffer was increased by addition of 10%
(wt/vol) dextran (mol mass 50 kDa). Finally, PTHrP release was
determined in a further group of experiments, in which either arginine
(100 µmol/l) or
N
-nitro-L-arginine
(L-NNA, 100 µmol/l) was added.
Endothelial cell preparations.
Coronary endothelial cells were isolated from 250-g male Wistar rats
and grown in culture as previously described (15). Briefly, hearts were perfused with collagenase, chopped, and dissolved into a suspension. From this suspension, the fraction of endothelial cells was purified. Cells were plated at a density of 106
cells/dish on 100-mm plastic petri dishes. The cells were
incubated at 37°C in medium 199 with Earle's salts, supplemented
with 100 IU/ml penicillin G, 100 µg/ml streptomycin, and 10%
(vol/vol) fetal bovine serum. The medium was renewed every second day.
After 4 days, when the cells had grown to confluence, they were
trypsinized in PBS [in mmol/l: 137 NaCl, 2.7 KCl, 1.5 KH2PO4, and 8 Na2HPO4 at pH 7.4, supplemented with 0.05% (wt/vol) trypsin and 0.02% (wt/vol) EDTA] and seeded at a density of 4 × 105
cells/cm2 on collagen-coated silicone dishes. As previously
reported (14), the purity of these cultures was >95%
endothelial cells as determined by uptake of acetylated low-density
lipoprotein labeled with
1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate,
contrasted by <5% cells positive for 
-smooth muscle actin.
Experiments were started 2 days later by exposing the cells to cyclic
strain (5-20%) at a constant frequency of 1 Hz. After 1 h,
experiments were terminated and supernatants and cell extracts were
used to determine PTHrP expression or release.
Analytic methods. During rat heart perfusion, 1-ml samples of the effluent were collected at the indicated times as described previously (17). To these samples, 100 µl of deoxycholate (100 mmol/l) for 10 min and thereafter 100 µl of trichloroacetic acid (100%) were added. Samples were kept for 30 min at 4°C. Proteins were precipitated by centrifugation (5 min, 13,000 g), and the pellet was redissolved in 35 µl of electrophoresis sample buffer [0.5 mmol/l Tris · HCl, 4% (wt/vol) SDS, 25% (vol/vol) glycerin, 1% (vol/vol) mercaptopropanediol, and 0.1% (wt/vol) bromophenol blue; pH 6.8] and heated at 65°C for 10 min. The pH was adjusted to 7 by the addition of 100% Tris. Plasma samples from swine were diluted 1:10 (vol/vol) with H2O, and 100 µl of this dilution were prepared as described above for the effluent of saline-perfused rat hearts. Supernatants of cell cultures were used as described for the effluent of the perfused rat hearts. Cell samples were prepared as described previously (17). Briefly, cells were washed with ice-cold PBS, homogenized by the addition of 100 µl of lysis buffer [50 mmol/l Tris · HCl, 2% (wt/vol) SDS, 2% (vol/vol) mercaptopropranediol, and 1 mmol/l Na3VO4; pH 6.7]. The dishes were shaken vigorously for 10 min. Thereafter, 10 µl benzonase (50 U/ml) was added and the samples were shaken again for 10 min. Finally, samples were removed with the aid of a rubber policeman, filled in a reaction tube, mixed with 100 µl of electrophoresis sample buffer, and heated at 65°C for 10 min.
PTHrP concentrations were measured in these samples by performing a nonradioactive immunoassay with alkaline phosphatase. Appropriate amounts of samples (35 µl of effluents, plasma samples, or culture supernatants) or samples containing 60 µg of protein (endothelial cells) were used for SDS-PAGE containing 12.5% (wt/vol) polyacrylamide. Electrophoretically separated proteins were transblotted on polyvinylidene difluoride (PVDF) membranes. After transfer, PVDF membranes were blocked with 2% (wt/vol) bovine serum albumin in Tris buffer (30 mmol/l; pH 7.4) overnight and incubated with antibodies directed against PTHrP [antibody GF08, Oncogene Research Products; purchased from Calbiochem, Bad Soden, Germany; directed against PTHrP-(38-64)] for 2 h. After incubation, the PVDF membranes were washed in 30 mmol/l Tris buffer (pH 7.4) and exposed to an alkaline phosphatase-coupled second antibody for 2 h. Finally, proteins were visualized with the use of 5-bromo-4-chloro-3-indolyl phosphate-nitro blue tetrazolium as alkaline phosphatase substrates. Densitometry on protein immunoblots was performed with Image Quant (Molecular Dynamics, Krefeld, Germany). The system was standardized by full-length PTHrP purified from coronary endothelial cells as described previously (17). Nitrite concentrations in the perfusate were determined as described previously (9). The nitrite content in the supernatant was measured by combining 500 µl of perfusate with 500 µl of Griess reagent (0.75% sulfanilamide in 0.5 N HCl-0.075% naphthylethylenediamine), and the concentration of the resulting chromophore was determined spectrophotometrically at 543 nm. Lactate dehydrogenase activities in the perfusate were photometrically determined as described previously (18).Determination of coronary resistance in isolated, perfused rat heart preparations. Isolated rat hearts were perfused as described above in the Langendorff mode. In the perfusion buffer, the concentration of KCl was corrected from 27 to 2.7 mmol/l to allow the hearts to beat. Hearts were paced at a constant frequency of 3 Hz and perfused at a constant pressure of 55 mmHg. At the indicated time, the effluent was collected for 1 min and the volume was measured. Coronary resistance was calculated from the perfusion pressure and calculated coronary flow and normalized to heart wet weight.
Statistics. Quantitative results are expressed as means ± SE. In experiments with more than two groups, ANOVA was used for comparison, with a Student-Newman-Keuls test for post hoc analysis. In cases in which two groups were compared, conventional t-tests were performed. A P < 0.05 indicated a significant difference between groups.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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PTHrP release from isolated, saline-perfused rat hearts.
In the effluent of hearts isolated from adult rats perfused at a
constant flow of 5 ml/min under nonbeating conditions, 84.3 ± 8.3 ng PTHrP/ml was detected, corresponding to a concentration of 1.7 nmol/l. The basal release rate was 422 ± 42 ng PTHrP/min (n = 8). Increases or decreases in coronary flow were
rapidly followed by concomitant changes in the release rate of PTHrP
(Fig. 1A). The data of
coronary flow and PTHrP release were positively correlated (Fig.
1B). As a result of this flow-dependent adaptation, PTHrP
concentration in the effluent remained nearly constant (Fig. 1C). No significant release of lactate dehydrogenase was
detectable.
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Influence of PTHrP on coronary resistance.
Isolated rat heart vessels were preconstricted by perfusion with
the -adrenoceptor agonist phenylephrine. In the presence of
phenylephrine, coronary resistance was increased from 8.87 ± 0.34 to 10.83 ± 0.19 mmHg · ml
1 · g. Synthetic
PTHrP-(1-34) or authentic PTHrP, which was purified from the plasma samples of the pigs, induced vasodilation, indicating functional PTHrP receptors (Table 2).
More importantly, basal PTHrP release decreased coronary resistance,
because the PTHrP receptor antagonist
[D12-Trp-PTH-(7-34)] increased coronary
resistance further by 10.9%. Under in vivo conditions, intracoronary
application of 15 µg of PTHrP-(1-34) decreased
coronary resistance from 3.1 ± 0.3 to 1.0 ± 0.1 mmHg · ml1 · min (n = 3;
P < 0.05) in pig hearts.
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PTHrP release from isolated coronary endothelial cells under cyclic
strain.
In isolated coronary endothelial cells exposed to increasing degrees of
cyclic strain, to mimic the mechanical influence of blood pressure on
these cells, PTHrP release was directly related to the degree of cyclic
strain (Fig. 5). Preincubation of
coronary endothelial cells with the calcium-chelating agent BAPTA
prevented the cyclic strain-dependent release of PTHrP (Fig.
6), suggesting a calcium-dependent
mechanism.
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Release of PTHrP in vivo from coronary vascular bed. In anesthesized pigs, arterial PTHrP concentration amounted to 277.9 ± 54.8 ng PTHrP/ml and coronary venous PTHrP concentration to 423.9 ± 56.8 ng PTHrP/ml, corresponding to 5.6 and 8.5 nmol/l, respectively. The coronary venous-arterial difference therefore averaged 146.0 ± 32.7 ng PTHrP/ml (n = 15 pigs), indicating a constant PTHrP release from the coronary vascular bed under in vivo conditions.
After baseline measurements with a flow rate resulting in a mean coronary arterial pressure of 111 ± 4 mmHg, the coronary flow was reduced to ~29% of its initial value. The hemodynamics are given in Table 3. PTHrP release was calculated again from the plasma concentrations in the arterial and coronary venous blood samples 5 min after flow reduction. In all hearts, reduction in coronary flow was followed by a reduced PTHrP release (Fig. 8).
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1 · min. Similar to the in vitro
results, addition of L-NNA under these conditions did not
change PTHrP release (4.28 ± 1.91 vs. 4.49 ± 6.71 µg
PTHrP/; n = 6 pigs; NS).
Influence of bradykinin on PTHrP release.
Because the data on the mechanosensitive release of PTHrP from the
vascular bed suggest a calcium-dependent mechanism, we finally
investigated whether an increase in intracellular calcium concentration
caused by the addition of bradykinin mimics the effects of
mechanotransduction. In isolated and cultured coronary endothelial
cells, bradykinin (10 µmol/l) caused a net release of PTHrP of
4.01 ± 0.83 pg/g protein. In the isolated, perfused rat heart
system, bradykinin caused an increase in flow of 39.7% and an increase
in PTHrP release of 51.3% (Fig.
9A). Under in vivo conditions
in the pig heart, bradykinin increased flow to 150.5% and PTHrP
release by 73% (Fig. 9B). In both set of
experiments, perfusion pressure was held constant to void
mechanosensitive release of PTHrP.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main findings of the present study are 1) PTHrP is constantly released from the coronary vascular bed under in vitro and in vivo conditions, 2) the release rate is changed in response to mechanical stress via intracellular calcium, and 3) alterations in flow are sufficient to induce a mechanosensitive release of PTHrP from the vascular bed. Shear stress seems not to be the mediator of this response. Finally, the basal PTHrP release is physiologically relevant, because inhibition of its biological activity by the addition of a PTHrP receptor antagonist increases coronary resistance.
Nonmalignant cells, which express PTHrP, require a certain kind of trigger for the release of the peptide. Therefore, systemic plasma levels of PTHrP in humans are normally low, although PTHrP is expressed in many cell types throughout the body. In agreement with these observations, cultures of coronary endothelial cells do not release PTHrP under no-flow conditions (17). In the present study, a significant correlation between flow and PTHrP release rate was found in saline-perfused rat hearts. Moreover, we demonstrated a net release from the coronary vascular bed in vivo, and this release was also modified by flow variations. All these observations strongly suggest that PTHrP, expressed in the vascular bed of the heart (6, 17), participates in the regulation of coronary flow and, indeed, blockade of the PTHrP receptor increases coronary resistance in vitro.
Blood flow generates distinct types of forces on the vascular bed (3). Our finding that an increase in perfusate viscosity does not increase basal PTHrP release suggests that shear stress is not involved in the mechanism causing the flow-dependent PTHrP release. This conclusion is further supported by the finding that the NO donor reduced PTHrP release under constant-flow conditions, when it caused a reduction in coronary perfusion pressure, but did not increase PTHrP release under constant-pressure conditions, under which flow was increased. In line with this assumption, coronary endothelial cells released PTHrP in vitro when exposed to cyclic strain, which evokes a passive load on the cell layer. Cyclic strain leads to an increase of intracellular calcium (16). This increase in intracellular calcium seems to be the trigger for PTHrP release from coronary endothelial cells, because in the presence of BAPTA, no release of PTHrP was observed. In accordance with these findings, bradykinin, which also increases intracellular calcium concentration in endothelial cells, caused PTHrP release from isolated coronary endothelial cells held under no-flow conditions, from isolated, perfused rat hearts, and in vivo (pig hearts). In the latter experiments, perfusion pressure was held constant to void mechanosensitive release. We (17) found previously that the coronary endothelial cells can release PTHrP under hypoxic conditions. It is interesting that under these conditions, intracellular calcium is also elevated (12), suggesting a common mechanism for PTHrP release from coronary endothelial cells under all three conditions.
Endothelial cells are directly exposed to mechanical forces generated by blood flow. Indeed, endothelial cells seem to contribute significantly to PTHrP released from isolated, perfused rat hearts, because basal PTHrP release and flow-dependent changes were reduced after denudation of the endothelium. Moreover, isolated and cultured endothelial cells, but not smooth muscle cells, released PTHrP under constant cyclic strain. Together, these results suggest that PTHrP is constantly released from the endothelial cell compartment in hearts in a flow-dependent manner. However, participation of other cell types in basal PTHrP release, like smooth muscle cells, cannot be excluded from these experiments.
We (19) recently showed that PTHrP expression is reduced or diminished in elderly spontaneously hypertensive rats. Under these conditions, basal coronary flow is also reduced (10). This might suggest that PTHrP, in addition to other known factors, contributes to the dysregulation of basal coronary flow in spontaneously hypertensive rats. In addition, PTHrP is released under energy-depleting conditions, pointing to a potential role for PTHrP in the hyperemic response of the heart after ischemia.
The coronary flow is regulated by various local vasoactive dilating factors. Of particular interest is the role of endogenous NO as it impairs the release of EDHF (1). A direct influence of NO on PTHrP release was not observed. Under constant-pressure conditions the NO donor or arginine increased flow but PTHrP release was not modified. Under constant-flow conditions, the NO donor caused a drop in perfusion pressure and a subsequent reduction in PTHrP release. This indicates that changes in perfusion pressure modify PTHrP release but not NO itself. Therefore, any alterations in the activity or expression of NO synthase under pathophysiological conditions will not necessarily impair the role of PTHrP in the regulation of coronary flow.
We are aware of the fact that reductions of flow might also induce an ischemia-dependent release of PTHrP. Although we (17) showed previously that coronary endothelial cells release PTHrP under energy-depleting conditions, this does not seem to play a role in the present study. The time for which we reduced flow (5 min) was too small to induce ischemia-dependent PTHrP release (30 min; Ref. 6). Similar concerns hold for the pig model, in which ischemia-dependent release of PTHrP could not be seen within the first 60 min under the apparent conditions (flow reduction to 10% of basal). Nevertheless, prolonged ischemia will necessarily lead to a situation in which factors associated with ischemia alter the release of the peptide as well.
In summary, our study provides direct evidence for a mechanosensitive release of PTHrP from the vascular bed. The data suggest that alterations in flow might change the local concentration of PTHrP.
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ACKNOWLEDGEMENTS |
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This study was supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 547, Project A1.
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FOOTNOTES |
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Address for reprint requests and other correspondence: K.-D. Schlüter, Physiologisches Institut, Aulweg 129, D-35392 Giessen, Germany (E-mail: Klaus-Dieter.Schlueter{at}physiologie.med.uni-giessen.de).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00925.2001
Received 1 October 2001; accepted in final form 10 June 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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