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CARDIOVASCULAR
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
Received November 1, 2005; accepted January 3, 2006.
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Abstract |
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1-adrenoceptor agonist phenylephrine (PE) but almost completely abolished the maximal endothelium-dependent relaxation to acetylcholine (Ach), reducing it from 93 ± 5 to 7 ± 4% (p < 0.001). After washout of LPC for 60 min, the vasodilator response to Ach partially recovered, whereas the vasoconstrictor response to PE was markedly enhanced, the pD2 value increasing from 7.50 ± 0.04 to 8.13 ± 0.15 and maximum response to 199 ± 24% of control (p < 0.001). Pretreatment with either indomethacin, a nonselective inhibitor of cyclooxygenase, or SQ-29548 [[1S-[1a,2a(Z),3a,4a]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino] methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptanoic acid], a selective thromboxane receptor antagonist, completely prevented the potentiation of the PE response after washout of LPC. In untreated MABs, only the highest concentration of PE produced a significant increase in thromboxane A2 (TxA2) production (assessed by enzyme-immunoassay of thromboxane B2 levels). This was prevented by perfusion with LPC but was significantly increased after LPC washout. The basal release of TxA2 was not modified by LPC. These results demonstrate that LPC exerts both immediate and residual effects on the reactivity of the rat MAB and that these effects are at least partially due to modification of PE-induced TxA2 production.
). On the other hand, elevated levels of LPC have been linked to the cardiovascular complications associated with diabetes, atherosclerosis, and ischemia (Takahara et al., 1997; Shi et al., 1999; Sonoki et al., 2003).
In the cardiovascular system, LPC adversely modifies vasoreactivity in conduit arteries. Hence, in large artery ring preparations, LPC can impair endothelium-dependent relaxation (EDR) (Fukao et al., 1995; Froese et al., 1999; Vuong et al., 2001) and enhance agonist-induced contractions. The latter effect includes potentiation of contractile responses induced by high-K+, UK14,304 [5-bromo-N-(2-imidazolin-2-yl)-6-quinoxalinamine] (Suenaga and Kamata, 2003), and angiotensin II (Galle et al., 2003; Suenaga and Kamata, 2003). These effects of LPC may be partially explained by the results of studies in cultured endothelial and vascular smooth muscle cells, where LPC was shown to activate protein kinase C (Kohno et al., 2001), increase intracellular Ca2+ (Terasawa et al., 2002), and activate or inhibit MAP kinase (Bassa et al., 1999; Rikitake et al., 2000). In addition to its role in modulating vascular contractility, it is generally accepted that LPC is the major pathological component of oxidized low-density lipoprotein in promoting atherosclerosis (Takahara et al., 1997; Sonoki et al., 2003).
Several lines of evidence also suggest a vasoprotective role for LPC. In rabbits, LPC produces potent endothelium-dependent vascular smooth muscle relaxation, both in vivo and in vitro (Menon and Bing, 1991; Wolf et al., 1991). In umbilical vein endothelial cells, LPC has been shown to enhance endothelial expression of endothelial nitric-oxide synthase and cyclooxygenase-2 (COX-2), leading to increased synthesis of nitric oxide (NO) and prostacyclin (PGI2) (Zembowicz et al., 1995a,1995b). NO and PGI2 act synergistically to block monocyte adhesion, smooth muscle cell proliferation, platelet activation, and vasoconstriction (Vane and Botting, 1995; Naseem, 2005).
Although it has been extensively studied, the contribution of LPC in regulating vascular resistance has not been completely elucidated, as the majority of previous studies have used either large blood vessels or isolated cells. The mesenteric arterial bed (MAB) is an important effector organ regulating blood pressure, with small structural and functional changes eliciting significant alterations in peripheral resistance (Caveney et al., 1998). The objective of the present study was to determine the vasoactive effects of LPC in the isolated perfused MAB and to investigate the underlying mechanisms of the changes it produced.
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Materials and Methods |
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Isolated, Perfused Rat Mesenteric Arterial Bed. Male Wistar rats (300–400 g) were anesthetized with sodium pentobarbital (60 mg/kg i.p.), and the MAB was isolated as described previously (He and MacLeod, 2002). In brief, the abdominal cavity was opened, and the superior mesenteric artery was cannulated through an incision at its confluence with the dorsal aorta. The whole MAB was then separated by cutting close to the intestinal border. The MAB was flushed with heparinized warm Krebs bicarbonate buffer with the following composition: 113 mM NaCl, 4.7 mM KCl, 11.5 mM glucose, 1.2 mM MgSO4, 2.5 mM CaCl2, 1.2 mM KH2PO4, and 25.0 mM NaHCO3. The pH of the buffer following saturation with a 95% O2, 5% CO2 gas mixture was 7.4. Subsequent to flushing, the MAB was transferred into a jacketed organ chamber and perfused through the cannula with Krebs buffer maintained at 37°C and gassed with 95% O2, 5% CO2. Perfusion rate was kept constant at 3 ml/min using a peristaltic pump (Buchler Instruments, Buchler Fort Lee, NJ). The perfusate flowed out through the cut ends of the mesenteric arterial bed. Vascular responses were detected as changes in perfusion pressure, and this was continuously measured and recorded using a pressure transducer (PD23ID; Gould, Statham, CA) placed between the perfusate and the cannula and connected to a Grass polygraph (model 79D; Grass Instruments, Quincy, MA). The perfused MAB was allowed to stabilize for 40 min before four bolus injections of KCl (0.4 mmol). Perfusion pressure was allowed to return to baseline after each injection of KCl. After further equilibration for 40 min, dose-response curves (DRCs) to various agonists were performed.
Vasoconstrictor Responses. To determine the effects of LPC on vasoconstrictor responses of the MAB, bolus injections of phenylephrine (PE) (0.9–300 nmol) or KCl (50–800 µmol) were given. These first DRCs to PE or KCl served as controls. Once perfusion pressure returned to baseline, palmitoyl-LPC (0.1–10 µM) was added to the perfusion buffer. In preliminary experiments, none of these concentrations of LPC per se produced any observable change in contractility. In all of the subsequent experiments, 10 µM LPC was used. After 40 min of perfusion with LPC, the second PE/KCl DRC was constructed in the presence of LPC. The tissues were then switched back to normal Krebs buffer and perfused for 1 h followed by construction of a third PE/KCl DRC. The 60-min washout was designed to test whether the expected effect of LPC was reversible or not. Perfusion pressure was allowed to return to baseline between each PE/KCl injection. To test whether the vascular responses are affected by time, a control experiment consisting of three consecutive DRCs to PE and KCl were done without the addition of LPC.
To determine the potential contribution of NO and thromboxane A2 (TxA2) to the observed modulatory effects of LPC on PE responses, the LPC perfusion and washout procedures described above were performed in the presence of a NOS inhibitor, L-NMMA (NG-monomethyl-L-arginine methyl ester; 300 µM), a COX inhibitor (indomethacin; 20 µM), or a TxA2 receptor antagonist, SQ-29548 [[1S-[1a,2a(Z),3a,4a]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptanoic acid; 0.3 µM]. All inhibitors were added to the perfusate after the first DRC and kept present throughout the second and third DRCs.
Vasodilatory Responses. To assess the effects of LPC on EDR, MABs were precontracted with submaximal concentrations of PE (1–3 µM). Subsequently, increasing concentrations of acetylcholine (Ach; 3 nmol–0.3 µM) were administered until maximal relaxation was attained. MABs were then perfused for 40 min with 10 µM LPC, and the response to PE and Ach was repeated. A third Ach response was obtained after washout of LPC for 1 h. Control experiments consisted of three consecutive Ach-induced responses in the absence of LPC.
Effluent Collection. To measure the content of TxB2, a stable metabolite of TxA2, in the MAB effluent, samples were collected for 2 min on six different occasions as follows: before the first application of PE, during the first PE-DRC at each PE dose, after the 40-min perfusion with LPC, during the second PE-DRC at each PE dose, after the 60-min washout of LPC, and during the third PE-DRC at each PE dose. Samples were stored at –70°C until assayed.
Enzyme Immunoassay of TxB2. The collected perfusates were extracted using Solid-Phase Extraction C-18 cartridges (Cayman Chemical, Ann Arbor, MI) after cartridge activation by 5 ml of methanol and 5 ml of ultrapure water. A 0.5-ml aliquot of each sample was acidified to 
pH 4.0 and loaded onto the cartridge. The cartridge was washed with 5 ml of ultrapure water followed by 5 ml of hexane. The TxB2 fraction was eluted with 5 ml of ethyl acetate containing 1% methanol. The eluate was dried under a stream of nitrogen and reconstituted with 0.5 ml of enzyme immunoassay buffer. The concentration of TxB2 in the eluate was determined by enzyme immunoassay, using a commercially available kit (Cayman Chemical).
Chemicals. L-Phenylephrine hydrochloride, 1-palmitoyl-sn-glycero-3-phosphocholine, and indomethacin were obtained from Sigma Chemical Co. (St. Louis, MO). L-NMMA and SQ-29548 were purchased from BIOMOL International, L.P. (Plymouth Meeting, PA). Stock solutions of PE (0.01 M), LPC (0.01 M), and L-NMMA (0.1 M) were prepared in distilled water. Indomethacin and SQ-29548 were dissolved in 100% ethanol and prepared as stock solutions of 0.1 M and 0.1 mM, respectively. Solutions of PE and indomethacin were made fresh. LPC and all of the inhibitors were further diluted to the required concentration in the perfusate reservoir. The final ethanol concentrations (0.03–0.3%, v/v) were without effect on contractile responses.
Data Analysis. KCl-induced vasoconstrictor responses were expressed as the absolute increase in perfusion pressure. PE responses were expressed as a percentage of the maximal response of the first PE-DRC. The negative log of the PE concentration producing 50% of maximum response (pD2) was obtained by nonlinear regression analysis of individual DRCs using GraphPad Prism, version 4.0 (GraphPad Software, Inc., San Diego, CA).
All of the data are presented as mean ± S.E.M. Data were analyzed for significant differences using Number Cruncher Statistical Systems. Student's unpaired t test was used for comparisons between two means. One-way ANOVA followed by Newman-Keuls test was used for comparison of more than two means. Two-way ANOVA, using the general linear model approach (repeated measures) followed by Newman-Keuls test, was used for comparisons between PE-DRCs and KCl-DRCs. P < 0.05 was considered statistically significant.
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Results |
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Involvement of NO and TxA2 in Mediating the Direct Effects of LPC Perfusion. Before LPC perfusion, Ach (0.1–0.3 µmol) produced a maximal relaxation of 93 ± 5% of the response to PE (Fig. 4, left). The Ach response remained unchanged over time (Fig. 4, right). LPC perfusion almost completely abrogated the response to Ach, reducing the maximal relaxation to 7 ± 4% (Fig. 4, left), suggesting that LPC is diminishing the actions of both NO and EDHF. In a separate experiment, we tested the effects of a NOS inhibitor on PE responses. As expected, pretreatment with L-NMMA significantly enhanced the PE response (Fig. 5A), with both an increase in the maximal response and pD2 value (control, 7.03 ± 0.45; L-NMMA, 7.49 ± 0.17; P < 0.001) being apparent. However, in the presence of LPC, the enhancement of the PE response by L-NMMA was prevented (Fig. 5A). These data suggest that, in addition to suppressing NO, LPC may be exerting other actions to limit vasoconstrictor release or responsiveness to PE.
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1-adrenoceptor stimulation in the MAB. To investigate the involvement of TxA2 in mediating PE responses, we measured levels of TxB2, the stable metabolite of TxA2. Basal release of TxB2 was stable over time. In untreated MAB, only the highest dose of PE tested (300 nmol) produced an increase in TxA2 production (Fig. 6). LPC perfusion for 40 min had no effect on basal levels of TxB2 but suppressed its enhancement by PE (Fig. 6), suggesting that LPC prevents the ability of PE to increase TxA2 production.
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Involvement of NO and TxA2 in Mediating the Indirect Effects (after Washout) of LPC. Washout of LPC induced partial recovery of the Ach response (Fig. 4). Despite this fractional recovery, contractile responses to PE were augmented (Fig. 3B), suggesting that amplification of vasoconstrictor pathways, in addition to reduction of vasodilators such as NO, may be responsible for this effect. To investigate this possibility, after washout of LPC, a DRC to PE was performed in the presence of L-NMMA (Fig. 5B). Interestingly, even in the presence of the NOS inhibitor, the response to PE was shifted to the left after LPC washout (pD2 value in the presence of L-NMMA alone, 7.54 ± 0.07; following LPC washout and in the presence of L-NMMA, 8.16 ± 2.05; P < 0.05). These data suggest that the enhancement of PE response after LPC washout is mediated by mechanisms in addition to NO inhibition.
To further investigate mechanisms facilitating the enhanced PE response after LPC washout, TxB2 levels in the perfusion medium were measured. Interestingly, TxB2 levels only increased after LPC washout (Fig. 6), suggesting a role for this vasoconstrictor in the magnified response to PE. MABs were then pretreated with either a COX inhibitor or a TxA2 receptor antagonist. Both indomethacin (pD2 value after LPC washout, 8.24 ± 0.07; LPC washout plus indomethacin, 7.74 ± 0.25; P < 0.05) and SQ-29548 (pD2 value after LPC washout, 8.24 ± 0.07; LPC washout plus SQ-29548, 7.73 ± 0.10; P < 0.05) completely prevented the enhancement of the PE DRC after LPC washout (Fig. 7). Neither indomethacin nor SQ-29548 significantly changed PE-induced vasoconstriction by themselves (data not shown).
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Discussion |
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The balance between vasodilators (NO, EDHF, and PGI2) and vasoconstrictors (TxA2 and endothelin-1) is pivotal in the regulation of vascular tone. Because most of these vasoactive factors originate from vascular endothelium, we examined the effects of LPC on endothelial function. Measurement of EDR supported the established view that LPC inhibits EDR, probably through inactivation of NO and EDHF (Cowan and Steffen, 1995; Froese et al., 1999; Rikitake et al., 2000). Impaired EDR is normally linked to potentiated vasoconstrictor responses, an observation we confirmed in preliminary studies, in which various methods were used to denude MAB of endothelial cells, including perfusion with air (Tatchum-Talom and Atkinson, 1997), distilled water, sodium deoxycholate (Cusma-Pelogia et al., 1993), and CHAPS (McCulloch and Randall, 1996). Mechanical denudation of endothelium, which was associated with loss of the relaxant response to Ach, caused an enhancement of PE responses (data not shown). However, the impaired Ach-induced EDR caused by LPC perfusion was not accompanied by an increased response to PE. Other studies using aortic rings from normal rats have also demonstrated similar effects of LPC, i.e., reduced EDR with no significant change in PE responses (Ceylan et al., 2004). These data suggest that, even in the presence of NO/EDHF inhibition by LPC, vasoconstrictor responsiveness or release may also be inhibited by LPC, thus preventing augmentation in responses to PE. This possibility is supported by the observation that LPC prevented amplification of PE responses in the presence of L-NMMA and reduced the PE-induced production of TxA2.
Unexpectedly, the response to PE was dramatically potentiated only after the removal of LPC. A time-dependent mechanism can be ruled out, as prolonged perfusion with LPC (150 min) did not produce any potentiation of PE responses. The enhancement of the PE response could be blocked by both indomethacin and SQ-29548, suggesting an important contribution of vasoconstrictor prostanoids, which was confirmed by the finding of potentiation of PE-induced TxA2 production. At present, the mechanism for this rebound production of excessive TxA2 is not known, nor is it clear whether this effect is global or localized to the MAB. The contribution of time in producing the potentiated contractile responses and TxA2 production in response to PE can be ruled out, as these were stable over time in the absence of LPC. These effects were unlikely to be due solely to continued endothelial impairment, because Ach-induced relaxation had partially recovered. Furthermore, the enhancement of PE responses produced by mechanical removal of the endothelium could not be abolished by pretreatment with SQ-29548 (data not shown).
As a potent inducer of platelet aggregation, vasoconstriction, and bronchoconstriction, TxA2 has been implicated in vascular pathogenesis (Dogne et al., 2004). Although the major source of TxA2 is platelets, this vasoconstrictor can also be produced within the vascular walls by both endothelial (Ally and Horrobin, 1980) and smooth muscle cells (Shiokoshi et al., 2002). The mechanism of TxA2 synthesis includes phospholipid hydrolysis by PLA2, release of arachidonic acid, and metabolism to TxA2 by the COX-TxA2 synthase pathway. 1-Receptor activation initiates phospholipid hydrolysis and release of TxA2 (Terzic et al., 1993; Nishio et al., 1996; Ruan et al., 1998; Bolla et al., 2002; Parmentier et al., 2004). To our knowledge, an effect of LPC on 1-adrenoceptor-mediated TxA2 production in the vasculature has not previously been reported. However, our observation that LPC abrogated the increase in TxA2 production produced by PE in the MAB is consistent with a previous study in platelets, in which an inhibitory effect of LPC on agonist-induced TxA2 production was observed (Yuan et al., 1996). Although we are not aware of any studies showing potentiation of TxA2 production by LPC, an interaction between these two agents has previously been suggested. For instance, LPC was found to enhance the ability of TxA2 to increase vascular smooth muscle cell proliferation (Koba et al., 2000). Taken together, these findings strongly suggest that LPC is able to alter the biosynthesis of TxA2, as well as its downstream signaling. Details of the mechanism of these modulatory effects need to be further investigated. Irrespective of the mechanism(s), the increased release of TxA2 could be a major contributor toward hypertensive (Seeger et al., 1989), thrombotic, and ischemic diseases (Ally and Horrobin, 1980; Muller, 1991).
It is tempting to speculate that conditions that evoke an increase in LPC levels initially trigger compensatory mechanisms to neutralize its injurious effects. Thus, the suppression of PE-induced TxA2 production could compensate for the endothelium dysfunction. Wu and co-workers (Zembowicz et al., 1995a,1995b) have also suggested that LPC is a double-faced molecule, which can produce both vasoprotective and proatherogenic mechanisms. An additional caveat is the suggestion that residual effects of LPC after washout could arise from its metabolism to lysophosphatidic acid (Tokumura, 2004). Given this complex biology, investigation of the in vivo temporal effects of LPC under normal and pathological conditions would be beneficial.
In conclusion, our results for the first time demonstrate the effects of LPC in the rat resistance arterial bed, even after washout. These included potentiated PE responses and enhanced TxA2 production. Thus, when evaluating the effects of LPC in the vasculature, both its immediate and residual effects need to be considered. Although unclear, the mechanism for this residual effect, especially the relationship between LPC and lysophosphatidic acid, is currently being evaluated.
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Footnotes |
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ABBREVIATIONS: LPC, lysophosphatidylcholine; Ach, acetylcholine; UK14,304, 5-bromo-N-(2-imidazolin-2-yl)-6-quinoxalinamine; COX, cyclooxygenase; DRC, dose-response curve; EDR, endothelium-dependent relaxation; EDHF, endothelium-dependent relaxing factor; L-NMMA, NG-monomethyl-L-arginine methyl ester; SQ-29548, [1S-[1a,2a(Z),3a,4a]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino] methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptanoic acid; NO, nitric oxide; NOS, nitric-oxide synthase; MAB, mesenteric arterial bed; PC, phosphatidylcholine; PE, phenylephrine; PLC, phospholipase C; PLD, phospholipase D; PGI2, prostacyclin; TxA2, thromboxane A2; TxB2, thromboxane B2; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid.
Address correspondence to: Dr. Kathleen M. MacLeod, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver V6T 1Z3, BC, Canada. E-mail: kmm{at}interchange.ubc.ca
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