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CARDIOVASCULAR
Departments of Physiology (S.A.G., M.S.W.) and Surgery, Division of Cardiovascular & Thoracic Surgery (E.A.Z., M.R.S.), New York Medical College and Westchester Medical Center, Valhalla, NY
Received May 4, 2004; accepted June 30, 2004.
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Abstract |
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,2(Z),3,4]]-7-[3-[2-(phenylamino)carbonyl]hydrazine]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ-29548)] potentiated the relaxation to hypoxia in IMA, but not RA, a response associated with increases in TxA2. Relaxation of IMA and RA to hypoxia appears to involve a calcium-reuptake mechanism inhibited by cyclopiazonic acid (0.2 mM), and it was not attenuated by a blocker of potassium channels (10 mM TEA). The recovery of force generation of IMA, but not RA, upon reoxygenation after 30 min of hypoxia was significantly reduced in the initial phase of reoxygenation by indomethacin and SQ-29548 and by endothelin receptor blocker BQ-123 [cyclo(L-Leu-D-Trp-D-Asp-L-Pro-D-Val)]. Thus, hypoxia relaxes IMA and RA by a postaglandin-independent mechanism potentially involving enhanced intracellular calcium reuptake. The prostaglandin-mediated alterations of responses to hypoxia-reoxygenation seen in IMA, but not in RA, may predispose IMA to vasospasm-related complications of CABG.
; Loop and Thomas, 1993). Potential causes of vasospasm include physical (e.g., mechanical or temperature changes), pharmacological (e.g., neuronal activators or vasoconstrictor substances), or physiological (e.g., changes in pO2) stimuli. Studies have shown that endothelium is more active in IMA as compared with RA, since IMA has been shown to produce more endothelium-derived nitric oxide (NO), hyperpolarizing factor, and prostacyclin (PGI2) (Chardigny et al., 1993; Liu et al., 2000). In addition, although vascular smooth muscle cells of RA have been suggested to show a greater endothelin-1 receptor density, an endothelin-1 protein kinase C (PKC) signaling cascade appears to be proactive in IMA (Woods et al., 1999). Despite improvements in cardiopulmonary bypass surgery techniques, hypoxemia (indicated by low PaO2/FIO2 ratios) caused by many conditions including hypoventilation, arrhythmia, etc., is often seen in patients immediately after CABG surgery (Weiss et al., 2000). Therefore, this study investigated the effects of vasoconstrictor substances and hypoxia-reoxygenation on the vasomotor function of IMA and RA.
Hypoxia elicits a complex set of physiologic responses that regulate vasomotor tone. In vivo studies have shown that hypoxia causes vasodilation of the systemic arteries to increase blood supply to stressed organs to meet the metabolic demand (Blitzer et al., 1996). In contrast, studies on the effect of hypoxia on human arteries have demonstrated that exposure of isolated IMA to hypoxia elicits a small transient relaxation followed by contraction with the relaxation potentially mediated by increased PGI2 and the contraction by generation of TxA2 in addition to the inhibition of basal production of endothelium-derived NO (Pearson et al., 1993). These were shown to be endothelium-dependent responses, which functioned to prevent a vascular smooth muscle (VSM) relaxation to hypoxia. Previous studies have reported that the relaxation of isolated coronary arteries to hypoxia-reoxygenation is prostaglandin- and NO-dependent (Kalsner, 1977; Jiang and Collins, 1994). In contrast, the primary response of isolated bovine calf and porcine coronary arteries to hypoxia-reoxygenation is independent of prostaglandins, NO, and reactive O2 species (Close et al., 1994; Mohazzab et al., 1996). Although the mechanisms underlying hypoxic relaxation are poorly understood, studies have indicated that inhibition of L-type Ca2+ channels (Franco-Obregon et al., 1995; Herrera and Walker, 1998), opening of ATP-dependent K+ channels (Daut et al., 1990; Kalsner, 1995), or accelerated sequestration of Ca2+ by sarcoplasmic reticulum (SR) (Close et al., 1994; Shimizu et al., 2000) potentially mediate relaxation of coronary arteries to hypoxia. Hyperpolarization of VSM by activation of K+ channels is one of the mechanisms of dilation of RA (Hamilton et al., 2001). Responses of RA to hypoxia and IMA and RA to posthypoxic reoxygenation have not been previously studied. Thus, the focus of this investigation was to investigate mechanisms regulating contractile function in responses of RA and IMA to hypoxia-reoxygenation and to examine if alterations in the influence of pO2-sensitive mechanisms (Gellai et al., 1973) including signaling mechanisms such as PKC involved in the generation of force to contractile agents, endothelium-derived mediators, prostaglandins, and endothelin contribute to differences in the responses that are observed.
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Materials and Methods |
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Collection of Human Arteries. Human IMA and RA were collected based on our institution's policies for the use of human tissues from patients undergoing elective CABG surgery. IMA and RA was harvested by routine protocols published earlier (Sarabu et al., 1987). Segments from distal sections of IMA and RA surgical discards were obtained immediately after harvesting but without treating with routinely used pharmacological agents employed to preserve and dilate these conduits prior to grafting to the aorta and coronary artery. After their removal, the IMA and RA segments were immediately placed in ice-cold plasmalyte solution (4°C) and transported to the laboratory for tension studies.
Preparation of IMA and RA for Tension Studies. IMA and RA segments (3–4 mm in length) were studied without removal of the endothelium in individually thermostated (37°C) 10-ml baths (Metro Scientific, Farmingdale, NY) on wire hooks attached to force displacement transducers (model FT-03; Grass Instruments, Quincy, MA) for measurements of changes in isometric force on a polygraph (model 7; Grass Instruments) employing adaptations of previously published methods (Mohazzab et al., 1996). After a 2-h incubation at an optimal passive tension in Krebs bicarbonate buffer (pH 7.4) containing 118 mM NaCl, 4.7 mM KCl, 1.5 mM CaCl2, 25 mM NaHCO3, 1.1 mM MgSO4, 1.2 mM KH2PO4, and 5.6 mM glucose and gassed with 21% O2/5% CO2/74% N2, the vessels were depolarized with Krebs bicarbonate containing KCl in place of NaCl. The arteries were then re-equilibrated with Krebs' solution for 20 to 30 min before the experiments were conducted.
To study the effects of hypoxia-reoxygenation, the arteries were contracted with 30 mM KCl. In a subset of experiments, the arteries were pretreated with drugs (10 µM indomethacin; 1 µM SQ-29548; 300 nM BQ-123) once a steady-state level of force was observed 15 to 20 min before exposing the arteries to a hypoxia-reoxygenation cycle. This cycle consisted of exposure to 30 min of hypoxia (95% N2/5% CO2, pO2 = 30–40 mm Hg), followed by reoxygenation with 21% O2/5% CO2/74% N2 for 60 min. IMA and RA rings were also contracted by phenylephrine (10 µM) or by PDBu (10 µM), a PKC activator, to examine the role of these systems in the relaxation elicited by hypoxia.
Estimation of 6-Keto-PGF2 and TxB2 Released in the Tissue by IMA and RA. Stable products of the vasodilator PGI2, 6-keto-PGF2, and the vasoconstrictor TxA2, TxB2 were measured in samples collected periodically from the tissue baths containing IMA or RA by an enzyme immunoassay method using kits purchased from Cayman Chemical. Samples were collected 20 min after addition of 30 mM KCl under normoxic conditions, 10 and 30 min after induction of hypoxia, and 10 min after reoxygenation.
Detection of COX-1, COX-2, and TxA2 Synthase Enzyme Localization by Immunohistochemistry. IMA and RA were frozen in liquid nitrogen, and the frozen sections of 6- and 7-µm thickness were mounted on glass slides, air-dried for 30 min, and fixed in acetone for 15 min at room temperature. Each tissue section (up to five of each tissue) was washed twice with PBS containing 0.1% Triton X-100. After washing in PBS, preincubation was carried out with 20% goat serum in PBS followed by overnight incubation at 4°C with polyclonal antibodies against COX-1, COX-2, and TxA2 synthase (purchased from Cayman Chemical) diluted in PBS containing 5% bovine serum albumin and 0.1% Tween 20. After three washings in PBS, sections were incubated with secondary goat IgG anti-rabbit conjugated with alkaline phosphatase for 2 h. Negative control in which tissue sections were not incubated with primary antibodies was performed for all three enzymes examined in this study. Staining was done by a protocol provided by Vector Laboratories (Burlingame, CA). Counterstaining with hematoxylin solution and mounting in Aquamount (Vector Laboratories, Burlingame, CA) completed the procedure.
Statistical Analysis. Data are expressed as mean ± S.E.M. Relaxation of the arteries to hypoxia is determined as percentage of changes in force from the precontracted steady-state level. The contractile force during reoxygenation is expressed as percentage of changes in force of the steady-state level prior to 30 min of hypoxia. Statistical significance between the results was analyzed by employing analysis of variance and post hoc Fisher's least significant difference (protected t test) or Student's t test.
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Results |
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Effects of Inhibitors of Prostaglandin Biosynthesis on Responses of IMA and RA to Hypoxia and Reoxygenation. To investigate whether prostaglandins mediated the differences in the response of IMA and RA to changes in pO2, we examined the effects of the cyclooxygenase inhibitor, indomethacin, and the TxA2-PGH2 receptor blocker, SQ-29548, on force generation during the hypoxia-reoxygenation cycle. As illustrated in Fig. 2A, indomethacin (10 µM; n = 10) and SQ-29548 (1 µM; n = 6) increased (p < 0.01) the relaxation of IMA to hypoxia. Indomethacin (n = 5) did not have any significant effect on the relaxation of RA elicited by hypoxia (Fig. 2B). Moreover, the contraction of IMA elicited by reoxygenation was attenuated (p < 0.05) by indomethacin and considerably by SQ-29548 (Fig. 2C). Indomethacin did not affect the contraction of RA (Fig. 2D).
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Effects of Hypoxia-Reoxygenation on the Biosynthesis of PGI2 and TxA2 by IMA and RA. The effects of hypoxia-reoxygenation on the synthesis of PGI2 in IMA and RA are shown in Fig. 3A. The levels of PGI2 that accumulated during the 20-min incubation under normoxia appeared to be increased in IMA (n = 7), but not in RA, during hypoxia. However, the apparent changes were not statistically significant. Upon reoxygenation, PGI2 levels were increased significantly in IMA and RA (n = 6). In Fig. 3B, the effects of hypoxia-reoxygenation on TxA2 are reported. The synthesis of TxA2 was elevated in IMA (n = 7), but not in RA (n = 6), during hypoxia. To study the source of prostaglandins and TxA2 in normal hypoxia-reoxygenation untreated IMA and RA, we conducted immunohistochemical studies, and the results are illustrated in Fig. 4. Red color staining indicates that COX-1, COX-2, and TxA2 synthase is localized in the endothelial and smooth muscle cells of IMA and RA (Fig. 4). However, the color intensity of TxA2 synthase staining is weak in RA and indistinguishable from the negative control.
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Effect of Endothelin Receptor Blocker on the Response of IMA and RA to Hypoxia and Reoxygenation. To study the effects of endothelin on the hypoxic responses of IMA (n = 5) and RA (n = 4), ETA receptors were blocked with BQ-123 (300 nM). Although BQ-123 did not affect the hypoxic relaxation (Fig. 5A), it attenuated the force generation during the early phase of reoxygenation in IMA (Fig. 5C). In the RA, BQ-123 had no effect on the relaxation to hypoxia (Fig. 5B) or contraction to reoxygenation (Fig. 5D).
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Effects of K+ Channel Blockade and Inhibition of Calcium Reuptake on Hypoxia-Elicited Relaxation in IMA and RA. To examine if hyperpolarization of VSM by the opening of K+ channels by hypoxia could contribute to the observed relaxation through the closing of voltage-gated Ca2+ channels, IMA (n = 7) and RA (n = 5) were exposed to hypoxia in the presence of TEA (10 mM), a nonspecific K+ channel inhibitor. TEA did not significantly prevent relaxation to hypoxia in IMA and RA (Fig. 6, A and B). In addition, the K+ channel blocker also did not have any effect on reoxygenation force generation in IMA (control: 75.25 ± 3.36% and TEA: 64 ± 12.7% at 10 min) and RA (control: 55.7 ± 13.6% and TEA: 59 ± 12.1% at 10 min). An inhibitor of SR, Ca2+-ATPase pumps, which mediate calcium reuptake by the SR, cyclopiazonic acid (200 µM) was examined for the role of this system in the relaxation to hypoxia. As shown in Fig. 7, this probe markedly attenuated relaxation to hypoxia implicating a role for an acceleration of calcium reuptake in this response.
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Effects of Hypoxia on Force Generation in IMA and RA Precontracted with PKC Activator and -Adrenergic Receptor Agonists. IMA and RA precontracted with 10 µM PDBu (n = 5), a PKC activator, and -adrenergic receptor agonists, 1 to 10 µM phenylephrine (n = 5–7, Fig. 6B) or norepinephrine (n = 3–5, data not shown), also relaxed to hypoxic stimulation. Surprisingly, there were no significant differences in relaxation to hypoxia between IMA and RA precontracted with PDBu (Fig. 8, A and B) and -adrenergic receptor agonists (Fig. 6B) presumably because activation of PKC by PDBu significantly inhibited relaxation of RA induced by hypoxia. Furthermore, PDBu-treated IMA (control: 75.2 ± 3.36% and PDBu: 53.5 ± 4.5%) and RA (control: 55.7 ± 13.6% and PDBu: 12.1 ± 9.7%) showed a significantly slower recovery of the contractile force in the early phase (at 10 min) of reoxygenation. However, at the end of the reoxygenation period (60 min), contractile force developed in IMA contracted with PDBu was 30 to 40% more than that developed in 30 mM KCl-treated IMA.
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Discussion |
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-adrenergic agonists and the PKC activator PDBu. Reoxygenation causes a rapid contraction with IMA showing a greater level of force development than RA with force slowly returning to prehypoxic steady-state levels by 60 min of reoxygenation.
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Observations in this study indicate that the synthesis of PGI2 and TxA2 are increased by hypoxia-reoxygenation. Although it has been reported that IMA show an endothelium-dependent transient relaxation followed by a contraction on exposure to hypoxia associated with increases in these cyclooxygenase-derived metabolites (Pearson et al., 1993), hypoxia-mediated relaxation of IMA or RA was the primary response observed in our study. This is probably because of differences in the experimental design, such as, stimulation of the endothelium with calcium was avoided by using a lower, more physiological, level of this ion in our buffer. Increased buffer calcium levels have previously been shown to markedly increase the influence of endothelial mediators in vascular responses to hypoxia (Mathew et al., 1991). The synthesis of dilator prostaglandins is known to be elevated by hypoxia in isolated coronary arteries (Kalsner, 1977). Paradoxically, the relaxation of IMA, but not of RA, elicited by hypoxia was attenuated by prostaglandins. The relaxation to hypoxia is impaired, and contraction during reoxygenation is potentiated through a mechanism that appears to involve stimulation of TxA2-PGH2 receptors by a cyclooxygenase-derived product. This interpretation is based on the alterations of responses in IMA caused by inhibition of prostaglandin synthesis and blocking TxA2-PGH2 receptors. The apparent increased generation of PGI2 during hypoxia in IMA and reoxygenation in RA and IMA were presumably insufficient to modulate pO2-elicited responses under the conditions examined. Although it is thought that the source of prostaglandins, endothelin, NO, and hyperpolarizing factor is endothelium, the response of IMA and RA to hypoxia was not altered by removal of the endothelium. Nevertheless, reoxygenation contraction was significantly suppressed in endothelium-denuded IMA thereby indicating that endothelin-1 may be derived from endothelium during reoxygenation. However, platelets are not a primary source of TxA2, since TxA2 synthase was observed to be present in endothelium and VSM of IMA, suggesting that these cell types appear to be the primary source of TxA2 generation. Thus IMA, but not RA, produce vasoconstrictor levels of TxA2 under hypoxia.
Studies have suggested that prostaglandins mediate hypoxic relaxation of coronary artery in various animal species (Kalsner, 1977; Jiang and Collins, 1994). In the present study, prostaglandins did not mediate relaxation of IMA and RA exposed to hypoxia. Instead, the elevated prostaglandins contributed to impairing relaxation to hypoxia and accentuating contraction initiated by reoxygenation of IMA. Additionally, ET1 synthesized during reoxygenation appeared to have a role in accelerating the posthypoxic contraction of IMA. It is possible that an interaction between activation of the TxA2-PGH2 receptors and the ET1 system could be a contributing factor in the response to reoxygenation, since TxA2 levels were not significantly increased during this period. Thus, the release of these vasoconstrictive factors by CABG may contribute to triggering contractions and spasms of arterial grafts leading to hypoperfusion of myocardium.
Signaling pathways in mediating hypoxic relaxation of systemic arteries remain elusive. Some reports have proposed that opening of K+ channels, inhibition L-type Ca2+ currents, and acceleration of Ca2+ uptake by SR may be involved in modulating VSMC responses to changes in oxygen tension (Close et al., 1994; Franco-Obregon et al., 1995; Herrera and Walker, 1998; Shimizu et al., 2000). Opening of K+ channels did not mediate hypoxia-elicited relaxation of IMA and RA because inhibiting K+ channels with TEA did not attenuate relaxation. Since hypoxia relaxed IMA and RA contracted with the PKC activator PDBu, this response does not appear to be mediated through changes in the stimulation of PKC. The additional studies on the mechanism of relaxation to hypoxia also generated data indicating that differences in relaxation of IMA and RA were not observed in arteries contracted with stimuli which activate PKC (PDBu and -adrenergic receptor agonists) or with KCl contractions in the presence of TEA. Although the origins of these observations were not investigated, they could originate from a diminished effect of a further activation of PKC by stimulation of TxA2-PGH2 receptor or an effect of K+ channels on the generation or action of TxA2. Furthermore, the data in Fig. 8B suggest that RA relaxation to hypoxia were significantly suppressed by the activation of PKC by PDBu. The attenuation of relaxation to hypoxia by inhibition of calcium reuptake by the SR Ca2+-ATPase pump suggests that this system is stimulated by hypoxia. Although prostaglandins do not appear to mediate the IMA and RA response to hypoxia, additional studies are needed to examine the role of prostaglandins in reducing sequestration of Ca2+ by activated SR Ca2+-ATPase.
A role of hypoxia-reoxygenation in inducing the release of spasmogens is not well studied. The handling of the arteries used in this study more closely simulates the handling of the IMA and RA as a free graft during surgery than the pedicle graft. However, differences such as the observed increased expression of enzymes that generate constrictor prostaglandins in the IMA should be independent of the handling of the arteries studied because they are immediately immersed in ice-cold saline after removal from the pedicle or free graft. IMA, a pedicle graft, receives blood flow from the subclavian artery and does not become hypoxic during CABG surgery, whereas the RA is routinely used as a free graft and pO2 in this tissue is not controlled during the CABG procedure. Grafts frequently become hypoxic postoperatively because hypoxemia commonly occurs in the patients after CABG surgery due to hypoventilation, atrial or ventricular arrhythmia, respiratory syndromes, etc. (Christenson et al., 1996; Willems et al., 1997; Tamis-Holland et al., 2000; Weiss et al., 2000). We have demonstrated that a mechanism independent of prostaglandins mediates relaxation of human IMA and RA to hypoxia, whereas vasoconstrictor prostaglandins impaired the relaxation and potentiated the contraction of IMA to hypoxia-reoxygenation. Therefore, hypoxia-reoxygenation may be a greater stimulus of vasospasm in IMA than RA through the TxA2-mediated and ET1 receptor-dependent mechanisms reported in this study. The increased generation of TxA2 by hypoxia-reoxygenation could be a contributing factor to spasm observed peri- and postoperatively, which are a leading cause of IMA graft occlusion in the early postoperative stage (Sarabu et al., 1987; Loop and Thomas, 1993). Cyclooxygenase inhibitors, TxA2 receptor blockers, and ET1 receptor blockers could potentially be beneficial in postoperative therapy for preventing the genesis of vasospasm and thrombosis, which promote ischemic events particularly in hypoxemic patients, as well as all patients undergoing elective CABG operations.
In summary, we have demonstrated that human systemic arteries relax in response to a decrease in oxygen tension through mechanisms that involve sarcoplasmic Ca2+ reuptake and do not appear to involve endothelium-derived mediators or the opening of membrane K+ channels. Although the mechanisms involved in increasing uptake of Ca2+ by SR by hypoxia in human arteries remains to be identified, our data support the notion that hypoxia elicits relaxation of IMA and RA conduits by accentuating sequestration of intracellular Ca2+. IMA conduit is thought to produce more endothelial factors than RA. This study provides evidence that activation of TxA2-PGH2 receptors and elevation of ET1 may be contributing factors to impairing relaxation to hypoxia and enhancing contraction to reoxygenation through the generation of TxA2 and endothelin, which could be factors triggering vasospasm, thrombosis, and graft failure early in the postoperative phase.
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Footnotes |
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ABBREVIATIONS: IMA, internal mammary artery; CABG, coronary artery bypass grafting; RA, radial artery; NO, nitric oxide; PG, prostaglandin; TxA2, thromboxane A2; VSM, vascular smooth muscle; PKC, protein kinase C; SR, sarcoplasmic reticulum; PDBu, phorbol-12, 13-dibutyrate; COX, cyclooxygenase; PBS, phosphate-buffered saline; ET, endothelin; SQ-29548, [1S-[1,2(Z),3,4]]-7-[3-[2-(phenylamino)carbonyl]hydrazine] methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; BQ-123, cyclo(L-Leu-D-Trp-D-Asp-L-Pro-D-Val); U46619
[GenBank]
, 9, 11-dideoxy-9, 11-methanoepoxy prostaglandin F2.
Address correspondence to: Dr. Michael S. Wolin, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail: mike_wolin{at}nymc.edu
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