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Ann Thorac Surg 2006;81:2147-2154
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Thromboxane Receptor Stimulation Suppresses Guanylate Cyclase-Mediated Relaxation of Radial Arteries

Muhammad Arshad, MD a , Venkataramana Vijay, MD b , Beverly C. Floyd, MS, MPH a , Brian Marks, BS a , Mohan R. Sarabu, MD b , Michael S. Wolin, PhD a , Sachin A. Gupte, MD, PhD a , *

a Department of Physiology, New York Medical College and Westchester Medical Center, Valhalla, New York
b Department of Cardiothoracic Surgery, Vassar Brothers Medical Center, Poughkeepsie, New York

Accepted for publication January 4, 2006.

* Address correspondence to Dr Gupte, Department of Physiology, Room 626, Basic Sciences Building, New York Medical College, Valhalla, NY 10595; (Email: sachin_gupte{at}nymc.edu).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: The internal mammary artery (IMA) and the radial artery (RA) are routinely used in coronary artery bypass grafting. However, RA grafts have a higher incidence of postoperative vasospasm and comparatively poor patency rates. The present study was undertaken to investigate the signaling pathways mediating contraction and relaxation in the IMA and RA with the aim of better understanding the mechanism underlying the propensity of RA grafts to spasm.

METHODS: We examined the contractile responses of the IMA and RA to KCl (a depolarizing agent), phenylephrine (an {alpha}-adrenergic agonist), and U46619 (a thromboxane analogue).

RESULTS: Contractions induced by KCl or U46619 did not significantly differ in IMA and RA. By contrast, phenylephrine evoked significantly greater contraction of the IMA than the RA. Contractions induced by both phenylephrine and U46619 were dose-dependently inhibited by nifedipine (an L-type calcium channel blocker). Estimation of thromboxane A2 (TxA2) and prostacyclin (PGI2) synthesis revealed that the TxA2 to PGI2 ratio in the RA was twice that in the IMA. Moreover, acetylcholine-induced and nitroglycerin-induced relaxation of RA precontracted with U46619 was significantly impaired, as compared with RA precontracted with phenylephrine. These data suggest that inhibition of nitroglycerin-induced soluble guanylate cyclase activity by U46619 was at least partially responsible for the diminished vasodilatory response of RA to nitric oxide.

CONCLUSIONS: Our findings suggest that by reducing nitric oxide-stimulated soluble guanylate cyclase activity, the higher TxA2 to PGI2 ratios in RA, and the elevated serum TxA2 levels seen during coronary artery bypass grafting operations, may underlie the vasospasm and poor patency rates seen with the RA.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
The radial artery (RA) is increasingly being used for coronary artery bypass grafting (CABG) as a conduit for myocardial revascularization [1, 2]. However, a major concern in using the RA is that it has a greater propensity to undergo spasm and poorer short-term and long-term patency rates than the internal mammary artery (IMA) [3–5]. Traditionally, the vasospastic tendency of RA grafts has been countered in the operating room (immediately after harvest) by treating the artery with papaverine or milrinone, or both, and placing it in a bath of heparinized saline containing nitroglycerin (NTG) or a combination of NTG and a calcium channel blocker. Similarly, protection from immediate postoperative and postdischarge vasospasm is sought through the use of intravenous or oral combinations of the aforementioned vasodilator drugs. However, it is well known from clinical studies that such vasodilatory precautions do not provide the expected protection from postoperative vasospasm of RA grafts. The IMA seems to be a superior graft because it has an active endothelium that produces substantial amounts of vasodilating autacoids like nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor [6, 7], which act on the underlying vascular smooth muscle and serve as important modulators of vascular tone. By contrast, the RA has less active endothelium and is more sensitive to receptor-mediated contractile agents [8, 9], which presumably predisposes it to higher incidences of spasm. In addition to vasodilators like PGI2 and NO, the endothelium also produces vasoconstrictors like thromboxane A2 (TxA2) and endothelin-1. Thromboxane A2, endothelin-1, and serotonin are highly potent spasminogens in arterial conduits, whereas norepinephrine and its pharmacological analogue, phenylephrine, are less spasmogenic [10]. Notably, all these vasoactive mediators are produced in abundance during the cardiopulmonary bypass run of CABG surgery; in particular, TxA2 is known to be released into circulation due to injury and destruction of platelets caused by the shear forces imposed on blood circulating through the cardiopulmonary bypass pump. Thus, the grafted arterial segment in CABG surgery is exposed to numerous agents that potentially promote vasospasms, which reduces the blood flow to the myocardium postoperatively. Vasospasms are a manifestation of an imbalance between contraction relaxation mechanisms, which are controlled through the regulation of complex signaling pathways that lead to vasoconstriction or vasodilation. Thromboxane A2 and {alpha}-adrenergic agonists elicit vascular smooth muscle contraction by inducing membrane depolarization, and thus influx of extracellular calcium through L-type calcium channels, calcium-induced calcium release from the internal stores, and myosin light chain phosphorylation [11, 12]. Conversely, NO and PGI2, respectively, act through guanosine 3',5'-cyclic monophosphate-dependent and adenosine 3',5'-cyclic monophosphate-dependent pathways to induce relaxation by mediating repolarization or hyperpolarization of the cell membrane and sequestration of calcium in the sarcoplasmic reticulum [13, 14]. In the present study, we compared the effects of vasoconstrictors and vasodilators on the IMA and RA with the aim of better understanding the mechanisms underlying the higher incidence of vasospasm among RA grafts.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Drugs
Acetylcholine, forskolin, phenylephrine, and norepinephrine were all obtained from Sigma Chemical Company (St. Louis, MO). We obtained U46619 from Cayman Chemical Company (Ann Arbor, MI). The nitroglycerin was from Park Davis (New York, NY). Other salts used in the study were from J. T. Baker Chemicals (Phillisburg, NJ).

Collection of Human Arteries
All experimental protocols were approved by our institutional review board (application dated July 30, 2002), and consent was obtained from all patients that participated in this study. Segments from distal sections of human IMA and RA surgical discards were collected from patients undergoing elective CABG surgery after grafts to the aorta and coronary artery. The IMA and RA segments were immediately placed in ice-cold (4°C) plasmalyte solution and were transported to the laboratory for tension studies.

Measurement of Isometric Tension
With the aid of a dissecting lens, the IMA and RA segments were carefully cleaned of fat and connective tissue and cut into rings (3 to 4 mm in length), leaving the endothelium intact. The arterial rings were mounted on wire hooks attached to force displacement transducers (Model FT-03, Grass, Hampshire, IL) for measurement of changes in isometric force, which were recorded on a polygraph (Model 7, Grass) as previously described [15]. Arteries were initially incubated for 2 hours at an optimal passive tension (ie, the optimal point of contraction elicited by 30 mM KCl) in individually thermostated (37°C) 10-mL baths (Metro Scientific Co., Chennai, India) filled with Krebs bicarbonate buffer (pH 7.4) containing (in mM) 118 NaCl, 4.7 KCl, 1.5 CaCl2, 25 NaHCO3, 1.1 MgSO4, 1.2 KH2PO4, and 5.6 glucose, and gassed with O2 (21%), CO2 (5%), and N2 (74%). After the 2-hour equilibration, the vessels were depolarized with Krebs bicarbonate in which the NaCl was replaced with KCl. This treatment enhanced the reproducibility of subsequent contractions. The arteries were then re-equilibrated in normal Krebs solution for 20 to 30 minutes before the experiments were begun. In different sets of experiments, the effects of vasoconstrictors (ie, phenylephrine, norepinephrine, and U46619) and vasodilators (ie, acetylcholine, forskolin, and nitroglycerin) were examined. Each individual ring was used for only one experiment with each of the agents studied.

Estimation of 6-Keto Prostaglandin F (PGF2{alpha}) and Vasoconstrictor TxA2 (TxB2) Released From IMA and RA
Levels of the stable end products of the vasodilator PGI2 (6-keto PGF2{alpha}) and vasoconstrictor TxA2 (TxB2) in solution collected from the tissue baths containing the IMA or RA were estimated using enzyme immunoassays. Samples were taken 20 minutes after adding 30 mM KCl to the bath, and the assays were carried out using protocols provided by the manufacturer (Cayman Chemical Company, Ann Arbor, MI).

Estimation of Soluble Guanylate Cyclase Expression and Activity
Expression of soluble guanylate cyclase (sGC) was evaluated by Western analysis, and its activity was assayed as previously described [16].

Statistical Analysis
Data is expressed as means ± standard error of the mean. Arterial relaxation was measured as the percent change in force from the precontracted steady-state level. The contractile force generated by the different contractile agents was expressed as the percent change from the force generated by 123 mM KCl. The significance of differences among the results was analyzed using repeated measure analysis of variance and post-hoc Fisher's LSD (protected t test) or the Student's t test. Arterial rings (n) from different patients were used in each experimental group.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Contraction of IMA and RA Elicited by KCl, {alpha}-Adrenergic Agonists, and U44619
We examined the effects of KCl (123 and 30 mM) on IMA and RA after a 2-hour stabilization period (Fig 1A). Depolarization of the plasma membrane using 123 mM KCl induced contractions in both artery types. Contractions elicited using 30 mM KCl were 25% smaller in the IMA (n = 30) and 50% smaller in the RA (n = 10) as compared with contractions induced by 123 mM KCl. Receptor-mediated contractions of the IMA (Fig 1B; n = 15 to 20) and the RA (Fig 1C; n = 8 to 10) were investigated using the TxA2 analogue U46619 and the {alpha}-adrenergic agonists norepinephrine and phenylephrine. The dose-response curves show U46619 to be significantly more potent than either of the {alpha}-adrenergic agonists (Figs 1B, C). There were no significant differences in the amplitudes of contractions elicited by 30 mM KCl or U46619 in the IMA and RA (Figs 2A, B), but at both effective doses tested (10-6 and 10-5 M), phenylephrine-evoked contractions were significantly smaller in the RA than the IMA (Fig 2C).


Figure 1
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  		Fig 1. Contraction of the internal mammary artery (IMA) and the radial artery (RA) evoked by KCl, U46619, norepinephrine (NE) and phenylephrine (Phen). (A) High (123 mM) and low (30 mM) KCl elicited force in the IMA (n = 30) and the RA (n = 10). In both (B) the IMA (n = 15 to 20) and (C) the RA (n = 8 to 10), U46619 was a more potent vasoconstrictor than either Phen or NE. Note error bars are small and they overlap with symbols.

 

Figure 2
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  		Fig 2. Comparison of contractions evoked in the internal mammary artery (IMA) and the radial artery (RA) by KCl, U46619, and phenylephrine. There were no significant differences in the force generated (A) by 30 mM KCl or (B) by U46619 in the IMA (n = 15 and n = 30, respectively) and in the RA (n = 10 and n = 8, respectively). (C) Phenylephrine-induced contractions were significantly stronger in the IMA (n = 20) than in the RA (n = 10).

 
Generation of TxA2 in IMA and RA
In vivo, the effects of TxA2 are normally antagonized by PGI2. Therefore we determined the TxA2-to-PGI2 ratios in IMA (n = 6) and RA (n = 6) based on levels of their stable metabolites (vasoconstrictor TxA2 [TxB2] and 6-keto-PGF2{alpha}, respectively) using previously described protocols [15]. We found that the TxA2 to PGI2 ratio in RA was more than twice that in the IMA (Fig 3).


Figure 3
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  		Fig 3. Basal thromboxane A2 (TxA2) to prostacyclin (PGI2) ratios in the IMA (n = 6) and in the RA (n = 6). Estimated were levels of vasoconstrictor TxA2 (TxB2) and Keto PGF2{alpha}, the stable metabolites of TxA2 and PGI2, respectively. (IMA = internal mammary artery; RA = radial artery.)

 
Effects of Nifedipine on Phenylephrine-Evoked and U46619-Evoked Contractions
To investigate the contractile mechanisms activated by U46619 and phenylephrine, we first investigated the effects of nifedipine, an L-type calcium channel blocker, on isometric force generation (Fig 4). The IMA (Fig 4A; n = 15) and the RA (Fig 4B; n = 5) precontracted by phenylephrine (1 to 10 µM) or U46619 (10 to 50 nM) were relaxed by nifedipine (1 nM to 10 µM) in a dose-dependent manner. Likewise, nifedipine relaxed IMA (n = 4) and RA (n = 4) precontracted with 30 mM KCl. However relaxation by nefidipine (100 nM) of the IMA (78 ± 3%) and the RA (99 ± 1%) precontracted with KCl was significantly greater in both artery types than was contracted with phenylephrine and U46619 (Fig 4).


Figure 4
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  		Fig 4. Effects of the L-type Ca2+ channel inhibitor nifedipine on internal mammary artery (IMA) and radial artery (RA) contraction. Nifedipine dose-dependently relaxed (A) IMA (n = 15) and (B) RA (n = 5) precontracted with phenylephrine or U46619. Note error bars are small and they overlap with symbols. (Phen = phenylephrine.)

 
Relaxation of IMA and RA Using Acetylcholine and NTG
The IMA (n = 20 each) and the RA (n = 10 each) were then precontracted to 70% of 123 mM KCl-induced force using either phenylephrine (1 to 10 µM) or U46619 (10 to 50 nM). Once the contractions had stabilized, the arteries were dose-dependently relaxed using acetylcholine, which stimulates endothelial NO synthesis, or NTG, an NO-donor (Fig 5). Relaxations elicited by these sources of NO in IMA precontracted with phenylephrine did not significantly differ from those in IMA precontracted with U46619 (Figs 5A, B). By contrast, evoked relaxations in RA precontracted with U44619 were significantly smaller (30% to 50%) than in RA precontracted with phenylephrine (Figs 5C, D). In addition, the endothelium-dependent acetylcholine-induced relaxation of RA precontracted with phenylephrine was significantly greater than in IMA, whereas the endothelium-independent, NTG-induced relaxation of IMA and RA did not differ. Precontraction with U46619 abolished the differences in the endothelium-dependent relaxation of IMA and RA, and diminished endothelium-independent relaxation by NTG to a significantly greater degree in the RA than in the IMA.


Figure 5
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  		Fig 5. Effects of acetylcholine and nitroglycerin on internal mammary artery (IMA) and radial artery (RA) contraction. (A, C) Acetylcholine or (B, D) nitroglycerin dose-dependently relaxed IMA (n = 20 each) and RA (n = 10 each) precontracted with either phenylephrine (Phen) or U46619. Note that both acetylcholine and nitroglycerine were significantly less effective at relaxing RA precontracted with U46619 than phenylephrine.

 
The sGC Expression and Activity
To better understand the mechanism by which U46619 suppressed NO-induced relaxation, we compared the activities of sGC in the IMA and in the RA (Fig 6). We found that 1 µM NTG increased sGC activity by 112% in the IMA (n = 6) and by 46% in the RA (n = 6). In the presence of 100 nM U46619, however, the NTG-induced increases in sGC activity were significantly suppressed in the RA, but not in the IMA, although U46619 had no significant effect on the basal sGC activity in the IMA and in the RA. Notably, the basal sGC activity was higher in the RA than in the IMA, although there were no differences in the levels of expression of sGC protein (Fig 6).


Figure 6
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  		Fig 6. Estimation of soluble guanylate cyclase (sGC) activity and protein in the internal mammary artery (IMA) and the radial artery (RA). The soluble guanylate cyclase (sGC) activity measured by estimating guanosine 3',5'-cyclic monophosphate (cGMP) levels was increased in the IMA (n = 6) and RA (n = 6) pretreated with nitroglycerin (NTG). The U46619 reduced NTG-induced sGC activity in the RA. The lower panel shows that levels of the sGC protein were similar in the IMA and the RA. (IB = immunoblotted; KD = kilodalton.)

 
Relaxation of IMA and RA by Forskolin
After precontracting the IMA (n = 20 each) and the RA (n = 10 each) to 70% of 123 mM KCl-induced force with phenylephrine (1 to 10 µM) or U46619 (10 to 50 nM), the adenylate cyclase activator forskolin dose-dependently relaxed both artery types to a similar degree, irrespective of whether they were precontracted with phenylephrine or U46619.


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Arterial grafts are routinely used in CABG to treat coronary heart disease and in revascularization of the myocardium [17, 18]. However, in some cases subsequent constriction of arterial conduits, which reduce blood flow to the myocardium and compromise myocardial function, necessitates administration of vasodilatory support or reoperation [19, 20]. In that regard, although there has been a surge in the use of RA grafts for myocardial revascularization, there is still significant apprehension about using the RA as a second graft because of its poor graft patency records as compared with the IMA grafts [3–5, 21, 22], and inherent propensity for vasospasm, leading to postoperative graft failure [23].

In the present study we have shown differences in the contractile properties of the RA and IMA, as well as in the dilatory responses evoked by the NO-sGC signaling pathway. We found that the TxA2 analogue U46619 is a potent contractile agent in both the RA and IMA, evoking contractions similar to those induced by membrane depolarization using a high concentration (123 mM) of extracellular KCl. Although the {alpha}-adrenergic agents are less potent vasoconstrictors than U46619, our results indicate that phenylephrine, which is routinely used clinically to elevate blood pressure and to enhance cardiac contractility, generates more force in the IMA than the RA, which is consistent with the previous observations [24]. On the other hand, there were no significant differences in U46619-evoked contractions between the two artery types (Fig 2), although it was previously reported that stronger receptor-mediated contractions can be evoked in the RA than in the IMA [9], and that RA grafts are more sensitive to TxA2 [10]. Consistent with earlier reports, we found that IMAs produce substantial amounts of both PGI2 and TxA2 [15]; nonetheless, the TxA2 to PGI2 ratio was significantly higher in the RA than in the IMA. Because PGI2 antagonizes the actions of TxA2, the higher TxA2 to PGI2 ratio implies that TxA2 would exert greater effects in the RA.

The endothelium and other sources of autacoids in the vessel wall are important contributors to the regulation of vascular tone, platelet function, and vascular growth through the production of mediators such as NO, endothelium-derived hyperpolarizing factor, PGI2, TxA2, and endothelin-1 [6, 7, 25–27]. Numerous studies have shown that inflammatory responses elicited by extracorporeal circulation triggers TxA2 synthesis during cardiopulmonary bypass surgery [28]. Platelet activation that occurs during bypass surgery is also a potential source of prostaglandins and TxA2. In addition, angiotensin-II and protamine-heparin complex also enhance the release of TxA2 [29, 30]. This significantly increases TxA2 to PGI2 ratios in the systemic circulation and in the lungs during CABG operations [31–34]. We have also shown that hypoxia and reoxygenation stimulates synthesis of TxA2 in the IMA and induces dysfunction of IMA conduits [15], whereas others have shown that the IMA produces TxA2 under hypoxic conditions, leading to vasoconstriction [25]. In the RA, hypoxia also induces endothelin-1 production and activation of thromboxane-dependent and endothelin-1-dependent signaling pathways that enhance contractility during reoxygenation [15]. In the context of those earlier studies, our present findings are consistent with the idea that elevated TxA2 to PGI2 ratios are potentially contributing factors to impairing postoperative RA graft function.

Several studies have implicated TxA2 and {alpha}-adrenergic agonists in the genesis of vasospasm [10, 24]. The effects of TxA2-adrenergic and {alpha}-adrenergic agonist-induced contraction of saphenous vein, RA, IMA, and epigastric artery used in CABG operations have been extensively investigated [24]. Nevertheless, the intracellular signaling pathways activated by TxA2-adrenergic and {alpha}-adrenergic agonists in the vascular smooth muscle of these conduits are not fully understood. We observed that nifedipine, a specific L-type Ca2+ channel blocker, dose-dependently suppresses U46619-induced and phenylephrine-induced contractions (Fig 4), and that nifedipine-induced relaxation seems to be shifted to higher doses with U46619-induced contraction. This shift may be related to a U46619-induced increase in the calcium sensitivity of the myofilaments mediated by Rho kinase [35]. Therefore, processes regulating intracellular Ca2+ can be important factors in altered reactivity that potentially contribute to promoting vasospasms in conduit arteries.

Studies have suggested that endothelial function is better in the IMA than in the RA based on observations that RA endothelium releases smaller amounts of vasodilating autacoids (ie, NO, endothelium-derived hyperpolarizing factor, and PGI2) than the IMA; however, others have shown that endothelial production of NO or vessel sensitivity to NO, or both, may actually be greater in the RA than in the IMA [6, 7, 27]. Consistent with that idea, our findings (Fig 5) suggest that endothelium-dependent relaxation and sGC-catalyzed synthesis of guanosine 3',5'-cyclic monophosphate, which mediates vasodilation induced by endothelium-derived NO, is significantly greater in the RA than in the IMA. Our results also indicate that the reactivity of RA to endothelium-derived NO or NO-donors may vary depending on the type of vasoconstrictors used during CABG surgery or released from endothelial cells or vascular smooth muscle. Nitroglycerin completely dilates both IMAs and RAs precontracted by {alpha}-adrenergic agonists, but when precontracted using U46619, NTG had a significantly weaker effect on the RA than on the IMA. It is plausible that this difference is the result of U46619-mediated inhibition of sGC activity. This may be a selective effect on the NO-sGC mechanism of vascular regulation, because relaxation induced by forskolin through adenylate cyclase-cAMP pathways did not differ in the RA contracted with U46619 and phenylephrine. The differences in the characteristics of IMA and RA vasodilation previously described may explain, at least in part, the differences in the reactivities of the RA and the IMA, and the predisposition of RA grafts to spasm (ie, activation of prostaglandin and thromboxane synthesis and thromboxane receptor-mediated signaling) may trigger episodes of vasospasm more frequently in the RA than in the IMA.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This study was supported by American Heart Association (grant no. 0435070N) and National Institutes of Health (grant no. HL 31069, grant no. HL 43023, and grant no. HL 66331).


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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