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Ann Thorac Surg 1998;65:1220-1225
© 1998 The Society of Thoracic Surgeons

Hypoxia Increases Vasodilator Release From Internal Mammary Artery and Saphenous Vein Grafts

^a Division of Cardiovascular Surgery, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA

Accepted for publication November 26, 1997.

Address reprint requests to Dr Schaff, Mayo Clinic, 200 First St SW, Rochester, MN 55905

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Greater release of endothelium-derived nitric oxide is implicated in the superior patency of the internal mammary artery (IMA) used in coronary artery bypass grafting. This study compared the release of endothelium-derived nitric oxide into the lumen of the IMA and the saphenous vein under normoxic versus hypoxic conditions.

Methods. Segments of canine IMA and saphenous vein were perfused in vitro. Vasorelaxant activity was measured as vasodilatation of coronary artery smooth muscle induced by the effluent.

Results. Effluents from the IMA and saphenous vein caused comparable vasodilatation of coronary artery smooth muscle. The vasodilatation reversed when perfusion was switched to a prosthetic conduit. Vasodilator activity from the IMA and saphenous vein was attenuated by removing the intima of the grafts or by adding N^G-monomethyl-L-arginine (10^-4 mol/L) or N^G-nitro-L-arginine (10^-4 mol/L), two inhibitors of nitric oxide synthesis. Indomethacin attenuated vasorelaxant activity from saphenous vein grafts but not IMA grafts (n = 10). Vasodilator release from the IMA and saphenous vein was augmented by hypoxia. This augmentation was inhibited by indomethacin (n = 10, p < 0.05). Hypoxic augmentation reversed with return to normoxia.

Conclusions. The release of endothelium-derived nitric oxide and prostacyclin from bypass grafts into the lumen, particularly during hypoxemia, could promote the vasodilatation of distal coronary arterial beds, enhancing myocardial perfusion.

	Introduction

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Direct coronary artery bypass is one of the most effective means of treating obstructive coronary artery disease. There is clear evidence that improved late clinical outcome correlates with the superior late patency of internal mammary artery (IMA) grafts compared with that of saphenous vein grafts [1, 2]. The mechanisms that account for the excellent patency of IMA grafts are not fully understood.

Both the arterial and the venous intima produce endothelium-derived relaxing factor [3]. The active component of this relaxing factor is the nitric oxide radical [4], which also is the active metabolite of nitrovasodilators such as sodium nitroprusside and nitroglycerin [5]. Thus, endothelium-derived nitric oxide (EDNO) functions as an endogenous nitrovasodilator [6]. An important physiologic role for EDNO is the protection of blood vessels against vasospasm and thrombosis [7, 8].

Previous in vitro studies showed that compared with the saphenous vein, the IMA produces greater amounts of EDNO [9, 10]. However, these experiments used organ chambers to measure the relaxation of vessel rings from which EDNO was released; thus, they could not compare quantitatively the amount of EDNO produced by these two blood vessels. In addition, organ chamber studies may overemphasize the relative contribution of abluminal release of EDNO (ie, from the endothelium to the underlying vascular smooth muscle) compared with intraluminal release of vasoactive factors from the endothelial cell [11]. Release of EDNO into the bloodstream may be particularly relevant in relation to coronary artery bypass grafting because EDNO inhibits platelet adhesion [12] and platelet aggregation [13] and promotes platelet disaggregation [13]. In addition, EDNO released into the lumen may dilate arterial beds downstream from the graft and enhance perfusion [14].

The purpose of our experiment was twofold: (1) to detect and to characterize the release of vasodilators from freshly harvested segments of IMA and saphenous vein into the vessel lumen and (2) to investigate whether hypoxia alters the release of vasoactive substances from IMA and saphenous vein grafts. Postoperative hypoxemia is common and may be due to low cardiac output, hypoventilation, intrapulmonary shunting of blood, or preexisting pulmonary disease. Therefore, it is important to determine the effect of hypoxia on the release of endogenous coronary vasodilators.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Harvesting of tissue
Heartworm-free mongrel dogs (25 to 30 kg) of either sex were anesthetized with intravenously injected pentobarbital sodium (30 mg/kg bolus injection; Fort Dodge Laboratories, Fort Dodge, IA) and exsanguinated. The beating heart, left IMA, and left saphenous vein were excised and immersed in cold oxygenated physiologic salt solution with the following composition: NaCl, 118.3 mmol/L; KCl, 4.7 mmol/L; MgSO₄, 1.2 mmol/L; KH₂PO₄, 1.22 mmol/L; CaCl₂, 2.5 mmol/L; NaHCO₃, 25.0 mmol/L; and glucose, 11.1 mmol/L. This was the control solution. The procedures and the handling of the animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Mayo Foundation.

In vitro experiments
The left circumflex coronary artery was meticulously dissected free from the heart and placed in the control solution. The left circumflex coronary artery, left IMA, and left saphenous vein then were cleaned of connective tissue, with care taken not to touch the intimal surface.

Bioassay experiments
In our experimental system, the biologic activity of EDNO released from segments of the IMA and the saphenous vein (approximately 5 cm long) was bioassayed by a ring of coronary artery (proximal left circumflex coronary artery) from which the endothelium had been removed mechanically (Fig 1) [11, 15]. The IMA and saphenous vein were perfused at a constant flow (5 mL/min), with the control solution aerated at 37°C. There was a transient delay of 1 second before the fluid reached the bioassay ring, which was suspended below the donor segment. The tension developed in the coronary bioassay ring was recorded with a force transducer (Grass FT03; Grass Instrument Company, Quincy, MA). The rings first were superfused for 60 minutes with control solution that passed through a stainless steel cannula (direct superfusion). During this time, the vessel was stretched progressively in a stepwise manner to its optimum length-tension relation (approximately 10 g). Control perfusion was provided from an aerated tower, and an adjacent aerated tower contained control solution plus prostaglandin F₂ (2 x 10^-6 mol/L).

View larger version (37K): [in this window] [in a new window]   Fig 1. Apparatus for the bioassay of nitric oxide, the active component of endothelium-derived relaxing factor (EDRF) from the perfused internal mammary artery and saphenous vein (SV). Vasoactivity of effluent from the perfused blood vessels is bioassayed on a ring of epicardial coronary artery (CA) smooth muscle.

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In 10 of the bioassay experiments, the IMA and saphenous vein segments were preserved in formalin. After the experiments were completed, all the segments were incised longitudinally to expose the luminal surface. The blood vessels then were mounted on specimen cards and photographed beside a pathologist’s measuring card; 8- by 10-inch enlargements of the photographs were made and the surface area of the segments was measured with computer-assisted planimetry. The absolute surface area was determined by calibrating the computer with the measuring card in the photograph.

Drugs
The following drugs were used: acetylcholine chloride, indomethacin, and prostaglandin F₂, obtained from the Sigma Chemical Company (St. Louis, MO), and N^G-nitro-L-arginine (NO-ARG) and N^G-monomethyl-L-arginine (L-NMMA), obtained from Calbiochem Corp (La Jolla, CA). All drugs were prepared daily with distilled water, except for indomethacin, which was dissolved in Na₂CO₃ (10^-5 mol/L). The concentrations were expressed as the final molar concentration in the organ chamber. When NO-ARG or L-NMMA was used, vascular segments were exposed to the compounds for at least 15 minutes before experimentation. When indomethacin (10^-5 mol/L) was used to prevent the synthesis of endogenous prostanoids, the tissue was treated with the compound for at least 40 minutes before experimentation.

Data analysis
The results were expressed as the mean plus or minus the standard error of the mean. In all experiments, n referred to the number of animals from which blood vessels were harvested. For bioassay experiments, relaxations were expressed as the percentage change in tension from the contraction of the bioassay ring in response to prostaglandin F₂. Statistical evaluation of the data was performed by analysis of variance and Student’s t test for either paired or unpaired observations. A p value of less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The addition of prostaglandin F₂ (2 x 10^-6 mol/L) to the perfusate induced stable contraction of the coronary artery bioassay segment (Fig 2). After the contraction in response to prostaglandin stabilized, perfusate flow over the bioassay ring was switched from the stainless steel cannula (direct superfusion) to either the IMA or the saphenous vein (endothelial superfusion), causing a stable relaxation of the bioassay ring to 29.02% ± 2.76% and 30.67% ± 2.36%, respectively, of the initial contraction produced by prostaglandin F₂ (n = 10) (Fig 2). There was no statistically significant difference between the magnitude of vasodilatation induced by the effluent from either the IMA or the saphenous vein. By switching perfusion back through the stainless steel cannula, the relaxation observed during endothelial superfusion was quickly reversed, and the coronary artery bioassay ring returned to its initial level of contraction. The relaxation induced by superfusion through the IMA and the saphenous vein could be prevented by mechanically removing the intima of the blood vessels (Figs 2, 3). These experiments document the release of EDNO into the lumen by the intima of the perfused IMA and saphenous vein.

View larger version (20K): [in this window] [in a new window]   Fig 2. Bioassay of endothelium-derived nitric oxide from canine left internal mammary artery (IMA) (original trace). When the coronary artery bioassay ring was exposed to prostaglandin F2 (PGF2) through the prosthetic conduit (direct line), it exhibited contraction (top trace). When the perfusion fluid was switched to pass through the IMA segment with endothelium (endothelial superfusion), the coronary artery relaxed, indicating a basal release of endothelium-derived nitric oxide. When the perfusion fluid was switched back to the direct line, the bioassay ring again constricted, indicating removal of the vasodilator action of endothelium-derived nitric oxide. When the endothelium was removed mechanically from the IMA segment, superfusion through the segment no longer induced relaxation of the coronary artery bioassay ring (top trace). Treatment of the IMA with either NG-nitro-L-arginine (NO-ARG) or NG-monomethyl-L-arginine (L-NMMA) completely abolished the vasodilator activity of the perfused IMA with endothelium but did not alter the ability of the coronary artery bioassay ring to relax to sodium nitroprusside (SNP) (10-7 mol/L) (bottom trace). Indomethacin treatment of the IMA did not alter the vasodilator activity of the effluent from the perfused vessel (bottom trace).

View larger version (11K): [in this window] [in a new window]   Fig 3. Bioassay of endothelium-derived nitric oxide from perfused canine left internal mammary artery (IMA). Values are presented as the mean plus or minus the standard error of the mean and represent the percentage relaxation of the canine coronary artery bioassay ring. Control denotes relaxation induced by effluent from the perfused IMA and Without endothelium denotes relaxation induced by effluent from the IMA from which the intima had been removed mechanically. Indomethacin, L-NMMA, and NO-ARG represent relaxation induced by effluent from the perfused IMA that had been treated with indomethacin, NG-monomethyl-L-arginine, and NG-nitro-L-arginine, respectively. (*Significantly different from control relaxation, p < 0.05.)

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View larger version (11K): [in this window] [in a new window]   Fig 4. Bioassay of endothelium-derived nitric oxide from perfused canine left saphenous vein. Values are presented as the mean plus or minus the standard error of the mean and represent the percentage relaxation of the contracted canine coronary artery bioassay ring. Control denotes relaxation induced by effluent from the saphenous vein and Without endothelium denotes relaxation induced by effluent from the saphenous vein from which the intima had been removed mechanically. Indomethacin, L-NMMA, and NO-ARG represent relaxation induced by effluent from the saphenous vein that had been treated with indomethacin, NG-monomethyl-L-arginine, and NG-nitro-L-arginine, respectively. (*Significantly different from control relaxation, p < 0.05; significantly different from relaxation in the presence of indomethacin, p < 0.05.)

The vasodilator activity of the effluent from both the IMA and the saphenous vein was augmented when the blood vessels were exposed to hypoxia (95% N₂/5% CO₂, oxygen tension = 50 mm Hg, pH = 7.4), producing relaxation of 50.66% ± 7.68% and 68.23% ± 7.43%, respectively, of the initial contraction in response to prostaglandin F₂ (n = 10, p < 0.05 for both blood vessels compared with control relaxation) (Figs 5, 6). This augmentation of vasodilator activity during hypoxia was reversed immediately when the oxygen tension of the perfusate was returned to the control level.

View larger version (11K): [in this window] [in a new window]   Fig 5. Effect of hypoxia on basal release of vasodilator from the perfused canine internal mammary artery (IMA) (original trace). When the coronary artery bioassay ring was exposed to prostaglandin F2 (PGF2) through the prosthetic conduit (direct line), it contracted. Perfusion through the IMA segment with endothelium (endothelial superfusion) induced coronary artery relaxation, indicating basal release of nitric oxide. Hypoxia augmented the vasodilator activity of effluent from the IMA (top trace). Hypoxic augmentation was reversed quickly on return to normoxia. Indomethacin treatment inhibited the hypoxic augmentation in the perfused IMA (bottom trace).

View larger version (14K): [in this window] [in a new window]   Fig 6. Effect of hypoxia on basal release of vasodilator from the perfused canine saphenous vein and internal mammary artery (IMA). Values are presented as the mean plus or minus the standard error of the mean and represent the percentage relaxation of the canine coronary artery bioassay ring that had contracted in response to prostaglandin F2 (2 x 10-6 mol/L). Control basal release denotes relaxation induced by effluent from the perfused IMA or saphenous vein, hypoxia denotes total relaxation induced by effluent from the perfused IMA or saphenous vein during exposure to hypoxia (95% N2/5% CO2), and hypoxia + indomethacin denotes total relaxation induced by effluent from the perfused IMA or saphenous vein during exposure to hypoxia in the presence of indomethacin (10-6 mol/L). (*Significantly different from control basal release, p < 0.05.)

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This study demonstrated the release of EDNO into the lumen from excised segments of the IMA and the saphenous vein. Both vessels produced a vasodilating substance in quantities sufficient to induce relaxation of coronary artery smooth muscle, which was used as a detector tissue. The vasodilator activity was produced by the endothelium, as evidenced by the almost complete absence of vasodilator activity of the effluent from blood vessels from which the intima had been removed.

The vasodilator was produced constantly and did not require the administration of an agonist to promote its release. Thus, even in the absence of drug-receptor interaction, the perfused IMA and saphenous vein exhibited a significant basal (unstimulated) release of EDNO.

In the perfused IMA, the vasodilator activity of the effluent was not blocked by cyclooxygenase inhibition, thus ruling out a role for prostacyclin. Furthermore, the administration of L-NMMA or NO-ARG, two inhibitors of nitric oxide synthesis [16, 17], completely inhibited endothelium-dependent relaxation in the IMA. On the basis of these observations, we conclude that the vasodilator released by the endothelium into the lumen of the perfused IMA is nitric oxide. The specificity of L-NMMA and NO-ARG for the IMA endothelium and the lack of effect of these compounds on the detector tissue were confirmed by the fact that they did not antagonize vasodilatation of the coronary artery smooth muscle in response to sodium nitroprusside.

Prostacyclin is the primary vasodilator prostanoid produced by the endothelium [18]. In the saphenous vein, cyclooxygenase blockade significantly inhibited production of vasodilator by the graft, suggesting an important role for prostacyclin. However, nitric oxide also contributes to the vasorelaxant activity of effluent from vein grafts under basal conditions. Inhibitors of nitric oxide synthesis completely inhibited the vasodilator activity of the effluent.

The paradoxical finding that either L-NMMA or NO-ARG can block completely vasodilator activity from the perfused saphenous vein may be explained by at least two mechanisms. First, there is synergism between the vasodilatation induced by prostacyclin and nitric oxide [18]. Compared with nitric oxide, prostacyclin is a relatively weak vasodilator of the epicardial coronary artery smooth muscle, but its action is enhanced by the presence of nitric oxide [18]. Indeed, subthreshold concentrations of nitric oxide also enhance the inhibitory action of prostacyclin on platelet aggregation [13]. Thus, nitric oxide possibly has an important synergistic vasodilator activity with the prostacyclin derived from the saphenous vein.

A second possible mechanism is that the prostacyclin derived from the saphenous vein stimulates local release of EDNO from the graft. In the porcine epicardial coronary artery, prostacyclin promotes vasodilatation by stimulating the release of EDNO [18]. Thus, by blocking cyclooxygenase in the saphenous vein, one could be decreasing the stimulation for nitric oxide production by the intima.

In both the IMA and the saphenous vein, hypoxia augmented the amount of vasodilator released by the perfused blood vessels. This augmentation was blocked by indomethacin but was unaffected by L-NMMA and NO-ARG, suggesting that hypoxia stimulates the production of an endothelium-derived prostanoid, most likely prostacyclin. Indeed, in the human isolated IMA, the onset of profound hypoxia stimulates an initial transient vasodilatation caused by endothelium-derived prostacyclin [19].

In our experiment, effluent from the perfused IMA and saphenous vein produced comparable relaxation. This finding is at odds with previous studies that demonstrated augmented relaxation of IMA grafts compared with saphenous vein grafts [9, 10]. However, these previous experiments evaluated the stimulated production of EDNO (ie, release induced by drugs); the basal release of relaxing factors was not examined. This is an important distinction because the basal release of relaxing factors may be the important determinant of vascular tone and blood vessel caliber [20].

Consistent with previous studies, we found that the IMA appears to release a greater amount of nitric oxide than the saphenous vein. Although effluent from the IMA and the saphenous vein produced comparable relaxation, the entire relaxant activity of the effluent from the IMA can be attributed to nitric oxide. Nitric oxide prevents adhesion of platelets to the intima [12] in addition to inhibiting cellular processes leading to atherosclerosis (two properties not shared by prostacyclin) [21]. The discovery that nitric oxide is produced in considerable amounts during basal conditions could account for the relative refractoriness of IMA grafts to early thrombosis and late atherosclerosis [1, 2].

The physiologic importance of endothelium-derived vasodilators cannot be overemphasized. Endothelium-dependent vasodilation is expressed early in vertebrate phylogeny, and there is striking homogeneity in the reactivity of canine and human blood vessels to mediators of endothelium-dependent vasodilation, particularly with regard to platelet aggregation [8]. Endothelium-derived nitric oxide is a major modulator of vascular tone in humans [22] and prevents the activation and aggregation of circulating platelets. Impaired production of EDNO has been implicated in the progression of atherosclerosis [23] and in coronary vasospasm [7]. With regard to coronary artery bypass grafts, the basal intraluminal release of endothelium-derived vasodilators (particularly EDNO) may be especially important in preventing early graft thrombosis and in retarding the development of graft atherosclerosis (Fig 7).

View larger version (47K): [in this window] [in a new window]   Fig 7. Proposed role of endothelium-derived vasodilators in vascular grafts. Under normal conditions (top), endothelium-derived nitric oxide (NO) synthesized from L-arginine (L-ARG) acts on the underlying vascular smooth muscle to induce cyclic guanosine monophosphate (cGMP)–mediated vasodilatation, and it chronically inhibits smooth muscle proliferation and mitogenesis (atherosclerosis). Intraluminally released NO inhibits platelet adhesion and platelet aggregation and promotes platelet disaggregation. Intraluminally released NO promotes the vasodilatation of arterial beds downstream. During moderate hypoxia (bottom), the production of prostacyclin (PGI2) from arachidonic acid (AA) in the endothelium augments cyclic adenosine monophosphate (cAMP)–mediated vasodilatation of the graft and luminally released PGI2 augments the vasodilatation of arterial beds downstream.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Paul J. Pearson Berent Discigil Hartzell V. Schaff Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pearson, P. J. Articles by Schaff, H. V. Search for Related Content PubMed PubMed Citation Articles by Pearson, P. J. Articles by Schaff, H. V.