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Ann Thorac Surg 1995;59:676-683
© 1995 The Society of Thoracic Surgeons

Overview of the Nature of Vasoconstriction in Arterial Grafts for Coronary Operations

The Albert Starr Academic Center for Cardiac Surgery, St. Vincent Heart Institute, Portland, Oregon

Accepted for publication November 18, 1994.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Many vasoconstrictors (spasmogens) may cause arterial graft spasm; however, there is lack of an overview of the nature of vasoconstriction in grafts. This study was designed to investigate the response of three major arterial grafts currently used for coronary artery bypass grafting to various vasoconstrictor substances. Segments of three arterial grafts (gastroepiploic [GEA], n = 28; internal mammary [IMA], n = 213; inferior epigastric [IEA], n = 24) taken from patients undergoing coronary artery bypass grafting were studied in organ baths under a physiologic pressure. Cumulative concentration–contraction curves were established for the following vasoconstrictor substances: endothelin-1, U46619, prostaglandin F₂, norepinephrine, methoxamine, phenylephrine, 5-hydroxytryptamine, and potassium chloride (K⁺). In IMA, the highest contraction force was induced by U46619 (5.69 ± 0.48 g), endothelin-1 (4.43 ± 0.4 g), PGF₂ (6.29 ± 1.42 g), and K⁺ (4.58 ± 0.5 g). Internal mammary artery is highly sensitive to endothelin-1 (EC₅₀, -8.13 ± 0.08 log M) and U46619 (EC₅₀, -8.21 ± 0.21 log M) (lower than any other vasoconstrictors, p < 0.001). Next sensitive vasoconstrictors were PGF₂ and norepinephrine. 5-Hydroxytryptamine induced significantly higher contraction force in the IMA without endothelium (2.8 ± 0.64 g versus 1.4 ± 0.23 g, p < 0.05). In GEA and IEA, endothelin-1 and U46619 were more potent vasoconstrictors (EC₅₀ for endothelin-1: -8.06 ± 0.02 log M in GEA and -8.22 ± 0.04 in IEA; for U46619: -8.49 ± 0.24 log M in GEA and -8.25 ± 0.09 in IEA) than that for norepinephrine (-6.86 ± 0.11 log M for GEA and -6.59 ± 0.18 log M for IEA, p < 0.0001), although all of them (and K⁺) evoked a strong contraction. In summary, the present study reveals that there are basically two types of vasoconstrictors that are important spasmogens in arterial grafts. Type I (endothelin, prostaglandins (thromboxane A₂ and prostaglandin F₂), and ₁-adrenoceptor agonists) are the most potent vasoconstrictors and they strongly contract arterial grafts even when endothelium is intact. Type II vasoconstrictors (such as 5-HT) only induce a weak vasoconstriction when endothelium is intact. However, those vasoconstrictors probably play an important role in the spasm of arterial grafts if endothelium is lost by surgical handling.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Because of the superior long-term results of the internal mammary artery (IMA) grafting, other arterial conduits such as radial artery, gastroepiploic artery (GEA), and inferior epigastric artery (IEA) have also been used for coronary artery bypass grafting (CABG). However, in contrast to saphenous vein grafts, arterial grafts have a small lumen and any further reduction in diameter by a vasoconstrictor stimulant could cause significant flow deprivation. For example, perioperative spasm of the IMA could be the cause of perioperative morbidity and mortality [1, 2]. There are reports of vasoactive drugs altering IMA graft flow [3, 4] and evidence that blood flow in arterial grafts is inadequate in some circumstances [5, 6]. Vasospasm is also reported for the gastroepiploic artery [7] and radial artery [8]. It is the experience of many surgeons that GEA has a higher tendency to spasm than IMA [7]. Although it is used by some surgeons with success, the spastic characteristic of this artery makes others hesitate to use this artery more frequently as a coronary graft. Similarly, spasm of the radial artery may be a serious problem, together with a low patency rate related to this characteristic of the artery, that has led to the abandonment of this arterial graft at its early stage in the 1970s [8]. This arterial graft is recently reused only after gaining the knowledge of spastic characteristics and of how to overcome the spasm using pharmacologic methods [9]. Although the effect of some vasoconstrictors on arterial grafts have been reported [10–18], there is lack of an overview on this topic and the nature of the constrictor substances that cause arterial graft spasm needs to be determined.

In general, vasospasm could be the response of a vessel to many stimulants. These stimulants may be physical (such as mechanical stimulation or temperature changes) or pharmacologic (such as nerve stimulation or vasoconstrictor substances). Exogenous and endogenous vasoconstrictors are particularly important for vasoconstriction and its extreme form-vasospasm.

Important vasoconstrictor substances, which may be spasmogens for blood vessels, are (1) endothelium-derived contracting factors such as endothelin; (2) prostaglandins such as thromboxane A₂ (TxA₂) and prostaglandin F₂ (PGF₂); (3) circulating sympathomimetic substances (-adrenoceptor agonists) such as norepinephrine and synthetic ₁-adrenoceptor agonists (methoxamine or phenylephrine); (4) platelet-derived contracting substances such as 5-hydroxytryptamine (5-HT) and TxA₂; (5) substances released from mast cells and basophils such as histamine; (6) muscarinic receptor agonists such as acetylcholine; (7) renin-angiotensin system-related substances such as angiotensin II; and (8) a depolarizing agent such as potassium ion. These vasoconstrictors may also be important in the nature of vasoconstriction in arterial grafts.

The present study was designed to investigate the response of three major arterial grafts currently used for CABG to various vasoconstrictor substances with emphasis on the most commonly used one-IMA. These studies may reveal the nature of the vasospasm of the grafts.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Human GEA, IEA, and IMA segments were collected from patients undergoing CABG using these grafts. Approval to use discarded GEA, IEA, and IMA tissue was given by the Institutional Review Board. After the arterial grafts were dissected, the required length was carefully measured. Any discarded segments of IMA, GEA, or IEA were immediately collected and put into a container with oxygenated physiologic (Krebs) solution maintained at 4°C, and then transferred to laboratory. The vessels were placed in a glass dish and dissected out from their surrounding connective tissue. The arteries were cut into 3-mm-long rings and then suspended on wires in organ baths [19, 20]. The number of the rings provided by each patient varied from 2 to 6. The Krebs' solution had the following composition (in mmol/L): Na⁺ 144, K⁺ 5.9, Ca²⁺ 2.5, Mg²⁺ 1.2, Cl^- 128.7, HCO₃^- 25, SO₄^2- 1.2, H₂PO₄^- 1.2, and glucose 11. The solution was aerated with a gas mixture of 95% O₂–5% CO₂ at 37 ± 0.1°C.

Organ Bath Technique
An organ bath technique that allowed normalization of vascular rings to a physiologic condition in vitro was used to set the vascular rings at a pressure comparable to that at the in vivo situation. The details of the technique were published previously [19, 20]. Briefly, each arterial ring was stretched-up in progressive steps to determine the individual length–tension curve. A computer iterative fitting technique was used to determine the exponential line, pressure, and the internal diameter. When the transmural pressure on the rings reached 100 mm Hg, determined from their own length–tension curves, the stretch-up procedure was stopped and the rings were then released to 90% of their internal circumference at 100 mm Hg. This degree of the passive tension was then maintained throughout the experiment.

Because of the importance of endothelium on vascular tone, we intentionally preserved the endothelium by cautiously dissecting and mounting the rings. Previously, we found that this technique allowed the experiments be carried out with an intact endothelium as determined by the functional relaxation response to acetylcholine [19, 21]. In some rings, endothelium was purposely removed by mechanical methods as previously described to study the constricting effect in endothelium-denuded vessels.

Protocol
After the normalization procedure, the vascular rings were equilibrated for 45 minutes. The following protocols were designed for the experiments.

Diameters of the IEA, GEA, IMA at a pressure of 100 mm Hg (D100) and resting tensions at 0.9 D100 (optimal point of the length–tension curves) were recorded from the normalization procedure. Full concentration–contraction curves were established in a cumulative manner. Only one concentration–contraction curve was obtained in each vascular ring. The cumulative concentration–contraction curve was established for the following vasoconstrictor substances in IMA rings: endothelin-1; U46619, a stable thromboxane A₂ (TxA₂) mimetic; PGF₂, a prostaglandin mainly stimulating FP receptors; norepinephrine, a full adrenoceptor agonist; methoxamine (synthetic pure ₁-adrenoceptor agonist); phenylephrine (synthetic ₁-adrenoceptor agonists); 5-HT; and membrane depolarizing agent, potassium chloride (K⁺). Due to sparsity of the tissue, only four vasoconstrictors (endothelin-1, U46619, norepinephrine, and K⁺) were tested in the GEA and IEA.

Data Analysis
Each concentration–response curve to the constrictor agents was fitted to logistic equation, E = MA^P/(A^P + K^P), where E is response, M is maximum response, A is concentration, K is EC₅₀ concentration, and P is the slope parameter [22]. From this fitted equation, computer estimates were determined of concentrations that gave 10%, 30%, 50%, 70%, and 90% of the maximum response. These EC₁₀–EC₉₀ values and the maximum responses were averaged for a group of rings, and the standard error of the mean was calculated.

``Sensitivity'' is used throughout this article to describe the location of the concentration–contraction curve and is measured by the fitted EC<sub>50</sub> value. ``Reactivity (contractility)'' describes the range of responses and is measured as the maximum contraction [19].

Analysis of variance (and Scheffé's F test as post-hoc test) was used to compare the contraction force and EC₅₀ for vasoconstrictors in each artery. The p value of less than 0.05 was considered significant.

Drugs
Drugs used in this study and their resources were: (-)norepinephrine bitartrate; 5-HT, methoxamine, phenylephrine, and PGF₂ (Sigma, St. Louis, MO); U46619 (Cayman Chemical); endothelin-1 (Peptides International, Louisville, KY). Stock solution of norepinephrine was freshly made each day. Stock solution of endothelin-1, U46619, and PGF₂ was held frozen until required.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The number of vascular rings studied were: 213 for IMA, 23 for IEA, and 27 for GEA. Table 1 gives the maximal contraction force and the EC₅₀ values to a number of vasoconstrictors tested in the IMA. There was a significant difference among the eight vasoconstrictors regarding the maximal contraction force (p < 0.0001, analysis of variance). Endothelin-1, U46619, and PGF₂ induced the highest contraction force and there was no significant difference between each of them (Fig 1). However, endothelin-1 induced a significantly higher contraction force than 5-HT (4.43 ± 0.4 g versus 1.89 ± 0.27 g, p < 0.05, Scheffé's F test). U46619-induced contraction force (5.69 ± 0.48 g) was significantly higher than that induced by norepinephrine (3.05 ± 0.29 g, p < 0.01), 5-HT (p < 0.0001), and methoxamine (p < 0.05). Similarly, PGF₂ and K⁺ evoked a significantly higher contraction force (6.29 ± 1.42 g for PGF₂ and 4.58 ± 0.5 g for K⁺) than that evoked by 5-HT (p < 0.01, Scheffé's F test for all comparisons between two groups). In regard to sensitivity, there was a significant difference (p < 0.05, analysis of variance) among the seven vasoconstrictors (K⁺ was excluded because the concentrations were extremely high compared to others and the difference is obvious) (see Table 1, Fig 1). The IMA is highly sensitive to endothelin-1 (EC₅₀, -8.13 ± 0.08 log M) and U46619 (EC₅₀, -8.21 ± 0.21 log M). The EC₅₀ for these two vasoconstrictors was significantly lower than any other vasoconstrictor (p < 0.001 for all comparisons, Scheffé's F test). Next sensitive vasoconstrictors were PGF₂ (EC₅₀, -6.42 ± 0.13 log M) and norepinephrine (EC₅₀, -6.04 ± 0.07 log M). These EC₅₀ were significantly lower than that for 5-HT or methoxamine (p < 0.01, Scheffé's F test). In 12 IMA rings, 5-HT evoked only minimum contraction (<0.5 g force). All these rings subsequently contracted to K⁺ to a contracting force comparable to other rings. In the IMA rings without endothelium, this was never observed. A comparison in all IMA rings taken from the same (distal) section revealed that there was a significant difference regarding the maximal contraction force between the IMA with and without endothelium (1.4 ± 0.23 g versus 2.8 ± 0.64 g, p < 0.05, Fig 2a). Similar trends were also seen in norepinephrine-contracted IMA rings (Fig 2b). However, the difference between IMA with or without endothelium did not reach statistical significance (p = 0.3), although the IMA without endothelium was more sensitive to norepinephrine (EC₅₀, -6.04 ± 0.07 versus -6.72 ± 0.29 log M, p < 0.01) (see Fig 2b).

View larger version (15K): [in this window] [in a new window]   Fig 1. . Mean concentration (-log M)-contraction (force, g) curves for vasoconstrictor substances in the internal mammary artery. Symbols represent data averaged from a group of rings (see Table 1 for the number of the rings). Vertical bars are 1 standard error of the mean. (ET = endothelin-1; 5-HT = 5-hydroxytryptamine; K = potassium; MO = methoxamine; NE = norepinephrine; PE = phenylephrine; PGF2 = prostaglandin F2.)

View larger version (19K): [in this window] [in a new window]   Fig 2. . Mean concentration (-log M)-contraction (force, g) curves for 5-hydroxytryptamine (5-HT) (a) and norepinephrine (b) in the internal mammary artery. Symbols represent data averaged from a group of internal mammary artery rings. Vertical bars are 1 standard error of the mean. (+E = with endothelium; -E = without endothelium.)

View larger version (19K): [in this window] [in a new window]   Fig 3. . Mean concentration (-log M)-contraction (force, g) curves for vasoconstrictor substances in the gastroepiploic artery. Symbols represent data averaged from six rings for NE and seven for other constrictors. Vertical bars are 1 standard error of the mean. (ET = endothelin-1; K = potassium; NE = norepinephrine.)

View larger version (19K): [in this window] [in a new window]   Fig 4. . Mean concentration (-log M)-contraction (force, g) curves for vasoconstrictor substances in the inferior epigastric artery. Symbols represent data averaged from five rings for NE and six for other constrictors. Vertical bars are 1 standard error of the mean. (ET = endothelin-1; K = potassium; NE = norepinephrine.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

2

In the present study, we established full concentration–contraction curves to the vasoconstrictor substances tested. Although the clinically relevant concentrations for these vasoconstrictors vary from one to another, these concentrations are included in the full concentration–contraction studies. For example, during cardiopulmonary bypass, the TxB₂ (a stable metabolite of TxA₂) level is 1.22 ± 0.62 ng/mL [23], which is fivefold higher than the control. This level translates to -8.48 to -8.35 log M, which would evoke 20% to 30% of the maximal contraction in the human IMA, according to our experimental results.

Endothelin has been proposed as the most potent vasoconstrictor known [24] and is one of the endothelium-derived contracting factors (EDCF). Elevated plasma level has been measured after cardiopulmonary bypass [25]. The present study has demonstrated that endothelin-1 is a potent and strong vasoconstrictor in all the arterial grafts investigated. Therefore, this vasoconstrictor may have a pathogenic significance in vasospasm related to coronary artery bypass grafts. However, the present study has failed to demonstrate that endothelin-1 is a more potent vasoconstrictor than U46619 in the human coronary artery bypass grafts, because this vasoconstrictor did not evoke higher contraction force, nor was the sensitivity to it higher (lower EC₅₀) compared to U46619 in the arteries tested in our experiments using fairly large number of vascular segments (29 IMA rings for endothelin-1 and 38 IMA rings for U46619; Table 1).

Thromboxane A₂ is also considered as one of the EDCFs [26] and it can also be derived from platelets. As mentioned above, elevated plasma level of TxA₂ during cardiopulmonary bypass has been found [23]. Due to increased plasma concentrations of TxA₂ during cardiopulmonary bypass, this vasoconstrictor may be highly suspected as a spasmogen for arterial grafts. In our experiments, the TxA₂ mimetic U46619 evoked a high contraction force in all three arterial grafts, which had no difference compared to endothelin-1-induced contraction, and TxA₂ was as potent as endothelin-1 in these arteries. These experiments stress that the TP receptor is one of the most important receptors mediating contraction in human coronary artery bypass grafts.

Other vasoconstrictors tested in the present study were PGF₂, norepinephrine, methoxamine, phenylephrine, 5-HT, and K⁺. This study has demonstrated that, similar to endothelin-1 and TxA₂, PGF₂ is a strong vasoconstrictor for the human IMA. Prostaglandin F₂ has been suggested to contract smooth muscle through the FP receptor [27], which is one of the subtypes of prostanoid receptors. In our study, this prostaglandin strongly contracted the artery and produced 6.29 ± 1.42 g force. However, this prostaglandin is not as potent as endothelin-1 or TxA₂. This can be reflected by a significantly higher EC₅₀ value for this vasoconstrictor than for endothelin-1 or TxA₂ in the IMA. Indeed, the EC₅₀ is 51.5-fold higher for PGF₂ compared with endothelin-1 (p < 0.001) and 61.7-fold higher than for U46619 (p < 0.001). This may suggest that PGF₂ is a strong but less potent vasoconstrictor for the human IMA. Another suggestion from this result is that the FP receptor may be less potent compared with TP receptors in this artery.

It has been well known that vascular endothelium plays an important role in maintaining vascular tone. Endothelium derives a number of vasoconstrictor as well as vasodilator substances. Vascular tone is maintained on the balance between vasoconstriction and vasodilatation caused by these substances. In addition, most vasoconstrictors have been demonstrated as being vasorelaxant agents through the mechanism of EDRF (NO). Recently, we have proposed a hypothesis that all the naturally secreted vasoconstrictors are also potential vasodilators as well through the mechanism of EDRF (NO) or EDRFs [28]. However, some vasoconstrictors are vasoconstriction predominant (type I). These substances contract blood vessels even when endothelium is present because they have a weak stimulating effect on EDRF (NO) or EDRFs. In contrast, other vasoconstrictors may have balanced effects (type II). These substances have a strong stimulating effect on the biosynthesis/release of EDRF (NO) or EDRFs. Therefore, when endothelium is present, they stimulate vasoconstriction concomitantly through the direct contraction effect on smooth muscle and vasodilatation through the biosynthesis/release of EDRF (NO) [29] or EDRFs. Therefore, in endothelium-intact blood vessels, these vasoconstrictors do not strongly contract the vessels. However, when endothelium is damaged or denuded, they evoke a strong contraction because of loss of the endothelium, which leads to an imbalance between vasoconstriction, induced by its direct contraction on smooth muscle, and vasodilatation, induced by EDRF (NO) or EDRFs release due to its stimulation to endothelium.

Another particularly important aspect is that many vasoconstrictor substances are released from platelets. Because EDRF (NO) also inhibits platelet aggregation, these vasoconstrictors have particularly important pathologic significance. 5-Hydroxytryptamine is an example of these vasoconstrictors. 5-Hydroxytryptamine contracts vascular smooth muscle directly through 5-HT₂ receptors [30] and relaxes blood vessels through EDRF (NO) mechanism, which is mediated by 5-HT_1D receptors [31] located in endothelium. When endothelium is lost, perhaps also when it is damaged, platelets aggregate in the area where endothelium is denuded and release substances such as 5-HT (also TxA₂) that strongly contract smooth muscle. We have demonstrated, in the present study, that 5-HT plays such a role in the human IMA. 5-Hydroxytryptamine has been suggested to be an important spasmogen in coronary spasm even when endothelium is present [32]. In our experiments, 5-HT does not strongly contract the IMA with intact endothelium. However, its constricting effect is unmasked when endothelium is denuded (see Fig 2a). Although we have not done this in other arterial conduits, because of the sparsity of the tissue, similar effects of 5-HT has been demonstrated in our previous study in porcine coronary arteries [28] and in studies by others in canine coronary arteries [30]. In fact, others [18] have demonstrated similar response of 5-HT in GEA.

In regard to norepinephrine, this vasoconstrictor contracts all the arterial grafts tested in the present study. Norepinephrine is a full adrenoceptor agonist. It stimulates both - and ß-adrenoceptors. As far as -adrenoceptors are concerned, this vasoconstrictor stimulates ₁-, possibly ₂-, as well in the smooth muscle to contract the vessel. On the other hand, norepinephrine relaxes vessels through two mechanisms. First, it stimulates ß-adrenoceptors located in the smooth muscle that directly mediates smooth muscle relaxation; second, it stimulates ₂-adrenoceptors located in endothelium to release EDRF (NO) [30], which causes smooth muscle relaxation. Because the human IMA is an artery with weak ß-adrenoceptor function [20], the direct action of this vasoconstrictor on smooth muscle is contraction. As previously demonstrated [21, 33], ₂-adrenoceptor agonists such as UK14304 and clonidine only evoked a tiny contraction force. However, release of EDRF (NO) (through stimulating ₂-adrenoceptors located in endothelium) may only play a minor role in the human IMA because norepinephrine evoked a slightly stronger contraction in this artery when the endothelium is denuded as shown in the Figure 2b. This effect is less significant compared with 5-HT-induced contraction. Others have demonstrated that there was no evidence of existence of endothelial ₂-adrenoceptors mediating relaxation in IMA [34]. From the similar reaction of IEA and GEA to norepinephrine, we suspect that these two arteries are also -adrenoceptor predominant and may also have weak function of ß-adrenoceptors. These results also suggest that the depression effect of endothelium on norepinephrine-induced contraction in GEA and IEA may be limited. Even in endothelium-intact arteries, this vasoconstrictor causes significant contraction. In fact, in 42 IMA rings, norepinephrine induced 3.05 ± 0.29 g force. However, the sensitivity of this vasoconstrictor is lower than either endothelin-1 (p < 0.0001) or U46619 (p < 0.0001).

Other synthetic -adrenoceptor agonists such as methoxamine and phenylephrine also induced contraction in the IMA. These vasoconstrictors are either pure ₁-adrenoceptor (methoxamine) or ₁-function predominant (phenylephrine) agonist and therefore, they do not stimulate EDRF (NO) release because they do not stimulate the ₂-adrenoceptor, which is the receptor mediating EDRF (NO) release. In a previous study [35], we have found that, in the human IMA, norepinephrine evoked a higher contraction force than phenylephrine and we suspected that the difference was due to possible role of ₂-adrenoceptor function. Because we have found in subsequent studies [21, 36] that the human IMA has little ₂-function we investigated in this study whether there is a difference in the contraction force between full -adrenoceptor agonists and ₁-adrenoceptor agonists. The study used a larger amount of samples (42 IMA rings for norepinephrine, 14 for methoxamine, and 13 for phenylephrine) and the results show that there was no significant difference among those agonists as far as the maximal contraction force is concerned. This demonstrates that all the ₁-adrenoceptor agonists may maximally stimulate the ₁-adrenoceptors in this artery. However, the sensitivity of norepinephrine is 19.5-fold higher than methoxamine (p < 0.0001), which reflects a different potency of these ₁-agonists.

In addition, the cellular membrane depolarizing agent-potassium ion-was also used to study contractility. The potassium-induced contraction in all the arterial grafts is expected as potassium depolarizes smooth muscle membrane to open the voltage-operated calcium channel that allows calcium influx, which eventually increases intracellular calcium concentration and contracts the smooth muscle cell.

In brief, the complex effects of vasoconstrictors on vascular tone and the possible receptors that mediate the action are outlined in Figure 5. This diagram describes the balance between vasoconstriction and vasodilatation. In general, most pharmacologic spasmogens have two opposite effects on blood vessels. On the one hand, these vasoconstrictors directly stimulate corresponding receptors located on the cellular membrane of smooth muscle and, through various mechanisms (either the opening of calcium channels or the release of intracellularly stored calcium), increase intracellular calcium concentration, which ultimately causes contraction of the smooth muscle cell. Those receptors are briefly illustrated. On the other hand, simultaneously, naturally secreted vasoconstrictors stimulate receptors located on the cellular membrane of endothelium and, through receptor–effector coupling mechanisms, cause an increase of the intracellular calcium concentration that, as second messenger, mediates the release of a number of EDRFs. Three such factors have been found. These are nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor. These EDRFs, through different mechanisms, reduce the intracellular calcium concentration in the smooth muscle cell and cause relaxation of the muscle. Vascular tone depends on the balance between these two actions-direct effect of contraction of the smooth muscle cells and indirect effect of relaxation through the release of EDRFs from the endothelial cells. Some vasoconstrictors (such as endothelin-1, U46619, PGF₂, and -adrenoceptor agonists) predominantly contract smooth muscle and have a weak stimulating effect on the release of EDRFs, whereas others such as 5-HT have a strong EDRF-stimulating effect that significantly depresses the contraction when endothelium is present. In addition, spontaneous (basal) release of EDRF (NO) from endothelium generally depresses the vasoconstrictor-induced contraction to some extent. Apart from receptor mechanisms, shear stress is another stimulant for EDRF (NO) release.

View larger version (45K): [in this window] [in a new window]   Fig 5. . Schematic diagram describing the balance between vasoconstriction and vasodilatation. Pharmacologic spasmogens directly stimulate corresponding receptors located on the cellular membrane of smooth muscle and increase intracellular calcium concentration, which ultimately causes contraction of the smooth muscle. Simultaneously, naturally secreted vasoconstrictors stimulate receptors located on the cellular membrane of endothelium and cause increase of the intracellular calcium concentration that, as second messenger, mediates release of a number of endothelium-derived relaxing factors (nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor), which through different mechanisms reduce the intracellular calcium concentration in the smooth muscle cell and cause relaxation. Spontaneous (basal) release of EDRF (NO) also depresses the contraction to some extent. (1 = 1-adrenoceptors; 2 = 2-adrenoceptors; AII = angiotensin II receptors; ACh = acetylcholine; ATII = angiotensin II; Ca2+ = intracellular calcium; EDHF = endothelium-derived hyperpolarizing factor; EDRF = endothelium-derived relaxing factor; ET = endothelin; FP = PGF2a receptors; H (H2) = histamine receptors; His = histamine; K = potassium; M(M2) = muscarinic receptors; MO = methoxamine; NE = norepinephrine; NO = nitric oxide; PE = phenylephrine; PGI2 = prostacyclin; S1D = 5-HT1D receptors; S2 = 5-HT2 receptors; TP = thromboxane-prostanoid receptors; VOC = voltage-operated channels.)

2

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was supported by the St. Vincent Medical Foundation, Portland, Oregon.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr He, Cardiovascular Research, The Albert Starr Academic Center for Cardiac Surgery, St. Vincent Heart Institute, 9155, Barnes Rd, Suite 240, Portland, OR 97225.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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