**3. Pharmacology of internal mammary artery**

Vasoconstriction may be evoked by various stimuli such as vasoconstrictor substances, nerve stimulation and mechanical trauma. Clinically, although all arterial grafts may develop vasospasm, it develops less frequently in IMA and IEA than in GEA and RA [7,27]. Compa‐ rative functional studies have demonstrated that there are differences in arterial grafts with regard to contractility and endothelial function. These differences, together with histological and anatomical diversity, may account for possible differences in the perioperative spasm.

As stated above, vasodilator agents are usually studied by precontracting the vessel. The level of precontraction force should be chosen in the range of 60% to 80% of the maximum contrac‐ tion of that agent. The precontractile tone should reach to a plateau and remain stable during the experimental period. The precontraction may dissipate in a time-dependent manner. This may lead researcher to ascribe decreased tone due to added drug instead of spontenaous relaxation. Therefore, a parallel time control is necessary to show that the precontraction is

It has been well known that vascular endothelium plays an important role in maintain‐ ing vascular tone. Endothelium derives a number of vasoconstrictor as well as vasodila‐ tor substances. Vascular tone is maintained on the balance between vasoconstriction and vasodilatation caused by these substances. Endothelial cell produces endothelium- de‐ rived contracting factors (EDCFs) such as endothelin (ET) and thromboxane A2 (TxA2) that cause an increase in the intracellular calcium concentration and mediate contraction of the smooth muscle. Endothelium-dependent relaxation is known to be the effect of a variety of different endothelium-derived relaxing factors (EDRFs). These are endotheli‐ um-derived nitric oxide (NO) [19,20], prostacyclin (PGI2) [21], and endothelium-derived hyperpolarizing factor (EDHF) [22-25]. These relaxing factors induce vasodilatation through different mechanisms by reducing 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. As in other vessels, endothelium plays a modu‐ latory role in contractility in CABGs [26]. Studies on endothelial function of CABGs have indicated that arterial endothelium has more ability to produce NO than venous endothe‐

Endothelin, prostanoids (TxA2 and PGF2α) and α1-adrenoceptor agonists are the most potent vasoconstrictors and they strongly contract arterial grafts even when endothelium is intact. On the other hand, some vasoconstrictors, i.e. serotonin (Serotonin (5-hydroxytryptamine, 5- HT)), have been demonstrated as being vasorelaxant agents through the mechanism of EDRF (NO). They induce contraction by their direct contractile effect on smooth muscle, and vasodilatation, induced by EDRF (NO) or EDRFs release due to its stimulation to endothelium. Therefore, these vasoconstrictors do not strongly contract the vessels in endothelium-intact blood vessels. However, when endothelium is damaged or denuded, they evoke a strong

Vasoconstriction may be evoked by various stimuli such as vasoconstrictor substances, nerve stimulation and mechanical trauma. Clinically, although all arterial grafts may develop vasospasm, it develops less frequently in IMA and IEA than in GEA and RA [7,27]. Compa‐ rative functional studies have demonstrated that there are differences in arterial grafts with

**2.2. Influence of endothelial functions on contractility of arterial grafts**

lium (11-13, 26). EDHF also plays a role in arterial grafts [17].

**3. Pharmacology of internal mammary artery**

stable [11,17,18].

256 Artery Bypass

contraction.

The contractility of IMA to vasoconstrictors has been studied extensively [10,13]. TxA2 is one of the several EDCFs, but it is also derived from platelets. Endothelin is also considered as one of the EDCFs. These two substances are two of the most potent vasoconstrictors known and they are very potent in IMA as well. Elevated plasma concentrations of ET [28] or TXA2 [29] have been found during cardiopulmonary bypass. Therefore,.these vasoconstrictors are prime candidates as spasmogens for arterial grafts during CABG surgery.

Some receptors on the smooth muscle of IMA have been characterized. For example, IMA is an α1-adrenoceptor-dominant artery with little α2- or β -function [30,31]. Other receptors functionally demonstrated in IMA are ETA, ETB [32], 5-HT [33], angiotensin [34],TP (throm‐ boxane-prostanoid) [35], vasopressin V1 receptors [36,37], and vasoactive intestinal peptide [38] receptors. Dopaminergic receptors have also been demonstrated in the IMA [39]. The agonists for these receptors may also be spasmogenic agents for the IMA.

As stated above, some vasoconstrictors have been demonstrated as being vasorelaxant agents. 5-HT is an example of this type of vasoconstrictors and it directly contracts vas‐ cular smooth muscle through 5-HT2 receptors [40] and relaxes blood vessels through en‐ dothelial NO release, mediated by 5-HT1D receptors, [41] located in the 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. Accordingly, studies have shown 5-HT does not strongly contract IMA with intact endothelium [13,42]. However, its contracting effect is unmasked when endothelium is denuded [13,42].

The endothelium-dependent relaxation exists in IMA [43]. It has also been demonstrated that vascular endothelial growth factor may induce endothelium-dependent relaxation in the human IMA [44]; the relaxation has recently been demonstrated to be mediated by both NO and PGI2 [45]. Further, physiological substances such as CRF induce both endo‐ thelium-dependent and -independent relaxation in the human IMA [46]. IMA releases both NO and EDHF [47]. Recent studies have demonstrated that the endothelium of the IMA releases more NO than the RA at both basal and stimulated levels [47]. Further, the IMA has a greater hyperpolarizing effect on bradykinin-stimulated release of EDHF than the RA does [47].

In addition, receptors, for common stimuli of EDRF such as acetylcholine, bradykinin, and substance P are present in the endothelium of arterial grafts [15,48,49]. The vascular endothelial growth factor (VEGF)-induced, endothelium- dependent relaxation, mediated by both NO and prostacyclin in the IMA, has been shown mainly through the KDR (kinase insert domain) receptors, rather than Flt-1 (fms-like thyrosine kinase-1) receptors [45]. Most recently, corti‐ cortropin-releasing factor (CRF) receptors CRF1, CRF2α, and CRF2β have been shown to be present in the IMA [45]. The CRF urocortin- induced endothelium-dependent relaxation in the IMA is likely through CRF receptors allocated in the endothelium of the IMA [50].

#### **3.1. Spasm of internal mammary artery**

Compared to saphenous grafts, IMA is more resistant to ischaemic changes due to high content of elastin with a low metabolic rate. Occasionally, there is severe contraction (spasm), which may be visible or be inferred by minimal free flow. Spasm of IMA can cause inadequate blood flow, which may be detrimental during periods of increased nutritional demand such as weaning from cardiopulmonary bypass [51] or postoperative hypovolemia [52]. In addition, IMAs with poor perioperative flow rates are more likely to occlude [53]. Severe spasm may lead to graft malfunction and even mortality [11,54]. It is essential to to determine whether the IMA should be discarded or alternatively relegated to graft a minor vessel. Thus, a dilator drug, preferably a fast-acting one suitable for intraluminal injection, should be used for maximal pharmacologic dilation of the IMA, which allows the surgeon to evaluate the flowcarrying capacity of the IMA and provides a relaxed, dilated distal vessel that facilitates a precise anastomosis. Vasodilation of the IMA pedicle during CABG surgery may also unmask small bleeding points, improve hemostasis and facilitate placement of anastomotic sutures [9]. **3.2. Effect of vasodilator substances on IMA**

tive but it is not recommended for systemic use.

adrenoceptors, or ET receptors) or depolarizing agent (K+

**Nitrovasodilators**

**Papaverine**

[9,55,56,58,59]. The vasodilator substances available are as follows:

To promote dilation of the IMA, some vasodilating substances have been applied to the outside of the pedicle [55-58] or injected intraluminally with or without hydrostatic dilation

Pharmacology of Arterial Grafts for Coronary Artery Bypass Surgery

http://dx.doi.org/10.5772/54723

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The traditional topical vasodilator papaverine was first recommended by George Green, the pioneer IMA surgeon, in early days of IMA grafting to overcome spasm [60]. It is still widely used due to its satisfactory vasorelaxant effect in arterial grafts [61,62]. Papa‐ verine is a non specific vasodilator substance which relaxes vessels via multiple mecha‐ nisms such as inhibition of phosphodiesterase [63], which increases cyclic guanosine monophosphate (cGMP) level in smooth muscle cells, decreasing calcium influx [64,65] or inhibition of release of intracellularly stored calcium [66]. Although hydrostatic dilation with papaverine dissolved in saline solution provides good dilation at high concentra‐ tions, it carries a potential risk of mechanical damage to the media and intima caused by cannulation and overstretching and by chemical damage as a result of the acidity of the solution [67-70]. The problem of acidity of papaverine solutions may be overcome by mixing the solutions with blood or albumin before its use [71]. However, the pharmaco‐ logical action is uncertain in such a mixture. Additionally, papaverine has a slower onset of the vasodilating effect when compared to other vasodilators such as nitroglycerin (NTG) and verapamil [10,62,72]. However, once its effect reaches a plateau, it is sus‐ tained [10,62,72]. Papaverine hydrochloride is relatively unstable in non-acidic solutions and a white precipitate is sometimes formed when papaverine is added to the plasma‐ lyte solution (pH approximately 7.4) [73]. In light of these points, papaverine is still an effective vasodilator for IMA. Its topical spray on the adventitia of the IMA may be effec‐

Nitrovasodilators (organic nitrates), NTG, glyceryl trinitrate (GTN) and sodium nitroprusside (SNP), are a diverse group of pharmacological agents that produce vascular relaxation by releasing NO, which activates guanylate cyclase, resulting in an accumulation of cyclic GMP in the smooth muscle cell. This in turn reduces intracellular calcium concentrations and leads to vasodilatation. These drugs are effective against a range of constrictor stimuli and they are widely used in CABG patients. Nitrovasodilators have been shown to be potent vasodilators in the human IMA [55,61,74-79]. It has been demonstrated that NTG is compares favorably with diltiazem in the prevention of IMA spasm [80] and it is effective for either topical, intraluminal, or systemic use [78,81,82]. Although, nitrates are slightly more effective in blocking receptor operated channels, they are effective in treating established vascular spasm, regardless of the nature of contraction, i.e., either receptor mediated (TxA2 receptors, α-

However, rapid tolerance (tachyphylaxis) of vessels develops to nitrovasodilators. Therefore, they are less potent in the prevention of vasospasm [54,74,75,83]. NTG is more potent in its

)- mediated contraction [10,54].

Vasoconstriction (or spasm) of IMA may be caused by multiple mechanisms. In addition, vasodilators relax vascular smooth muscle through a specific mechanism or mechanisms. Several vasodilators have been suggested to prevent graft spasm; including papaverine, phenoxybenzamine, calcium antagonists and nitrates. However, there is no "perfect" vasodi‐ lator which is effective for every situation.

**Figure 2.** Endothelium-derived relaxing factor (EDRF) is produced and released by the endothelium to promote smooth muscle relaxation. NO, nitric oxide; AII, angiotensin II receptors; ACh, acetylcholine; EDHF, endothelium-de‐ rived hyperpolarizing factor; ET, endothelin; FP, PGF2α receptors; H (H2), histamine receptors; His, histamine; K, potassi‐ um; M (M2), muscarinic receptors; NE, norepinephrine; PE, phenylephrine; PGI2, prostacyclin; 5-HT, 5 hydroxytryptamine (serotonin); TP, thromboxane-prostanoid receptors; VOC, voltage operated channels; α, adrenergic receptors
