**3.2. Effect of vasodilator substances on IMA**

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

#### **Papaverine**

**3.1. Spasm of internal mammary artery**

258 Artery Bypass

lator which is effective for every situation.

receptors

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].

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‐

**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

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‐ tive but it is not recommended for systemic use.

#### **Nitrovasodilators**

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, αadrenoceptors, or ET receptors) or depolarizing agent (K+ )- mediated contraction [10,54]. 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 vasorelaxing effect when it is compared to SNP. However, SNP is more effective in inhibition ANGII and α-adrenoceptor-mediated contraction in the IMA [34].

The degree of vasodilatory effect of calcium antagonists is dependent on the nature of contraction. Calcium antagonists are less effective in blocking receptor-operated than voltage-

and intracellular [Ca2+] to rise, resulting in smooth muscle contraction. Therefore, a VOCC

hand, the contraction caused by receptor agonists is partly caused by calcium influx and partly caused by calcium release from intracellular sources. Consequently, calcium antagonists are weak in either preventing or treating TxA2, α-adrenoceptor, or VP<sup>1</sup> receptor-mediated

Drugs that open potassium channels (potassium channel openers, KCOs) can exert antivaso‐ constrictor and vasorelaxant actions, that is, they reduce or prevent cellular response ro excitatory stimuli, repolarize or hyperpolarize the cell membrane, overcome a contraction once it has developed, and strengten the resting state of the vessel. KCOs are considered to comprise a heterogeneous group of organic compounds [94]. These are apricalim, bimakalim, celikalim, cromakalim, levokromakalim, diazoxide, L-27,152, P 1075, minoxidil sulphate, pinacidil, and nicorandil. KCOs act by stimulating ion flux through a distinct class of potassium channels which are inhibited by intracellular adenosine triphosphate (ATP) and activated by intracel‐ lular nucleoside diphosphates. They restrain the opening probability of voltage-dependent Land T-type calcium-channels and decrease agonist-induced Ca2+ release from intracellular sources through inhibition of inositol trisphosphate (IP3) formation, and lower the efficiency of calcium as an activator of contractile proteins [95]. Additionally, they may accelerate

outcome of these effects is to reduce the membrane excitability and to drive vascular myocytes into a relaxed state. Particularly, vascular smooth muscle is sensitive to KCOs [96-99]. In view of these points, KCOs are of great value as therapeutic agents [98,99,] and aprikalim [100,102] have been studied in the human IMA and found to be potent vasodilators in a number of receptor-mediated contractions. Therefore, this group of drugs may become clinically useful

IMA is an α1-adrenoceptor-dominant artery with little α2- or β -function [30,31,103]. Theoret‐ ically, a selective α -receptor antagonist may be a highly effective antispastic agent because the site of interaction is same. Herewith, the use of α-adrenoceptor antagonists such as phenoxy‐ benzamine as an antispastic agent has a rationale. However, the nature of vasoconstriction is complex and may involve many other vasoconstrictors (Table 1). It has been demonstrated that, α- adrenoceptor antagonists are not effective in reversing the contraction evoked by other vasoconstrictors such as vasopressin, angiotensin II, endothelin-1, and KCl [104]. From pharmacological point of view, use of phenoxybenzamine is inappropriate as the sole anti‐ spastic agent in the arterial grafts. Moreover, a novel α1-adrenergic receptor blocking substance with calcium antagonist with activity, AJ-2615, has been studied with regard to inhibition of


antagonist such as nifedipine would readily relax a tissue precontracted by K+

depolarizes smooth muscle

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

. On the other

261

channels. This effect allows VOCC to open

Pharmacology of Arterial Grafts for Coronary Artery Bypass Surgery

/Ca2+ exchange pathway [95]. The functional

operated calcium channels. For example, increased extracellular K+

membrane by closing of the hyperpolarizing K+

**) channel openers**

clearance of intracellular free calcium via the Na+

antispastic agents by their relaxing action on IMA.

**α-Adrenoceptor antagonists**

contraction, in comparison to K+

**Potassium (K+**

#### **Phosphodiesterase inhibitors**

Phosphodiesterases (PDE) are a diverse family of enzymes that hydrolyse cyclic nucleotides and thus play a key role in regulating intracellular levels of the second messengers cyclic adenosine monophosphate (cAMP) and cGMP which modulate vascular smooth muscle tone. Concentrations of cAMP and cGMP are controlled through synthesis by cyclases and through hydrolysis by PDEs. Non-selective PDE inhibitors including papaverine have been injected routinely by surgeons, in and around the artery to prevent IMA spasm, but papaverine is not administered systemically. The discovery of eleven types of PDEs [84,85] provides an impetus for the development of isoenzyme selective inhibitors for the treatment of various diseases. Inamirinone (previously called amrirone) and milrinone are bipyridine compounds that inhibit phosphodiesterase (PDE) III, a form found in cardiac and smooth muscle. Therefore, they increase myocardial contractility and vasodilation, and they are called as 'inodilators'. These drugs are useful in postoperative management of patients who undergo open heart surgery, particularly in patients who present ventricular dysfunction and receive arterial grafts for coronary artery bypass surgery. Favorable effects of inamrinone on the IMA [76,86-88] have been reported. In addition, it has been demonstrated that inamrinone has a greater than additive vasodilatory effect when used in combination with NTG [76]. It was also demon‐ strated that systemically administered milrinone and nitroglycerin dilate the IMA after cardiopulmonary bypass [82]. Levosimendan is a new agent developed for the treatment of acute and decompensated heart failure. It exerts potent positive inotropic action and peripheral vasodilatory effects. The mechanism of vasodilation by levosimendan may involve reduction of Ca2+ sensitivity of contractile proteins in vascular smooth muscle, the lowering of intracel‐ lular free Ca2+, the potential inhibition of PDE III, and an opening of K+ channels [89,90]. We have recently shown that levosimendan effectively and directly decreases the tone of IMA [91]. Therefore, levosimendan may be a cardiovascular protective agent by its relaxing action on IMA.

#### **Calcium antagonists**

It has been known since the late 1800s that calcium influx was necessary for he contraction of smooth and cardiac muscle. The discovery of calcium channel in smooth and cardiac muscle was followed by the finding of several different types calcium channels including VOCC (L, T, N and P types) and receptor -operated calcium channels, (ROCC). The discovery of these channels made possible the development of clinically useful new generation calcium antago‐ nists (calcium channel blockers). These drugs are consist of three chemically divergent groups: Dihydropyridine (nifedipine, etc.), phenylalkylamines (verapamil, etc.), and benzothiazepines (diltiazem, etc.). Important differences in vascular selectivity exist among the calcium antag‐ onists. In general, nifedipin is the most potent. In addidion, verapamil is more potent than diltiazem. It has been demonstrated that nifedipine is more potent than diltiazem with regard to the vasorelaxant effect in the human IMA [54].

The degree of vasodilatory effect of calcium antagonists is dependent on the nature of contraction. Calcium antagonists are less effective in blocking receptor-operated than voltageoperated calcium channels. For example, increased extracellular K+ depolarizes smooth muscle membrane by closing of the hyperpolarizing K+ channels. This effect allows VOCC to open and intracellular [Ca2+] to rise, resulting in smooth muscle contraction. Therefore, a VOCC antagonist such as nifedipine would readily relax a tissue precontracted by K+ . On the other hand, the contraction caused by receptor agonists is partly caused by calcium influx and partly caused by calcium release from intracellular sources. Consequently, calcium antagonists are weak in either preventing or treating TxA2, α-adrenoceptor, or VP<sup>1</sup> receptor-mediated contraction, in comparison to K+ -mediated contraction [54,74,92,93].

#### **Potassium (K+ ) channel openers**

vasorelaxing effect when it is compared to SNP. However, SNP is more effective in inhibition

Phosphodiesterases (PDE) are a diverse family of enzymes that hydrolyse cyclic nucleotides and thus play a key role in regulating intracellular levels of the second messengers cyclic adenosine monophosphate (cAMP) and cGMP which modulate vascular smooth muscle tone. Concentrations of cAMP and cGMP are controlled through synthesis by cyclases and through hydrolysis by PDEs. Non-selective PDE inhibitors including papaverine have been injected routinely by surgeons, in and around the artery to prevent IMA spasm, but papaverine is not administered systemically. The discovery of eleven types of PDEs [84,85] provides an impetus for the development of isoenzyme selective inhibitors for the treatment of various diseases. Inamirinone (previously called amrirone) and milrinone are bipyridine compounds that inhibit phosphodiesterase (PDE) III, a form found in cardiac and smooth muscle. Therefore, they increase myocardial contractility and vasodilation, and they are called as 'inodilators'. These drugs are useful in postoperative management of patients who undergo open heart surgery, particularly in patients who present ventricular dysfunction and receive arterial grafts for coronary artery bypass surgery. Favorable effects of inamrinone on the IMA [76,86-88] have been reported. In addition, it has been demonstrated that inamrinone has a greater than additive vasodilatory effect when used in combination with NTG [76]. It was also demon‐ strated that systemically administered milrinone and nitroglycerin dilate the IMA after cardiopulmonary bypass [82]. Levosimendan is a new agent developed for the treatment of acute and decompensated heart failure. It exerts potent positive inotropic action and peripheral vasodilatory effects. The mechanism of vasodilation by levosimendan may involve reduction of Ca2+ sensitivity of contractile proteins in vascular smooth muscle, the lowering of intracel‐

ANGII and α-adrenoceptor-mediated contraction in the IMA [34].

lular free Ca2+, the potential inhibition of PDE III, and an opening of K+

have recently shown that levosimendan effectively and directly decreases the tone of IMA [91]. Therefore, levosimendan may be a cardiovascular protective agent by its relaxing action on

It has been known since the late 1800s that calcium influx was necessary for he contraction of smooth and cardiac muscle. The discovery of calcium channel in smooth and cardiac muscle was followed by the finding of several different types calcium channels including VOCC (L, T, N and P types) and receptor -operated calcium channels, (ROCC). The discovery of these channels made possible the development of clinically useful new generation calcium antago‐ nists (calcium channel blockers). These drugs are consist of three chemically divergent groups: Dihydropyridine (nifedipine, etc.), phenylalkylamines (verapamil, etc.), and benzothiazepines (diltiazem, etc.). Important differences in vascular selectivity exist among the calcium antag‐ onists. In general, nifedipin is the most potent. In addidion, verapamil is more potent than diltiazem. It has been demonstrated that nifedipine is more potent than diltiazem with regard

channels [89,90]. We

**Phosphodiesterase inhibitors**

260 Artery Bypass

IMA.

**Calcium antagonists**

to the vasorelaxant effect in the human IMA [54].

Drugs that open potassium channels (potassium channel openers, KCOs) can exert antivaso‐ constrictor and vasorelaxant actions, that is, they reduce or prevent cellular response ro excitatory stimuli, repolarize or hyperpolarize the cell membrane, overcome a contraction once it has developed, and strengten the resting state of the vessel. KCOs are considered to comprise a heterogeneous group of organic compounds [94]. These are apricalim, bimakalim, celikalim, cromakalim, levokromakalim, diazoxide, L-27,152, P 1075, minoxidil sulphate, pinacidil, and nicorandil. KCOs act by stimulating ion flux through a distinct class of potassium channels which are inhibited by intracellular adenosine triphosphate (ATP) and activated by intracel‐ lular nucleoside diphosphates. They restrain the opening probability of voltage-dependent Land T-type calcium-channels and decrease agonist-induced Ca2+ release from intracellular sources through inhibition of inositol trisphosphate (IP3) formation, and lower the efficiency of calcium as an activator of contractile proteins [95]. Additionally, they may accelerate clearance of intracellular free calcium via the Na+ /Ca2+ exchange pathway [95]. The functional outcome of these effects is to reduce the membrane excitability and to drive vascular myocytes into a relaxed state. Particularly, vascular smooth muscle is sensitive to KCOs [96-99]. In view of these points, KCOs are of great value as therapeutic agents [98,99,] and aprikalim [100,102] have been studied in the human IMA and found to be potent vasodilators in a number of receptor-mediated contractions. Therefore, this group of drugs may become clinically useful antispastic agents by their relaxing action on IMA.

#### **α-Adrenoceptor antagonists**

IMA is an α1-adrenoceptor-dominant artery with little α2- or β -function [30,31,103]. Theoret‐ ically, a selective α -receptor antagonist may be a highly effective antispastic agent because the site of interaction is same. Herewith, the use of α-adrenoceptor antagonists such as phenoxy‐ benzamine as an antispastic agent has a rationale. However, the nature of vasoconstriction is complex and may involve many other vasoconstrictors (Table 1). It has been demonstrated that, α- adrenoceptor antagonists are not effective in reversing the contraction evoked by other vasoconstrictors such as vasopressin, angiotensin II, endothelin-1, and KCl [104]. From pharmacological point of view, use of phenoxybenzamine is inappropriate as the sole anti‐ spastic agent in the arterial grafts. Moreover, a novel α1-adrenergic receptor blocking substance with calcium antagonist with activity, AJ-2615, has been studied with regard to inhibition of vasoconstriction in the IMA [44]. Further studies on this kind of substances may provide development of new antispastic protocols.

sponse to testosterone may occur in via large-conductance Ca2+-activated K+ channelopening action [112]. Clinical studies of testosterone therapy in male patients with coronary artery disease raised promising results. Therefore, the use of testosterone, i.e. direct topical administration on adventitia, as a vasorelaxant agent may be considered for

Pharmacology of Arterial Grafts for Coronary Artery Bypass Surgery

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

263

It has been demonstrated that botilinum toxin may prevent arterial spasm in vitro [120]. Iloprost, a PGI2 analogue, may be considered as an alternative antispastic agent in arteri‐

The use of the RA as a graft for coronary revascularization was already introduced in the 1970s, but shortly thereafter it was abandoned due to high incidence of vasospasm and comparatively poorer short-term and long-term patency rates than IMA [27,122-124]. This was partly due to the inability to recognize RA spasm, but it was also due to lack of proper pharmacological tools to prevent this. It was later noted that radial grafts were indeed patent in patients long after their surgery. Thereafter, the RA was reassessed and its role as an alternative arterial graft was

Because of the dual blood supply to the hand, RA occlusion is not associated with major clinical sequelae but prevention is important. RA spasm rarely leads to serious vascular complications but can cause patient discomfort and can result in prolonging or failure of the procedure. Several studies now suggest that 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 NTG or a combi‐ nation of NTG and a calcium channel blocker to prevent spasms. Similarly, protection from immediate postoperative and postdischarge vasospasm is sought through the use of intrave‐ nous or oral combinations of the aforementioned vasodilator drugs. However, clinical studies indicate that such vasodilatory precautions do not provide the expected protection from postoperative vasospasm of RA grafts. Although the patency rate of RA is debatable, mid-term and long-term patency rates may reach 90% and greater, that makes the RA a valuable addition

RA has less active endothelium compared to IMA and is stronger receptor-mediated contrac‐ tions can be evoked in the RA than in the IMA [49,127], which presumably predisposes it to higher incidences of spasm. Additionally, it was previously reported that RA grafts are more sensitive to TxA2 [13]. Furthermore, it has been reported that IMAs produce substantial amounts of both PGI2 and TxA2 [128]; 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. Contraction to KCl

antispastic therapy in arterial grafts.

**4. Pharmacology of other arterial grafts**

**Iloprost and botilinum toxin**

al grafts [121].

**4.1. Radial artery**

re-established.

in arterial grafting [125,126].

### **Vascular endothelial growth factor**

Vascular endothelial growth factor (VEGF) has been studied in the human IMA and found to be a potent vasodilator through KDR receptors and NO -and PGI2 -mediated mechanisms [44,45]. However, VEGF has potent hypotensive effect due to systemic vasodilaton [44,45]. Therefore, the use of VEGF as a vasorelaxant agent may not be the primary consideration for antispastic therapy in arterial grafts.
