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]. Comparative 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.
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 , 5-HT , angiotensin ,TP (thromboxane-prostanoid) , vasopressin V1 receptors [36,37], and vasoactive intestinal peptide  receptors. Dopaminergic receptors have also been demonstrated in the IMA . 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 vascular smooth muscle through 5-HT2 receptors  and relaxes blood vessels through endothelial NO release, mediated by 5-HT1D receptors,  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].
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 . Most recently, corticortropin-releasing factor (CRF) receptors CRF1, CRF2α, and CRF2β have been shown to be present in the IMA . The CRF urocortin- induced endothelium-dependent relaxation in the IMA is likely through CRF receptors allocated in the endothelium of the IMA .
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:
The traditional topical vasodilator papaverine was first recommended by George Green, the pioneer IMA surgeon, in early days of IMA grafting to overcome spasm . It is still widely used due to its satisfactory vasorelaxant effect in arterial grafts [61,62]. Papaverine is a non specific vasodilator substance which relaxes vessels via multiple mechanisms such as inhibition of phosphodiesterase , which increases cyclic guanosine monophosphate (cGMP) level in smooth muscle cells, decreasing calcium influx [64,65] or inhibition of release of intracellularly stored calcium . Although hydrostatic dilation with papaverine dissolved in saline solution provides good dilation at high concentrations, 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 . However, the pharmacological 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 sustained [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 plasmalyte solution (pH approximately 7.4) . In light of these points, papaverine is still an effective vasodilator for IMA. Its topical spray on the adventitia of the IMA may be effective but it is not recommended for systemic use.
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  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-adrenoceptors, 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 .
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 . It was also demonstrated that systemically administered milrinone and nitroglycerin dilate the IMA after cardiopulmonary bypass . 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 intracellular 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 . Therefore, levosimendan may be a cardiovascular protective agent by its relaxing action on IMA.
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 antagonists (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 antagonists. 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 .
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-operated 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 VP1 receptor-mediated contraction, in comparison to K+-mediated contraction [54,74,92,93].
Potassium (K+) channel openers
Drugs that open potassium channels (potassium channel openers, KCOs) can exert antivasoconstrictor 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 . 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 intracellular nucleoside diphosphates. They restrain the opening probability of voltage-dependent L- and 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 . Additionally, they may accelerate clearance of intracellular free calcium via the Na+/Ca2+ exchange pathway . 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.
IMA is an α1-adrenoceptor-dominant artery with little α2- or β -function [30,31,103]. Theoretically, 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 phenoxybenzamine 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 . From pharmacological point of view, use of phenoxybenzamine is inappropriate as the sole antispastic 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 . Further studies on this kind of substances may provide development of new antispastic protocols.
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.
β-Adrenoceptor agonists: Dopamine and dobutamine
Albeit at least three distinct beta-adrenoceptors exist in IMA , β -receptor function is weak . Consequently, it has been demonsted that use of β -adrenoceptor agonists is unlikely relax the IMA significantly . Same study also indicated that beta-receptor agonist dobutamine exerts weak vasodilator effect in IMA. Dopamine-induced responses are complex and dose-dependent, inasmuch as the complexity of interaction between dopamine and dopamine receptors as well as α1-adrenoceptors . In IMA, dopamine induced a vasorelaxation on the norepinephrine contraction only at higher concentrations . Similar to VEGF, the use of dopamine and dobutamine may not be the primary consideration for antispastic therapy. On the other hand, vasodilator effect of β-adrenoceptor agonists in IMA at high concentrations should be kept in mind when these agents are used primarily as inotropic agents.
TxA2 is one of the the most potent vasoconstrictors known and it is very potent in IMA as well [10,13]. Inasmuch as its importance in thrombosis together with its elevated plasma concentrations during cardiopulmonary bypass, specific TxA2 antagonists may be useful in the antispastic therapy of IMA. Accordingly, specific TxA2 antagonist GR30191 is a potent vasodilator for TxA2-mediated contraction in IMA . However, to date, no clinical data are available.
5-HT receptor antagonists
Studies on human IMA have shown that 5-HT directly contracts IMA through 5-HT1D and 5-HT2 receptors [33,108-110]. In IMA, 5-HT receptor mediated contractions are unmasked when endothelium is denuded [13,42]. Additionally, studies have shown 5-HT may interact synergistically with other vasoconstrictor substances, such as TxA2 released from platelets during thrombus formation, and 5-HT receptor mediated contractions may be unmasked or amplified [33,108-110]. 5-HT2A receptor antagonist ketanserin has antihypertensive properties and it’s recently used to reduce the severity and frequency of the vasospasm in Raynaud’s phenomenon . Therefore, it may have potential to overcome IMA spasm when it’s applied topically.
Testosterone may exert vasorelaxant effects on several vascular tissues [112-119]. We have studied effects of testosterone in the human IMA and found that vasorelaxant response to testosterone may occur in via large-conductance Ca2+-activated K+ channel-opening action . 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 antispastic therapy in arterial grafts.
Iloprost and botilinum toxin
It has been demonstrated that botilinum toxin may prevent arterial spasm in vitro . Iloprost, a PGI2 analogue, may be considered as an alternative antispastic agent in arterial grafts .