THE internal mammary artery (IMA) is widely used as a conduit for coronary artery surgery. Numerous clinical studies have demonstrated the superiority of the IMA regarding short‐ and long‐term potency compared with the saphenous vein. [2,3]
Further, endothelium‐dependent relaxations are greater in the IMA than in the saphenous vein, 
and the vasoconstrictive tone of the IMA has been described to be not as potent as in other arterial conduits. 
It is noteworthy that gastroepiploic and other grafts including radial arteries have not been uniformly effective as arterial grafts because of their vasospastic properties. [6,7]
Vasospasm does occur during IMA grafting, however, and may compromise myocardial perfusion. 
The pathophysiology of this vasoconstriction is complex and includes mechanical, physical, and pharmacologic stimulations. 
Platelet activation and release of thromboxane A2
may be important causal factors. 
In addition, the reversal of the vasospasm is often challenging, and the most effective therapy is not well defined. In vitro studies have described separately the efficacy of nitrovasodilator drugs, calcium channel blockers, and phosphodiesterase inhibitors on the IMA, [11–14]
but there are few data comparing different pharmacologic classes of drugs. Therefore, we investigated the effects of different classes of vasodilator drugs on human IMA precontracted with a thromboxane A2
analogue or with norepinephrine.
Segments of right and left IMA were collected from 60 patients undergoing coronary artery bypass surgery. The discarded distal end was removed carefully and placed in chilled modified Krebs HEPES buffer of the following composition (in mmol/l): NaCl 118, KCl 4.69, CaCl2 3.35, MgSO (4) 1.04, NaHCO3 25, D‐glucose 11.1, and HEPES 21.8, pH 7.40 +/‐ 0.05. The vessels were transferred to the laboratory and then cleaned of adherent connective tissue. The time delay between vessel harvest and preparation was < 15 min. The IMA segments were cut into 3‐mm ring segments. One to six rings were obtained from each vessel.
Experiments with Isolated Vascular Rings
The rings were suspended between two wire hooks in organ chambers filled with 25 ml Krebs‐Henseleit solution (37 [degree sign]C, pH 7.40) aerated with 95% O2/5% CO2. The upper hook was connected to a force transducer (Kent‐Scientific Corporation, Litchfield, CT), and changes in isometric force were recorded (MacLab [R] system, ADI Instruments; Milford, MA). A resting tension (4 g) initially defined by preliminary studies was progressively applied, and the rings were allowed to stabilize for 45 min. For the contraction experiments, cumulative concentration ‐ response curves were obtained with KCl, norepinephrine, and the thromboxane A2 analogue. Increasing concentrations of the thromboxane A2 analogue and norepinephrine were added to the organ bath in 0.5 log unit steps and in 0.2 log unit steps for KCl. For the relaxation studies, the rings were prepared by precontraction with norepinephrine (1 [micro sign]M) or the thromboxane A (2) analogue (10 nM). The concentrations were determined from the cumulative contraction ‐ response curves to achieve 50 ‐ 80% of the maximum contraction. Segments of IMA were allowed another equilibration period of 15 min and then exposed to increasing concentrations (in 0.5 log unit steps) every 15 min using vasodilator agents, which included nitroglycerin, milrinone, papaverine, prostaglandin E1, and isradipine.
The following drugs were used: a thromboxane A2 analogue (U46619) and prostaglandin E1 (provided by Upjohn Company, Kalamazoo, MI); norepinephrine (ampules from Abbott Laboratories, Chicago, IL); and nitroglycerin (ampules from Solopack Laboratories, Elk Grove Village, IL). Papaverine and KCl were obtained from Sigma Chemical Company (St. Louis, MO), and isradipine was a gift from Sandoz Pharmaceutical (East Hanover, NJ). The thromboxane A2 analogue was diluted in ethanol (95%) to 1 mM and then serially diluted in distilled water. Isradipine was diluted in ethanol, propylene glycol, and distilled water to a concentration of 20 mM and then serially diluted using ethanol/H2 O (40:60). The final concentration of ethanol in the bath did not exceed 0.8%. Additional experiments showed that ethanol has a slight vasoconstrictive effect on the IMA at concentrations > 1.5% in the organ bath. Prostaglandin E1 was dissolved in ethanol to reach a concentration of 30 mM and then serially diluted in distilled water. Nitroglycerin was serially diluted in distilled water. Drugs were prepared before each experiment and stored on ice. The concentrations of the drugs are expressed as final molar concentrations in the bath solution.
Data and Statistical Analysis
Contraction responses to KCl, norepinephrine, and the thromboxane A2 analogue were expressed in gain of tension (in grams). Relaxation responses were calculated as percentage of norepinephrine or the thromboxane A2 analogue ‐ induced contraction. Data are averaged for each patient in all experiments. The effective concentration of vasodilator agent that caused 50% of relaxation (EC50) was determined for each IMA (responses from vascular segments were averaged for one IMA) by the logistic curve fitting the equation: E = (Emax x C sup [Greek small letter gamma])/(C sup [Greek small letter gamma] + EC50 sup [Greek small letter gamma]), where E is the response, Emax is the maximal relaxation, C is the concentration, and [Greek small letter gamma] is the slope parameter.
Results are expressed as mean +/‐ SD. A nonparametric test for unpaired comparison (Mann ‐ Whitney U test) was used to compare the EC50 values of the vasodilators according to the vasoconstrictor agent. Statistical analysis was performed with one‐way analysis of variance followed by a Scheffe's post hoc test to assess the differences between maximal contractions obtained with KCl, norepinephrine, and the thromboxane A2 analogue. A probability value <0.05 was considered significant.
As shown in Figure 1
and Table 1
, the IMA segments exhibited greater contraction in the presence of the thromboxane A2
analogue (6.4 +/‐ 0.5 g) compared with norepinephrine (4.9 +/‐ 0.5 g) and KCl (4.1 +/‐ 0.7 g). The difference is significant between KCl and the thromboxane A2
analogue and between norepinephrine and the thromboxane A2
analogue. Nitroglycerin, papaverine, milrinone, and isradipine allowed 90 ‐ 100% of the maximum relaxation of the IMA segments contracted with norepinephrine (Figure 2
) or the thromboxane A2
analogue (Figure 3
). Nitroglycerin was more potent in relaxing vessels contracted with norepinephrine than vessels contracted with the thromboxane A2
= 0.9 +/‐ 0.6 vs 24.6 +/‐ 14.9 nM, respectively; P < 0.01). There was no difference for milrinone, papaverine, and isradipine. The EC50
values calculated for the different vasodilators are shown in Table 2
(IMA precontracted with norepinephrine) and Table 3
(IMA precontracted with the thromboxane A2
analogue). We noted that prostaglandin E1
only partially reversed thromboxane A2
‐induced contraction compared with nitroglycerin (73 +/‐ 6% vs 94 +/‐ 2% respectively; P < 0.01).
The current study shows that nitroglycerin, milrinone, papaverine, and isradipine effectively reversed thromboxane A2
analogue ‐ induced contraction of IMA segments, although prostaglandin E1
was ineffective. These drugs are clinically used and represent the major different classes of vasodilators, as shown in Table 4
. We also found that nitroglycerin is the most potent drug for reversing precontracted IMA with the thromboxane A2
analogue or with norepinephrine. Therapeutic concentrations of nitroglycerin in plasma range from 1 ‐ 20 nm. 
The in vitro evaluation of the effects of nitrates, however, shows that they are extremely variable according to the regional vascular bed and the constrictive pharmacologic stimulation. 
Further, the concentration of nitrovasodilator agents in plasma may not be related to the therapeutic effect because the drugs are inactive in their parent molecule. 
values for the relaxant effects of milrinone (1 [micro sign]M for norepinephrine and 3 [micro sign]M for thromboxane A2
analogue ‐ induced contraction) were also almost included in the range of the therapeutic concentrations in plasma reported in patients (0.5 ‐ 2.0 [micro sign]M 
). For prostaglandin E (1
), the therapeutic concentrations in plasma are unknown. Papaverine is only used in intra‐ and extraluminal application intraoperatively to prevent vasospasm during the manipulations of the IMAs. The therapeutic concentration in plasma determined for isradipine ranges from 2 ‐ 27 nM. 
This concentration was not effective in relaxing the IMA segment contracted with norepinephrine or the thromboxane A2
= 8 and 10 [micro sign]M for norepinephrine‐ and the thromboxane A2
analogue ‐ induced contractions, respectively).
The metabolism of nitroglycerin involves enzymatic and nonenzymatic pathways that generate nitric oxide. 
Nitric oxide produces vasodilation in activating soluble guanylate cyclase, and the consequent formation of cyclic guanosine monophosphate in the smooth muscle cell leads to the smooth muscle relaxation. 
Organic nitrate esters remain the most potent vasodilator in vitro 
and in vivo compared with other pharmacologic agents. Unfortunately, development of tolerance to nitrate may occur. The mechanisms include a reduction of nitrate biotransformation and neurohumoral reflex mechanisms, which are not yet completely understood. 
In the current experiments, all vessels relaxed to nitroglycerin, although 6 of the 12 patients were exposed to nitrate therapy at variable times before surgery.
Milrinone also completely reversed both norepinephrine‐ and the thromboxane A2
analogue ‐ induced contraction. Thorin‐Trescases et al. demonstrated a greater effect of milrinone compared with sodium nitroprusside. 
Recently, Liu et al. showed that the vasodilator effect of milrinone is endothelium independent. 
Milrinone is a derivative of bipyridine that selectively inhibits the phosphodiesterase type III and prevents the degradation of cyclic adenosine monophosphate. Its vasodilator effect on human IMA and the relation between the EC50
value and the therapeutic level are in agreement with previous studies. 
Papaverine, a benzylisoquinoline‐derived and a nonspecific phosphodiesterase inhibitor, prevents the degradation of both cyclic adenosine monophosphate and cyclic guanosine monophosphate 
and is used exclusively in topical applications.
was ineffective at completely reversing thromboxane A2
analogue ‐ induced vasoconstriction in IMA. Prostaglandin E1
activates adenyl cyclase independently of the [Greek small letter beta]‐receptors and increases production of cyclic adenosine monophosphate. The use of prostaglandin E1
has been suggested in association with norepinephrine in the treatment of pulmonary hypertension with right ventricular failure. 
Its rapid pulmonary metabolism, which may decrease its systemic vasodilator effect, is another potential advantage of prostaglandin E1
in this indication. Prostaglandin E1
, however, like prostaglandin I2
(prostacyclin), has a profound inhibitory effect on platelets caused by stimulation of cyclic adenosine monophosphate. 
Further, in a clinical trial, a synergistic action of prostaglandin E1
and a nitric oxide donor in reducing platelet function has been established. 
The dihydropyridine calcium channel inhibitor, isradipine, produced a vasodilator effect in IMA contracted with the thromboxane A2
analogue. Vasodilation is achieved, however, at higher concentrations than the therapeutic concentrations in plasma reported in patients. 
Data regarding the effect of calcium channel inhibitors on precontracted IMA are variable. It appears that different calcium blockers, such as verapamil or the dihydropyridine agents nifedipine and nicardipine, showed a greater vasodilator effect when the vessel contraction is mediated by a voltage‐dependent mechanism (i.e., KCl) rather than mediated by a receptor‐dependent mechanism (i.e., the thromboxane A2
Another perspective concerns the potential negative inotropic and conductive effects of nondihydropyridine agents (e.g., verapamil, diltiazem) related to the nonselective inhibition of L‐type calcium channels located in the myocardium. Clevidipine, a third‐generation ultra ‐ short‐acting dihydropyridine agent, however, appears to have a potent and selective vasodilator effect. 
Although the segments of IMA are human tissue samples, the in vitro experiments exclude most of the mechanisms of the vascular tone regulation, such as the sympathetic reflexes or the responses to the shear stress. Moreover, as shown in the tables, there is a tremendous variability in vasodilator and vasoconstrictive effects among the vessel segments. The atherosclerotic process is likely involved in these changes. Consequently, the EC50
value might not be correlated with the dose leading to an expected vasodilator effect in vivo. We also used different vasoconstrictor agonists separately because the IMA vasospasm mechanisms may be the response to simultaneous neurohumoral stimulations, such as catecholamines, prostaglandins, vasopressin, and renin ‐ angiotensin release. 
The current data demonstrate that the most commonly used vasodilator agents, except prostaglandin E1, although they act through different pathways, effectively reverse precontracted IMAs in vitro at concentrations similar to those encountered clinically.
The authors thank Mary Torkelson from Upjohn Laboratories for support.
[double dagger] Huraux C, Makita T, Montes F, Szlam F, Duncan RA, Levy JH: What is the best therapy for internal mammary artery vasospasm? (abstract). Anesthesiology 1995; 83:A613.
1. Kolessov V: Mammary artery-coronary artery anastomosis as method of treatment for angina pectoris. J Thorac Cardiovasc Surg 1967; 54:535-44
2. Grondin CM, Campeau L, Lesperance J, Enjalbert M, Bourassa MG: Comparison of late changes in internal mammary artery and saphenous vein grafts in two consecutive series of patients 10 years after operation. Circulation 1984; 70(suppl I):I-208-12
3. Camereon A, Davis K, Green G, Schaff V: Coronary bypass surgery with internal-thoracic-artery grafts: Effects on survival over a 15-year period. N Engl J Med 1996; 334:216-9
4. Luscher TF, Diederich D, Siebenmann R, Lehmann K, Stulz P, Von Segesser L, Yang Z, Turina M, Gradel E, Weber E, Bulher FR: Difference between endothelium-dependent relaxation in arterial and in venous coronary bypass grafts. N Engl J Med 1988; 319:462-7
5. Chardigny C, Jebera V, Acar C, Descombes J-J, Verbeuren T, Carpentier A, Fabiani J-N: Vasoreactivity of the radial artery, Comparison with the internal mammary artery and gastroepiploic arteries with implications for coronary artery surgery. Circulation 1993; 88(part 2):115-27
6. Fisk RL: Experience with the radial artery graft for coronary bypass. Ann Thorac Surg 1976; 21:513-8
7. Suma H: Spasm of the gastroepiploic artery graft. Ann Thorac Surg 1990; 49:168-9
8. Sarabu MR, McClung JA, Fass A, Reed GR: Early post-operative spasm in left internal mammary artery bypass grafts. Ann Thorac Surg 1987; 44:199-200
9. He G-W, Yang C-Q, Starr A: Overview of the nature of vasoconstriction in arterial grafts for coronary operations. Ann Thorac Surg 1995; 59:676-83
10. Davies GC, Sobel M, Salzman EW: Elevated plasma fibrinopeptide A and thromboxane B2 levels during cardiopulmonary bypass. Circulation 1980; 61:808-14
11. Liu JJ, Johnston CI, Buxton BF: Synergistic effect of nisoldopine and nitroglycerin on human internal mammary artery. J Pharmacol Exp Ther 1994; 268:434-40
12. Jett KG, Arcici JM, Hatcher C, Abel PW, Guyton RA: Vasodilatator drug effects on internal mammary artery and saphenous vein grafts. J Am Coll Cardiol 1988; 11:1317-24
13. Thorin-Trescases N, Dimitri WR, Dominiczak AF, Hamilton CA, Reid JL: Vasorelaxant properties of isolated human internal mammary arteries and saphenous veins: Comparative effects of milrinone and sodium nitroprusside. J Cardiovasc Pharmacol 1993; 22:673-80
14. Salmenpera M, Levy JH: The in vitro effects of phosphodiesterase inhibitors on the human internal mammary artery. Anesth Analg 1996; 82:954-7
15. Mueller RL, Scheidt S: Nitroglycerin, Cardiovascular Drug Therapy. 2nd edition. Edited by Messerli FH. Philadelphia, W. B. Saunders, 1996, pp 865-76
16. Ahlner J, Andersson RGG, Torfgard K, Axelsson KL: Organic nitrate esters: Clinical use and mechanisms of actions. Pharmacol Rev 1991; 43:351-423
17. Harrison DG, Bates JN: The nitrovasodilators: New ideas about old drugs. Circulation 1993; 87:1461-7
18. Bailey JM, Levy JH, Kikura M, Szlam F, Hug CC: Pharmacokinetics of intravenous milrinone in patients undergoing cardiac surgery. Anesthesiology 1994; 81:616-22
19. Fitton A, Benfield P: Isradipine: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs 1990; 40:31-74
20. Munzel T, Harrison DG: What causes nitroglycerin tolerance? Clin Cardiol Primary Cardiol 1994; 20:40-7
21. Levy JH, Ramsay JM, Bailey JM: Pharmacokinetics and pharmacodynamics of phosphodiesterase III inhibitors. J Cardiothorac Anesth 1990; 4(suppl):7-16
22. Liu JJ, Doolan LA, Xie B, Chen JR, Buxton BF: Direct vasodilator effect of milrinone, an inotropic drug, on arterial coronary bypass grafts. J Thorac Cardiovasc Surg 1997; 113:108-13
23. D'Ambra MN, Laraia PJ, Philbin DM, Watkins WD, Hilgenberg AD, Buckley MJ: Prostaglandin E1: A new therapy for refractory right heart failure and pulmonary hypertension after mitral valve replacement. J Thorac Cardiovasc Surg 1985; 89:567-72
24. Sinzinger H, Fitscha P, O'Grady J, Rauscha F, Rogatti W, Vane JR: Synergistic effect of prostaglandin E1 and isosorbide dinitrate in peripheral vascular disease. Lancet 1990; 335:627-8
25. He G-W, Acuff TE, Ryan WH, Yang C-Q, Douthit MB, Bowman RT, Mack MJ: Inhibitory effects of calcium antagonists on a-adrenoreceptor-mediated contraction on the human internal mammary artery. Br J Clin Pharmacol 1994; 37:173-9
26. Nordlander M, Bjorkman J-A, Regardh C-G, Thalen P: Pharmacokinetics and haemodynamic effects of an ultrashort-acting calcium antagonist (abstract). Br J Anaesthesia 1996; 76(suppl II):12
© 1998 American Society of Anesthesiologists, Inc.