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Background . Angiotensin II (AII) has been suggested to be one of the important factors for genesis of graft spasm in coronary artery bypass surgery. The aim of this work was to investigate the effects of the nonpeptide angiotensin receptor AT 1 antagonist GR117289C on the contraction induced by AII and other vasoconstrictors in isolated human internal mammary artery (IMA) preparations. Methods . Two hundred eight IMA rings taken from 64 patients undergoing coronary artery bypass grafting were studied in organ baths. The interaction between GR117289C and AII or the other vasoconstrictors (U46619, norepinephrine, endothelin-1, and potassium chloride) was investigated in two ways. Results . GR117289C induced near-maximal relaxation (94.5% ± 2.9%) in IMA rings precontracted by AII. In IMA rings incubated with 1 or 10 nmol/L GR117289C, contractile responses to AII were attenuated in a concentration-related manner, whereas the dose-response curve did not shift to the right when higher doses of AII were administered, suggesting that the AT 1 receptor blockade was noncompetitive in nature. Moreover, GR117289C also induced significant relaxation (82.9% ± 8.1%) in IMA rings precontracted by U46619, but no inhibitory responses to U46619 could be observed when IMA rings were incubated with GR117289C. GR117289C did not alter responses to potassium chloride, norepinephrine, and endothelin-1. Conclusions . These results indicate that GR117289C is a potent, selective, noncompetitive AT 1 receptor antagonist that may have a possible antagonistic effect on the thromboxane A 2 receptor. Because AII and thromboxane A 2 are important vasoconstrictors in the genesis of graft spasm, GR117289C may become an alternative treatment to relieve graft spasm.

The action of antagonists for endothelin type A (ET(A)) and type B (ET(B)) on the vasoconstriction mediated by various vasoconstrictors in the human bypass grafts have not been well-defined. We studied the role of antagonists for both ET(A) and ET(B) receptors in vasoconstriction mediated by endothelin-1 and other vasoconstrictors in the human internal mammary artery (IMA).Isolated IMA rings (n = 192, taken from 49 patients) were studied in organ bath for the interaction between endothelin-1, angiotensin II, U46619, and potassium chloride and the antagonist for ET(A) (BQ-123) or ET(B) (BQ-788).Significant relaxations were observed by BQ-123 (agonist: endothelin-1, 84.9 +/- 7.9%; angiotensin II, 45.5 +/- 5.1%; and U46619, 30.7 +/- 5.7%) or BQ-788 (agonist: endothelin-1, 66.5 +/- 11.3%; angiotensin II, 38.9 +/- 4.2%; and U46619, 30.8 +/- 4.0%), but not to potassium chloride-induced precontraction. Incubation of IMA with BQ-123 or BQ-123 + BQ-788 significantly shifted the concentration-contraction curve to endothelin-1 rightward (p0.05 vs control) with effective concentration causing 50% of maximal response (EC50) (-7.59 +/- 0.04 or -7.81 +/- 0.05 vs -8.47 +/- 0.05 log M in the control, p0.001), whereas BQ-788 alone did not affect the contraction curve (p = 1.0 vs control). In contrast, none of the endothelin-1 inhibitors and the combination demonstrated significant depression effects on angiotensin II, U46619, or potassium chloride-induced contraction.The present study demonstrates the role of ET(A) and ET(B) antagonists in the endothelin-1-mediated contraction in the human IMA and indicates the dominant role of ET(A) receptors. Although these effects are specific to endothelin-1, cross-action between endothelin-1 and angiotensin II exists. These findings provide useful knowledge for the future development of the clinical antispastic protocol in coronary bypass surgery.

Background . Vascular endothelial growth factor (VEGF) has been shown to have potential to treat ischemic diseases. Moreover, its vasorelaxing or vasodilatory effect might be favorable for relieving graft spasm. In this study, we examined the vasorelaxing effects of recombinant VEGF in isolated human internal mammary artery (IMA) and compared the responses to acetylcholine and nitroglycerin. Methods . Isometric tension of IMA ring segments was measured with an organ bath technique. With an optimal resting tension determined from its individual length-tension curve, precontraction was induced by 10 −8 M U46619 and cumulative concentration-relaxation was measured by application of VEGF (10 −12 to 10 −8.5 M), acetylcholine (10 −10 to 10 −5 M), and then nitroglycerin (10 −4.5 M). Results . Vascular endothelial growth factor induced concentration-dependent relaxation (EC 50 : −9.89 ± 0.05 log M; E max : 63.2% ± 7.3%) in IMA with intact endothelium. The relaxant responses to VEGF were significantly attenuated by pretreatment with N ω -nitro-l-arginine (L-NNA) alone and indomethacin + L-NNA, and totally abolished by removal of the endothelium or pretreatment with indomethacin + L-NNA + oxyhemoglobin. Internal mammary arteries became more sensitive to VEGF in the presence of indomethacin alone. However, acetylcholine-induced relaxation was not abolished by treatment with indomethacin + L-NNA + oxyhemoglobin (E max : 16.9% ± 2.7%). The endothelium-independent relaxations induced by nitroglycerin were also significantly inhibited by administration of oxyhemoglobin. Conclusions . The results demonstrate that VEGF-induced endothelium-dependent relaxation in the human IMA is mainly due to nitric oxide release. Although the vasorelaxing effect is not the primary advantage of this drug when it is used for angiogenesis, such effect may be advantageous in patients who also need a coronary artery bypass operation.

Arterial grafts for coronary artery bypass grafting such as the internal mammary artery (IMA) may develop spasm perioperatively. The purpose of this study was to investigate the effects of the potassium channel opener, aprikalim, on the receptor-mediated vasoconstriction in the human IMA in vitro.We studied 160 IMA rings taken from coronary artery surgery in organ baths. The interaction between aprikalim and four vasoconstrictors 5-hydroxytryptamine (5-HT), norepinephrine (NE), endothelin-1 (ET-1), and angiotensin II (AII) was investigated in two ways.Aprikalim relaxed IMA rings precontracted by the vasoconstrictors to 66.40 +/- 5.9% for 5-HT (EC50: -6.78 +/- 0.26 LogM), 57.40 +/- 5.5% for NE (-6.54 +/- 0.39 LogM), 81.00 +/- 6.7% for ET-1 (-6.58 +/- 0.26 LogM), and 93.90 +/- 2.5% for AII (-7.80 +/- 0.23 LogM). The relaxation in endothelium-denuded rings contracted by AII was similar to that in the endothelium-intact rings. The relaxation was attenuated by glibenclamide (3 microM) in 5-HT or NE-precontracted IMA. Pretreatment with aprikalim at 1 microM depressed AII-induced contraction (33.20 +/- 7.5% versus 59.70 +/- 7.3%, p0.01) but only shifted the curves rightward for 5-HT or NE (EC50 3.1 or 4.3-folds higher, p0.05), whereas at 30 microM it also significantly depressed the maximal contraction for 5-HT (35.70 +/- 4.9% versus 103.30 +/- 9.8%, p0.001) and NE (90.60 +/- 15.6% versus 125.60 +/- 7.9%, p0.05). In contrast, aprikalim did not significantly depress the contraction induced by ET-1 (p0.05).We conclude that aprikalim has vasorelaxant effects on IMA and the effect is vasoconstrictor-selective and endothelium-independent. Aprikalim may provide clinically useful vasorelaxant effects in coronary bypass surgery.