Role of Endothelin-1 Receptor Antagonists in Vasoconstriction Mediated by Endothelin and Other Vasoconstrictors in Human Internal Mammary Artery

Background The action of antagonists for endothelin type A (ETA) and type B (ETB) 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 ETA and ETB receptors in vasoconstriction mediated by endothelin-1 and other vasoconstrictors in the human internal mammary artery (IMA). Methods 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 ETA (BQ-123) or ETB (BQ-788). Results 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 (p < 0.05 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, p < 0.001), 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. Conclusions The present study demonstrates the role of ETA and ETB antagonists in the endothelin-1-mediated contraction in the human IMA and indicates the dominant role of ETA 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.