Role of endothelin-1 receptor antagonists in vasoconstriction mediated by endothelin and other vasoconstrictors in human internal mammary artery

Abstract

Background: 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).

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 ET(A) (BQ-123) or ET(B) (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 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.