The involvement of endothelin (ET), ETA receptors and nitric oxide (NO) in the contractions induced by cyclosporine A (CyA) were investigated in guinea pig isolated gallbladder strips. Both BQ-123, a selective ETA receptor antagonist, and phosphoramidon, an ET converting enzyme inhibitor, inhibited the contractile responses to the parenteral and oral CyA preparations, whereas L-NOARG, a NO synthase inhibitor, potentiated these contractions. Additionally, the pattern of the concentration-dependent contractions in response to ET-1 was similar to that of CyA preparations in gallbladder strips. Both bosentan, a non-selective ET receptor antagonist, and BQ-123 inhibited the ET-1-induced contractions. These findings suggest that an ET-1-mediated mechanism contributes to the contractile response to CyA preparations in guinea pig isolated gallbladder strips. ETA receptor activation is likely to be involved in this process. We also speculate that CyA-induced stimulation of NO production might act as a counter-regulatory mechanism in the effect of CyA preparations in this tissue. (C) 2004 Elsevier Ltd. All rights reserved.