The synergistic effects of cyclosporine and endothelin—demonstration of an important cardiodepressor action

Cyclosporine represents the foundation for current immunosuppressive therapy following solid organ transplantation. CsA use is associated with renal insufficiency and systemic hypertension. We hypothesized that CsA would enhance the vascular actions of endo-thelin (ET). Three groups of anesthesized dogs (n=15) were studied. Group 1 received CsA alone (1 mg/kg), group 2 received E T alone (1 ng/kg/min), and group 3 received combined CsA (1 mg/kg) and ET (1 ng/kg/min). The hemodynamic and renal effects were evaluated after 30 min. Combined treatment resulted in a profound reduction in mean arterial pressure (—62±14 mmHg (J?<.05) and cardiac output (-2.2±0.4 1/min (P<.05). The reduction in mean arterial pressure and cardiac output were significantly greater than that observed with CsA or ET alone. Systemic vascular resistance was not significantly changed. Combined CsA and ET resulted in a significant reduction in renal blood flow (195±18to 101+11 ml/mm P<.05)but without evidence of active renal vasoconstriction. The decline in GFR (31.8±5.6 ml/min to being unmeasurable) was of greater magnitude than the change in renal blood flow, suggesting enhanced afferent anteriolar vasoconstriction or an alteration in the ultrafiltration coefficient. These studies demonstrate an important and synergistic cardiode-pressor effect when CsA and ET are combined.