Cyclosporin A (CSA) causes an acute vasoconstriction of hind limb arterial vessels. To determine the mechanism of action of CSA on the peripheral arterial bed, studies were performed on the isolated femoral artery perfused at constant flow in 61 dogs. Changes in femoral perfusion pressure reflected variations in vascular resistance. Pure powder CSA was dissolved in autologous blood and injected at doses of 1,5,10, and 20 mg. Infusions of 1 and 5 mg CSA caused nonsignificant mean increases of 4±2 mm Hg (95% confidence interval [CI], 0–8;p>0.05) and 10±4 mm Hg (95% CI, 0–21;p>0.05) in femoral perfusion pressure, with CSA blood levels in the femoral vein averaging 40±16 and 126±50 nmol/l, respectively, at the end of the injections. Infusions of 10 and 20 mg CSA caused significant increases in femoral perfusion pressure averaging of 8±3 mm Hg (95% CI, 1–14;p<0.05) and 20±4 mm Hg (95% CI, 11–29;p<0.05) in femoral perfusion pressure. CSA blood levels at the end of injections averaged 271±99 and 431±146 nmol/l, respectively, in the femoral vein. Blockade of α-adrenergic receptors with phentolamine and surgical lumbar sympathectomy decreased significantly the CSA vasoconstrictive effect in peripheral arterial vessels, with increases in perfusion pressure averaging 29±5 mm Hg before and 14±3 mm Hg after phentolamine (p<0.05) and 30±2 mm Hg before and 8±2 mm Hg after sympathectomy (p<0.05). The response to CSA was not due to cerebral stimulation, nor was it caused by stimulation of arterial chemoreceptors or intrathoracic receptors, since bolus injections of CSA in the carotid artery and in the right atrium did not cause significant changes in hind limb perfusion pressure. After lumbar sympathectomy, injections of 1, 2, and 4 μg norepinephrine caused average increases of 16±3, 36±5, and 56±6 mm Hg (p<0.05) in femoral perfusion pressure, respectively. After injection of CSA, 1, 2, and 4 μg norepinephrine caused increases of 28±3, 48±4, and 65±5 mm Hg in perfusion pressure, respectively. During CSA infusion, tyramine (50 μg/kg) caused an increase of 23±3 mm Hg (95% CI, 17–29) in perfusion pressure compared with 38±4 mm Hg (95% CI, 30–46) before CSA injection, indicating a significant difference (p<0.05). Therefore, in the dog, CSA causes an acute vasoconstriction of peripheral arterial vessels through an increase in adrenergic activity, resulting at least partly from the inhibition of neuronal norepinephrine reuptake. No central or reflex effects appear to be involved in the response.