The overflow of endogenous angiotensin-(1-8)octapeptide (angiotensin II) from blood-perfused canine gracilis muscle vasculature in situ was studied. A positive veno-arterial concentration difference for angiotensin II over the gracilis muscle was found, indicating a net generation of angiotensin II under basal conditions. Angiotensin II levels in the venous effluent were elevated during 2 Hz (4-min) nerve stimulation, suggesting enhanced local angiotensin II generation both in the presence and absence of alpha-adrenoceptor blockade. Thus, our results in this in vivo model demonstrate a local overflow of angiotensin II from the skeletal muscle vasculature which can be enhanced by nerve stimulation. Whether this overflow of angiotensin II is due to conversion of circulating angiotensin I to angiotensin II or local de novo synthesis of angiotensin II remains to be established.