Endothelin (ET) is a potent vasoconstrictor peptide that may have pathophysiological roles in the microcirculation of the peripheral nervous system. We examined the local action of epineurial ET-1 on sciatic endoneurial blood flow using serial hydrogen clearance measurements in anesthetized, paralyzed, and ventilated Sprague-Dawley rats. In separate rats, we made serial measurements of sciatic motor multifiber conduction before and then after application of epineurial ET (saline on contralateral nerve) 2 and 24 h and 4 and 7 days later. Epineurial bathing solutions of ET increased microvascular resistance and reduced local endoneurial blood flow in a dose-responsive fashion with a half-maximum effective concentration of 10(-8) M. Maximum vasoconstriction at 10(-6) M ET was associated with a fall in endoneurial blood flow from 18.7 (pre-ET) to 7.2 ml x 100 g-1 x min-1. Epineurial norepinephrine (10(-7) to 10(-10) M) also resulted in vasoconstriction, but of lesser degree. Pretreatment with intraperitoneal nimodipine, a dihydropyridine Ca2+ channel antagonist, but not phentolamine, prevented the vasoconstrictive action of ET. Three of eight animals developed temporary but complete axonal conduction block at the site of ET administration (10(-5) M) and four others had partial conduction block. Contralateral saline-treated sciatic fibers were unaffected. Local ET action on extrinsic epineurial microvessels results in reversible ischemia of the underlying endoneurium that may be associated with conduction block. ET's action is more potent than norepinephrine and appears dependent on L-type voltage-gated Ca2+ channels.