We reported previously that simulating sleep apnea by exposing rats to eucapnic intermittent hypoxia (E-IH) causes endothelin-dependent hypertension and increases constrictor sensitivity to endothelin-1 (ET-1). In addition, augmented ET-1-induced constriction in small mesenteric arteries (sMA) is mediated by increased Ca²⁺-sensitization independent of Rho-associated kinase (ROK). We hypothesized that exposing rats to E-IH augments ET-1-mediated vasoconstriction by increasing protein kinase C (PKC)-dependent Ca²⁺-sensitization. In sMA, nonselective PKC inhibitor GF-109203x (3 µM) significantly inhibited ET-1-stimulated constriction in E-IH arteries but did not affect ET-1-stimulated constriction in Sham arteries. Phospholipase C inhibitor U-73122 (1 µM) also inhibited constriction by ET-1 in E-IH but not Sham sMA. In contrast, the cPKC inhibitor (Go6976, 1 µM) had no effect on ET-1-mediated vasoconstriction in either group but a PKC-selective inhibitor (rottlerin, 3 µM) significantly decreased ET-1-mediated constriction in E-IH but not in Sham sMA. ET-1 increased PKC phosphorylation in E-IH but not Sham sMA. In contrast, ET-1 constriction in thoracic aorta from both Sham and E-IH rats was inhibited by Go6976 but not by rottlerin. These observations support our hypothesis that E-IH exposure significantly increases ET-1-mediated constriction of SMA through augmented PKC activation and modestly augments ET-1 contraction in the thoracic aorta through activation of one or more cPKC isoforms. This suggests that upregulation of a PKC pathway may contribute to elevated ET-1-dependent vascular resistance in this model of hypertension.