Mechanism of enhanced calcium sensitivity and α2-AR vasoreactivity in chronic NOS inhibition hypertension

Abstract

PKC augments calcium sensitivity in spontaneously hypertensive rats and contributes to α2-adrenergic receptor (AR) contraction in rabbit saphenous vein. We showed previously that denuded aortic rings from N ω-nitro-l-arginine-treated hypertensive rats (LHR) contract more to CaCl2 and to the α2-AR agonist UK-14304 than do rings from normotensive rats (NR). We hypothesized that enhanced PKC activity or a change in PKC isoform contributes to augmented calcium sensitivity and enhanced α2-AR contraction in LHR aorta. Current studies demonstrate that non-isoform-specific PKC inhibitors reduced UK-14304 contraction in both NR and LHR aorta. However, the calcium-dependent PKC inhibitor Gö-6976 only attenuated contraction in LHR aorta. Additionally, UK-14304 translocated PKC-δ to the membrane in NR aorta, whereas PKC-α was translocated to the membrane in LHR aorta. Finally, in ionomycin-permeabilized aorta Gö-6976 eliminated enhanced basal and augmented α2-AR-stimulated calcium sensitivity in LHR aorta but did not affect NR contraction. Together, these data suggest that PKC-α contributes to augmented calcium sensitivity and α2-AR reactivity after chronic nitric oxide synthase inhibition hypertension.