Role of the PKC/CPI‐17 pathway in enhanced contractile responses of mesenteric arteries from diabetic rats to α ‐adrenoceptor stimulation

Protein kinase C (PKC) may contribute to enhanced contractile responses of arteries from streptozotocin‐diabetic rats to stimulation of G‐protein coupled receptors. This was investigated by comparing the effects of PKC inhibitors on contractile responses of mesenteric arteries from diabetic and age‐matched control rats to noradrenaline (NA) and endothelin‐1 (ET‐1). The effects of NA and ET‐1 on the distribution of three isoforms of PKC implicated in contraction were also determined. In addition, the effect of NA on phosphorylation of CPI‐17, a substrate for PKC, was investigated. Contractile responses of endothelium‐denuded arteries from diabetic rats to NA were enhanced, but were normalized by PKC inhibition. In contrast, contractile responses to ET‐1 were not significantly different, and were blocked to a similar extent by PKC inhibition, in arteries from control and diabetic rats. NA produced only a small increase in particulate levels of PKC ɛ in control arteries (to 125±8% of levels in untreated arteries), but a significant increase in particulate PKC α (to 190±22%) and a much greater increase in particulate PKC ɛ (to 230±19%) in arteries from diabetic rats. ET‐1 increased particulate PKC α and ɛ to a similar extent in arteries from control and diabetic rats. NA significantly enhanced CPI‐17 phosphorylation from a basal level of 22±10 to 71±7% of total in arteries from diabetic rats, and this was prevented by PKC inhibition. NA had no detectable effect on CPI‐17 phosphorylation in arteries from control rats. These data suggest that NA‐induced activation of PKC and CPI‐17, its downstream target, is selectively enhanced in arteries from diabetic rats, and mediates the enhanced contractile responses to this agonist.British Journal of Pharmacology (2005) 146 , 972–982. doi: 10.1038/sj.bjp.0706398