Protein kinase C-mediated contractile responses of arteries from diabetic rats.

1. The role of protein kinase C (PKC) in mediating enhanced contractile responses of aortae and mesenteric arteries from male rats with 12-14 week streptozotocin-induced diabetes to noradrenaline (NA) was investigated using the PKC activator, phorbol 12,13-dibutyrate (PDB), and the PKC inhibitor, staurosporine. 2. Maximum contractile responses of aortae and mesenteric arteries from diabetic rats to NA were significantly enhanced compared with responses of arteries from age-matched control animals. The maximum NA responses were increased by 59.6 +/- 7.9% in aortae and by 54.9 +/- 7.4% in mesenteric arteries from diabetic animals, compared to their respective controls. 3. Pretreatment of aortae and mesenteric arteries from both control and diabetic animals with staurosporine (5 x 10(-8) M) caused marked inhibition of contractile responses to a maximum concentration of NA (10(-5) M in aortae; 3 x 10(-5) M in mesenteric arteries). In the presence of staurosporine, no difference was observed in the magnitude of contractile responses of arteries from control and diabetic rats to NA. 4. Maximum contractile responses of mesenteric arteries from diabetic rats to PDB were significantly increased (by 45.0 +/- 4.9%) compared to responses of arteries from control animals. In contrast, no significant difference was found in the magnitude of contractile responses or aortae from control and diabetic rats to PDB. 5. Staurosporine (5 x 10(-8) M caused marked attenuation of contractile responses of arteries from control and diabetic rats to a maximum concentration of PDB (3 x 10(-6) M). In the presence of staurosporine, the difference in magnitude of contractile responses of mesenteric arteries from control and diabetic rats to PDB was abolished. 6. Contractile responses of aortae and mesenteric arteries from control and diabetic rats to PDB were reduced in the absence of extracellular Ca2", and in the presence of the Ca2 + channel blockers, nifedipine (3 x 10-6 M) or verapamil (3 x 10-6 M). Under these conditions, no difference was found in the magnitude of contractile responses of mesenteric arteries from control and diabetic rats to PDB. 7. These data suggest that enhanced contractile responses of aortae and mesenteric arteries from streptozotocin-induced diabetic rats to NA may result, at least in part, from increased activation of PKC. In addition, increased activation of PKC-mediated processes, which are dependent on the presence of extracellular Ca2+, may further contribute to the enhanced contractile responses of diabetic mesenteric arteries to NA.