PROTEIN-KINASE-C SUPPRESSES RECEPTOR-MEDIATED PIAL ARTERIOLAR RELAXATION IN THE DIABETIC RAT

CEREBRAL vasodilatory responses are selectively impaired in chronicall y hyperglycemic, diabetic rats. In this study, we tested the hypothesi s that chronic hyperglycemia-induced protein kinase C (PKC) activation can account for the suppression of 2 separate receptor-mediated vascu lar relaxation processes: (1) endothelium-derived nitric oxide (NO) re lease, and (2) NO-independent beta-adrenergic receptor (beta-AR) activ ation. The in vivo reactivity of pial arterioles was evaluated in anes thetized rats (streptozotocin-treated diabetics and controls) using a closed cranial window and intravital microscopy. Compared with control s, diabetic rats showed a substantial attenuation or loss of the arter iolar relaxation response accompanying suffusion of the receptor-linke d, NO-dependent agonists, acetylcholine (Ach) and adenosine diphosphat e (ADP), and the beta-AR-agonist, isoproterenol(ISO). The vasodilatati on induced by the direct NO donor, sodium nitroprusside (SNP), was the same in both groups. In the presence of the PKC inhibitor, staurospor ine (STAURO), the Ach, ADP, and ISO responses were, largely restored a nd the SNP response was unaffected. STAURO produced no changes in Ach, ADP, ISO, or SNP responses in non-diabetic rats. These results sugges t that PKC activation in chronically hyperglycemic, diabetic rats supp resses receptor-dependent NO release and desensitizes beta-ARs.