Protein kinase C suppresses receptor-mediated pial arteriolar relaxation in the diabetic rat.
Cerebral vasodilatory responses are selectively impaired in chronically hyperglycemic, diabetic rats. In this study, we tested the hypothesis that chronic hyperglycemia-induced protein kinase C (PKC) activation can account for the suppression of 2 separate receptor-mediated vascular relaxation processes: (1) endothelium-derived nitric oxide (NO) release, and (2) NO-independent beta-adrenergic receptor (beta-AR) activation. The in vivo reactivity of pial arterioles was evaluated in anesthetized rats (streptozotocin-treated diabetics and controls) using a closed cranial window and intravital microscopy. Compared with controls, diabetic rats showed a substantial attenuation or loss of the arteriolar relaxation response accompanying suffusion of the receptor-linked, NO-dependent agonists, acetylcholine (Ach) and adenosine diphosphate (ADP), and the beta-AR-agonist, isoproterenol (ISO). The vasodilatation induced by the direct NO donor, sodium nitroprusside (SNP), was the same in both groups. In the presence of the PKC inhibitor, staurosporine (STAURO), the Ach, ADP, and ISO responses were, largely restored and the SNP response was unaffected. STAURO produced no changes in Ach, ADP, ISO, or SNP responses in non-diabetic rats. These results suggest that PKC activation in chronically hyperglycemic, diabetic rats suppresses receptor-dependent NO release and desensitizes beta-ARs.
Pelligrino
D A
DA
Department of Anesthesiology, University of Illinois, Chicago.
Koenig
H M
HM
Wang
Q
Q
Albrecht
R F
RF
D000109:Acetylcholine / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000503:physiopathology*; D004789:Enzyme Activation; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D010841:Pia Mater / Q000098:blood supply*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D000470:Alkaloids; D009599:Nitroprusside; D000244:Adenosine Diphosphate; D011493:Protein Kinase C; D019311:Staurosporine; D007545:Isoproterenol; D000109:Acetylcholine