Obligatory roles of protein kinase C and nitric oxide in the regulation of cerebral vascular tone: an implication of a pathogenesis of vasospasm after subarachnoid haemorrhage.
We previously showed that a canine basilar artery manifested tonic and potent, protein kinase C (PKC)-dependent contractions when nitric oxide (NO) was inhibited. We also reported a linear correlation between chronological changes in the angiographic severity of vasospasm, enhanced PKC, and attenuated guanosine, 13',15'-cyclic monophosphate (cGMP) activity in a canine subarachnoid haemorrhage model. The activity of cGMP is an indicator of NO-function. Based on this evidence, we have hypothesized that PKC and NO regulate cerebral vascular tone. We particularly focused on the role of NO in a negative feedback mechanism on PKC activity in the maintenance of vascular tone. To further confirm our hypothesis, we investigated the effect of PKC down-regulation on the tonic vascular contraction induced by NO-inhibition. Canine basilar artery was used in the experiment. Significant down-regulation of PKC activity in vascular smooth muscle cells was obtained by incubation with 10(-5) mole/L of phorbol 12-myristate 13-acetate (PMA) for 24 hours. The tonic and potent contraction induced by NO-inhibition was completely suppressed in the PKC down-regulated artery, even though the artery manifested a significant contraction in high-K+ solutions. These results indicate an obligatory role of PKC activity in tonic contraction when NO is inhibited, and support our previous data. Nitric oxide induces vascular relaxation by inhibiting PKC activity. Subarachnoid haemorrhage impairs this inhibition, resulting in PKC-dependent vascular contraction, such as vasospasm.
Nishizawa
S
S
Department of Neurosurgery, Hamamatsu University School of Medicine, Japan.
Yokota
N
N
Yokoyama
T
T
Uemura
K
K
D000818:Animals; D001488:Basilar Artery / Q000503:physiopathology; D001921:Brain / Q000098:blood supply; D004285:Dogs; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D002546:Ischemic Attack, Transient / Q000503:physiopathology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D009569:Nitric Oxide / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D013345:Subarachnoid Hemorrhage / Q000503:physiopathology*; D014655:Vascular Resistance / Q000502:physiology*
D009569:Nitric Oxide; D011493:Protein Kinase C