Chronological Changes of Arterial Diameter, cGMP, and Protein Kinase C in the Development of Vasospasm

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Abstract
Background and Purpose We hypothesized that nitric oxide exerts a negative feedback control on protein kinase C (PKC) activation, and the disturbance of the feedback control after subarachnoid hemorrhage results in vasospasm due to PKC activation. This study was undertaken to verify this hypothesis. Methods Different dogs were prepared for three separate experiments: measurement of the angiographic diameter of the basilar artery and determination of cGMP and PKC activity in vascular smooth muscle cells. In each experiment, two models were used: the single-hemorrhage model for mild vasospasm and the two-hemorrhage model for severe vasospasm. In both models, chronological changes of these three parameters were examined from day 1 until day 7. Results In the single-hemorrhage model, mild vasospasm and a slight decrease of the cGMP level were noted on day 4, then both returned to the baseline levels on day 7. PKC activity was slightly enhanced throughout the study period. In the two-hemorrhage model, severe vasospasm and a significant decrease of the cGMP level were observed on day 5 and persisted until day 7. PKC activity was remarkably enhanced from day 5 until day 7. The differences between the two models with regard to the three parameters were statistically significant. Conclusions The decrease of cGMP level and the enhancement of PKC activity were obviously associated with the development of severe vasospasm. We conclude that subarachnoid hemorrhage disturbed the feedback control exerted by nitric oxide on PKC activation, leading to PKC-dependent vasospasm.