Cerebrovascular alterations in protein kinase C-mediated constriction in stroke-prone rats

Background and Purpose-Cerebrovascular pressure-dependent constriction may involve the smooth muscle production of diacylglycerol, which could facilit ate constriction by activating protein kinase C (PKC). A dysfunctional PKC system could promote the loss of pressure-dependent constriction. We attemp ted to determine whether the alterations in pressure-dependent constriction in the middle cerebral arteries (MCAs) observed in relation to stroke deve lopment in Wistar-Kyoto stroke-prone spontaneously hypertensive rats (SHRsp ) were associated with defects in the ability of the arteries to constrict in response to PKC activation. Methods-MCAs were sampled from SHRsp before and after stroke development an d in stroke-resistant Wistar-Kyoto spontaneously hypertensive rats. A press ure myograph was used to test the ability of the arteries to constrict in r esponse to a 100 mm Hg pressure step and subsequently to contract in respon se to phorbol 12,13-dibutyrate in the presence of nifedipine (3 mu mol/L). Results-Pressure-dependent constriction and constriction in response to pho rbol dibutyrate in the MCAs were inhibited by PKC inhibitors (staurosporine [40 nmol/L], chelerythrine [12 mu mol/L], bisindolylmaleimide [5 mu mol/L] ), declined with age before stroke development in SHRsp, and were absent af ter stroke. There was a significant relationship between pressure- and phor bol dibutyrate-induced constriction (r=0.815, P<0.05). Conclusions-Phorbol esters interact with the same activation site as diacyl glycerol to stimulate PKC. An inability to constrict in response to phorbol dibutyrate may reflect unresponsiveness to diacylglycerol and may contribu te to the loss of pressure-dependent constriction associated with stroke in the MCAs of SHRsp. The loss of this autoregulatory function before stroke could increase the risk of cerebral hemorrhage.