Abstract 222: Upregulation Of Cyp4a1 Gene Expression Restores The Impaired Myogenic Response And Autoregulation Of Cerebral Blood Flow In Dahl Salt Sensitive Rats

Abstract

We have reported that a reduction in the expression of CYP4A and the production of 20-HETE in the renal outer medulla contributes to development of hypertension in Dahl salt sensitive (SS) rats. The present study examined whether 20-HETE production is also reduced in the vasculature and if a deficiency in the formation of 20-HETE in the vasculature alters vascular tone and promotes end organ damage. The production of 20-HETE, the myogenic response of middle cerebral arteries (MCA) and autoregulation of cerebral blow flow (CBF) was compared in SS, CYP4A1 transgenic SS rats and SS.5BN consomic rats in which chromosome 5 from Brown Norway (BN) was transferred into the SS genetic background. 20-HETE production was 6-fold higher in cerebral arteries obtained from CYP4A1 transgenic (n=25) and SS.5BN (n=4)rats than in SS (n=17) rats 0.77 ± 0.08 versus 0.12 ± 0.03 pmol/mg/min). The luminal diameter of MCA decreased to 70 ± 3 % in CYP4A1 transgenic rats and to 65 ± 6 in SS.5BN when perfusion pressure was increased from 40 to 140 mmHg, whereas it remained unaltered in SS rats. Administration of the inhibitor of the synthesis of 20-HETE, HET0016 (10 uM), abolished the myogenic response in MCA of CYP4A1 transgenic and SS.5BN rats but had no effect in SS rats. CBF was poorly autoregulated and increased by 49 ± 6% in SS rats as MAP was increased by 60% from 100 to 160 mmHg. In contrast, CBF was only increased by 26 ± 5% and in SS.5BN rats and by 19 ± 2% in CYP4A1 transgenic rats when MAP was increased in the same range. These results indicate that a genetic deficiency of 20-HETE contributes to an impaired myogenic response in autoregulation of CBF in SS rats which may contribute to vascular remodeling, stroke and dementia following the onset of hypertension.