Submitted on June 4, 2004
Accepted on March 10, 2005
Restoration of Normal Vascular Relaxation Mechanisms in Cerebral Arteries by Chromosomal Substitution in Consomic SS.13BN Rats
Ines Drenjancevic-Peric1, Shane A Phillips1, John R Falck2, and Julian H Lombard2*
1 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA
* To whom correspondence should be addressed. E-mail: jlombard{at}mcw.edu.
This study sought to identify the mechanisms of vascular relaxation that are rescued in middle cerebral arteries (MCA) of SS.13BN consomic rats by substituting chromosome 13 containing the renin gene from Brown Norway (BN) rats into the Dahl salt sensitive (SS) genetic background. Isolated MCA from SS rats exhibited an indomethacin-sensitive constriction in response to acetylcholine (ACh) and hypoxia. ACh-induced dilation was NO dependent and hypoxic dilations were cyclooxygenase-dependent in BN and SS.13BN rats. In SS rats, hypoxic dilation was restored by indomethacin and abolished by inhibiting CYP450 epoxygenases, suggesting a role for epoxyeicosatrienoic acids (EETs). MCA from SS rats and SS.13BN constricted and MCA from BN dilated in response to the stable prostacyclin analogue iloprost. MCA from SS.13BN and BN rats (but not SS rats) dilated in response to the EP2 receptor agonist butaprost. Hypoxia increased prostacyclin release in cerebral arteries from all the strains, while thromboxane A2 production was reduced in BN vessels only. These data suggest that SS rats may be less sensitive to vasodilator prostaglandins and that normalization of renin-angiotensin system regulation causes a switch from production of COX derived vasoconstrictor metabolites (in SS rats) toward NO-dependent relaxation in response to ACh and prostaglandin-dependent dilation in response to hypoxia in SS.13BN rats.
