17beta-estradiol restores endothelial nitric oxide release to shear stress in arterioles of male hypertensive rats.

BACKGROUND: Endothelial nitric oxide (NO)-mediated responses are impaired in arterioles of male spontaneously hypertensive rats (SHR), but they are still present in female SHR. We hypothesized that in vitro incubation of arterioles of male SHR with estrogen will restore NO-mediated responses by upregulation of endothelial NO synthase. METHODS AND
RESULTS: Responses to increases in perfusate flow (from 0 to 25 microL/min) and to the calcium ionophore A23187 (5 x 10(-8) to 10(-6) mol/L), norepinephrine (NE; 10(-7) to 3 x 10(-7) mol/L), sodium nitroprusside (SNP; 10(-8) to 10(-6) mol/L), and adenosine (ADO; 10(-6) to 5 x 10(-5) mol/L) were studied in cannulated and pressurized gracilis muscle arterioles ( approximately 75 microm in diameter) isolated from 12-week-old male SHR before and after incubation with 10(-9) mol/L 17beta-estradiol (17beta-E(2)) for 16 to 18 hours. After incubation with 17beta-E(2), basal diameter of arterioles was significantly increased (by approximately 10%), and flow-induced dilation was significantly enhanced (79.8+/-2.9 versus 103.7+/-3.7 microm at 25 microL/min), resulting in a lowered shear stress (62.0+/-9.1 versus 32.5+/-4.2 dyne/cm(2)). Also, vasoconstrictions to A23187 were reversed to dilations (-18.7+/-2.2 versus 18.8+/-1.7 microm), and constrictions to NE were significantly attenuated (-30.7+/-3.0 versus -21.2+/-2.8 microm). These alterations were eliminated by ICI 182,780 (10(-7) mol/L), an estrogen receptor antagonist; 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole (10(-5) mol/L), a transcription inhibitor; or N(omega)-nitro-L-arginine methyl ester (10(-4) mol/L), an inhibitor of NO synthase, whereas they were not affected by aminoguanidine (5 x 10(-5) mol/L), a specific inhibitor of inducible NO synthase. Arteriolar responses were not altered by incubation with 17alpha-estradiol.
CONCLUSIONS: Estrogen, via a receptor-mediated pathway, upregulates endothelial NO synthase gene expression, leading to increased NO production, and restores the regulation of wall shear stress in arterioles of male SHR.