Cyclooxygenase and thromboxane/prostaglandin receptor contribute to aortic endothelium-dependent dysfunction in aging female spontaneously hypertensive rats

Department of Kinesiology, Faculty of Applied Health Sciences, University of Waterloo, Waterloo, Ontario, Canada Submitted 18 June 2008 ; accepted in final form 17 August 2009 Cyclooxygenase (COX)-derived vasoconstrictory prostanoids contribute to impaired endothelium-dependent vasorelaxation in aging male (m) spontaneously hypertensive rats (SHR); however, vasomotor responses in aging female (f) SHR and sex differences in aging SHR are unknown. Examining mechanisms governing dysfunction in aging fSHR will contribute to understanding sex-dependent vascular complications in advanced hypertension. Aortic endothelium-dependent relaxation dose responses (ACh) of 16- and 30-wk-old mSHR and fSHR and normotensive Wistar-Kyoto rats were examined in the absence (no drug control) and presence of COX inhibition [indomethacin (Indo)] and thromboxane/prostaglandin receptor inhibition (SQ-29548). No drug control-treated 16-wk mSHR exhibited considerable blunting of the peak relaxation response to ACh (e.g., 77 ± 4% relaxation to 10 –5 mol/l) vs. Wistar-Kyoto controls (89 ± 6%), and greater dysfunction occurred in 30-wk mSHR (63 ± 2%). Interestingly, ACh relaxations of fSHR were unimpaired at 16 wk (101 ± 2% to 10 –5 mol/l), but blunted in 30 wk (76 ± 4%). Indo and SQ-29548 restored robust ACh vasorelaxation in all groups (e.g., 113 ± 3 and 112 ± 3%, respectively, in Indo- and SQ-29548-treated 30-wk fSHR). Aortic COX-1 protein expression was elevated by 75% in 30-wk vs. 16-wk fSHR, whereas group-averaged ACh-stimulated aortic PGI 2 release (assessed as 6- keto-PGF 1 ) was 30% greater in 30-wk vs. 16-wk fSHR (9,926 ± 890 vs. 7,621 ± 690 pg·ml –1 ·mg dry wt –1 ), although this did not reach significance ( P = 0.0758). Dramatic deterioration of endothelium-dependent vasomotor function in fSHR across this age range involves COX and thromboxane/prostaglandin receptor, supporting a mechanism of impairment similar to that which occurs in aging mSHR. endothelium-derived contracting factor; prostanoid; nitric oxide; sex difference; endothelium-dependent relaxation; prostaglandin I 2 ; thromboxane/prostaglandin receptor; SQ-29548 Address for reprint requests and other correspondence: J. W. E. Rush, Dept. of Kinesiology, Faculty of Applied Health Sciences, Univ. of Waterloo, 200 Univ. Ave. West, Waterloo, ON, Canada N2L 3G1 (e-mail: jwerush{at}uwaterloo.ca ).