Submitted on June 28, 2007
Accepted on August 30, 2007
Roles of vasoconstrictor prostaglandins, COX-1 and -2, AT-1, -2 and TP receptors in a rat model of early 2K,1C hypertension
William J. Welch1, Kinjal Patel1, Paul Modlinger1, Margarida Mendonca1, Noritaka Kawada1, Kathryn Dennehy1, Shakil Aslam1, and Christopher S. Wilcox1*
1 Nephrology and Hypertension, Georgetown University, Washington, District of Columbia, United States
* To whom correspondence should be addressed. E-mail: wilcoxch{at}georgetown.edu.
Angiotensin II (Ang II) activating AT1 receptors (Rs) enhances superoxide anion (O2.-) and arachidonate (AA) formation. AA is metabolism by cyclooxygenases (COXs) to PGH2 which is metabolized by thromboxane A2 synthase (TxA2-S) to TxA2 or is oxidized to 8-isoprostane PGF2
(8-Iso) by O2.-. PGH2, TxA2 and 8-Iso activate thromboxane-prostanoid receptors (TP-Rs). We investigated the hypothesis that BP in a rat model of early (3 week) 2K,1C Goldblatt hypertension is maintained by AT1- or AT2-Rs, driving COX-1 or -2-dependent products that activate TP-Rs. Compared to sham, 2K,1C Goldblatt rats had increased MAP (120±4 vs. 155±3 mmHg; p<0.001), plasma renin activity (22±7 vs. 48±5 ng∙ml -1 ∙hr -1; p<0.01), plasma malondialdehyde (1.07±0.05 vs. 1.58±0.16 nmol∙L -1; p<0.01) and TxB2 excretion (26±4 vs. 51±7 ng∙24h -1; p<0.01). Acute iv graded doses of benazeprilat (angiotensin converting enzyme inhibitor) reduced MAP at 20 min (-36±5 mmHg; p<0.001) and the excretion of TxA2 metabolites. Indomethacin (non-selective COX antagonist) or SC-560 (COX-1 antagonist) reduced MAP at 20 min (-25±5 and -28±7 mmHg; p<0.001), whereas valdecoxib (COX-2 antagonist) was ineffective (-9±5 mmHg; ns). Losartan (AT1-R antagonist) or SQ -29,548 (TP-R antagonist) reduced MAP at 150 min (-24±6 and -22±3 mmHg; p<0.001), whereas PD-123,319 (AT2-R antagonist) was ineffective. Neither acute blockade of TP-Rs, COX-1 or -2 changed PRA but TxB2 generation by the clipped kidney was reduced by blockade of COX-1 and increased by blockade of COX-2. 2K,1C hypertension in rats activates renin, O2.- and vasoconstrictor PGs. Hypertension is maintained by AT1- Rs and by COX-1, but not -2 products that activate TP-Rs.
