CALL FOR PAPERS Cardiovascular-Renal Mechanisms in Health and Disease Roles of vasoconstrictor prostaglandins, COX-1 and -2, and AT1, AT2, and TP receptors in a rat model of early 2K,1C hypertension

Welch WJ, Patel K, Modlinger P, Mendonca M, Kawada N, Dennehy K, Aslam S, Wilcox CS. Roles of vasoconstrictor prostaglandins, COX-1 and -2, and AT1, AT2, and TP receptors in a rat model of early 2K,1C hypertension. Am J Physiol Heart Circ Physiol 293: H2644–H2649, 2007. First published August 31, 2007; doi:10.1152/ajpheart.00748.2007.—Angiotensin (ANG) II activating type 1 receptors (AT1Rs) enhances superoxide anion (O2 ) and arachidonate (AA) formation. AA is metabolized by cyclooxygenases (COXs) to PGH2, which is metabolized by thromboxane (Tx)A2 synthase to TxA2 or oxidized to 8-isoprostane PGF2 (8-Iso) by O2 . PGH2, TxA2, and 8-Iso activate thromboxane-prostanoid receptors (TPRs). We investigated whether blood pressure in a rat model of early (3 wk) two-kidney, one-clip (2K,1C) Goldblatt hypertension is maintained by AT1Rs or AT2Rs, driving COX-1 or -2-dependent products that activate TPRs. Compared with sham-operated rats, 2K,1C Goldblatt rats had increased mean arterial pressure (MAP; 120 4 vs. 155 3 mmHg; P 0.001), plasma renin activity (PRA; 22 7 vs. 48 5 ng ml 1 h ; P 0.01), plasma malondialdehyde (1.07 0.05 vs. 1.58 0.16 nmol/l; P 0.01), and TxB2 excretion (26 4 vs. 51 7 ng/24 h; P 0.01). Acute graded intravenous doses of benazeprilat (angiotensin-converting enzyme inhibitor) reduced MAP at 20 min ( 36 5 mmHg; P 0.001) and excretion of TxA2 metabolites. Indomethacin (nonselective 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; not significant). Losartan (AT1R antagonist) or SQ-29548 (TPR antagonist) reduced MAP at 150 min ( 24 6 and 22 3 mmHg; P 0.001), whereas PD-123319 (AT2R antagonist) was ineffective. Acute blockade of TPRs, COX-1, or COX-2 did not change 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 AT1Rs and by COX-1, but not COX-2, products that activate TPRs.