title: Roles of vasoconstrictor prostaglandins, COX-1 and -2, and AT1, AT2, and TP receptors in a rat model of early 2K,1C hypertension.
abstract: Angiotensin (ANG) II activating type 1 receptors (AT(1)Rs) enhances superoxide anion (O(2)*(-)) and arachidonate (AA) formation. AA is metabolized by cyclooxygenases (COXs) to PGH(2), which is metabolized by thromboxane (Tx)A(2) synthase to TxA(2) or oxidized to 8-isoprostane PGF(2alpha) (8-Iso) by O(2)*(-). PGH(2), TxA(2), 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 AT(1)Rs or AT(2)Rs, 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 x ml(-1) x h(-1); P < 0.01), plasma malondialdehyde (1.07 +/- 0.05 vs. 1.58 +/- 0.16 nmol/l; P < 0.01), and TxB(2) 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 TxA(2) 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 (AT(1)R antagonist) or SQ-29548 (TPR antagonist) reduced MAP at 150 min (-24 +/- 6 and -22 +/- 3 mmHg; P < 0.001), whereas PD-123319 (AT(2)R antagonist) was ineffective. Acute blockade of TPRs, COX-1, or COX-2 did not change PRA, but TxB(2) 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, O(2)*(-), and vasoconstrictor PGs. Hypertension is maintained by AT(1)Rs and by COX-1, but not COX-2, products that activate TPRs.
authors.affiliation: Division of Nephrology and Hypertension, Georgetown University, Washington, DC 20007, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Welch
authors.forename: Kinjal
authors.initials: K
authors.lastname: Patel
authors.forename: Paul
authors.initials: P
authors.lastname: Modlinger
authors.forename: Margarida
authors.initials: M
authors.lastname: Mendonca
authors.forename: Noritaka
authors.initials: N
authors.lastname: Kawada
authors.forename: Kathryn
authors.initials: K
authors.lastname: Dennehy
authors.forename: Shakil
authors.initials: S
authors.lastname: Aslam
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilcox
mesh_terms: D000818:Animals; D001794:Blood Pressure; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D017482:Receptors, Thromboxane / Q000378:metabolism*; D014661:Vasoconstriction
chemical_list: D008565:Membrane Proteins; D011453:Prostaglandins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D017482:Receptors, Thromboxane; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat