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Am J Physiol Heart Circ Physiol. 2007 Nov;293(5):H2644-9. Epub 2007 Aug 31.

Roles of vasoconstrictor prostaglandins, COX-1 and -2, and AT1, AT2, and TP receptors in a rat model of early 2K,1C hypertension.

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Division of Nephrology and Hypertension, Georgetown University, Washington, DC 20007, USA.


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.

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