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Previous studies have shown that endothelin (ET)-1 stimulates thromboxane (Tx)A2 production and so we hypothesized that inhibiting prostanoid TP receptors would prevent the pressor and intrarenal haemodynamic response to an acute infusion of ET-1.

Male Sprague-Dawley rats were anaesthetized with Inactin (Sigma Chemical, St Louis, MO, USA; 50 mg/kg) and catheters were inserted into the femoral artery and vein for recording mean arterial pressure (MAP) and infusion of ET-1 and receptor antagonists, respectively. A jugular vein catheter was used for the infusion of bovine serum albumin (6.2% in saline) during surgery (1.25% bodyweight). The pressor response to a 1 h infusion of ET-1 (6 pmol/kg per min) was determined in rats that had been pretreated with vehicle (0.9% NaCl) or the TP receptor antagonist SQ29548 (2 mg/kg per h). Laser Doppler single-optic fibres were implanted in the left kidney for the measurement of medullary blood flow (MBF) and cortical blood flow (CBF).

Prostanoid TP receptor blockade completely inhibited the acute pressor response to ET-1; the change in MAP was 14 2% versus -3 4% in vehicle and SQ29548 groups, respectively (P < 0.05). Endothelin-1 reduced CBF (-15.2 3.3%), a response that was not significantly changed by SQ29548 (-6.2 7.6%). Similarly, the ET-1-mediated response in MBF was not altered by the TP receptor antagonist (7.7 4.9 vs 6.5 5.2%).

To determine the influence of the ETB receptor in modulating the response to ET-1 during TP receptor blockade, additional groups were pretreated with A-192621, an ETB receptor-selective antagonist (10 mg/kg, i.v.). A-192621 potentiated the increase in MAP produced by ET-1 (32 5%; P < 0.05 vs ET-1 alone). SQ29548 significantly inhibited, but did not completely block, the increase in MAP produced by ET-1 during ETB antagonist treatment (18 4%; P < 0.05). Endothelin-1-induced decreases in CBF were significantly enhanced in rats that were pretreated with A-192621, whereas ET-1 also significantly decreased MBF following A-192621 treatment. During ETB receptor blockade, TP receptor inhibition had no effect on the ET-1-mediated response of CBF and MBF.

These results suggest that TP receptor activation is not involved in the renal haemodynamic responses to ET-1. However, TP receptor activation contributes to the acute pressor response to ET-1, but does not account for the potentiated increase in MAP during ETB receptor blockade.
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Keywords: ETB receptor; TP receptor; cortical blood flow; endothelin; medullary blood flow

Document Type: Research Article

Publication date: March 1, 2006

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