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1 Cardiovascular Kidney Institute and Division of Nephrology and Hypertension, Georgetown University, Washington, DC, USA
2 Division of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
* To whom correspondence should be addressed. E-mail: wilcoxch{at}georgetown.edu.
We investigated the hypothesis that thromboxane A2 (TxA2)- prostaglandin H2 receptors (TP-Rs) mediate the hemodynamic responses and increase in reactive oxygen species (ROS) to angiotensin II (AngII; 400ng.kg-1.min-1 s.c. for 14 days) in TP-R knockout (TP-/-) and wild (+/+) mice. TP-/- had normal basal mean arterial blood pressure (MAP) and glomerular filtration rate but reduced renal blood flow (RBF) and increased filtration fraction (FF) and renal vascular resistance (RVR) and markers ofROS (TBARS and 8-isoprostane PGF2
) and nitric oxide (NOx). Infusion of AngII into TP+/+ increased ROS and thromboxane B2 (TxB2), and increased RVR and FF. AngII infusion into TP-/- mice reduced angiotensin I and
increased aldosterone, but caused a blunted increase in MAP (TP-/-; +6±2 vs. TP+/+; +15±3mmHg) and failed to increase FF, ROS or TxB2, but
increased nitric oxide (NOx) and paradoxically decreased RVR (-2.1+1.7 vs.+2.6±0.8mmHg.ml-1.min-1.g-1). Blockade of AT1-receptor of TP-/- mice
infused with AngII reduced the MAP (-8mmHg) and aldosterone, but did not change the RVR or ROS.
In conclusion: during an AngII slow pressor response, AT1-receptors activate TP-Rs that generate ROS and prostaglandins but inhibit NO. TP-Rs mediate all of the increase in RVR and FF, part of the increase in MAP, but
are not implicated in the suppression of angiotensin I or increase in aldosterone. TP-/- mice have a basal increase in RVR and FF associated with ROS.
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