on January 12, 2004
Published online before print January 12, 2004, doi: 10.1161/01.HYP.0000112225.27560.24
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Submitted on September 29, 2003
From Divisions of Nephrology (H.P., K.A., T.M.C.) and Cardiology (L.M., H.R.), Department of Medicine, Duke University, and Durham VA Medical Centers, Durham, NC. * To whom correspondence should be addressed. E-mail: tcoffman{at}acpub.duke.edu.
Abstract--To evaluate the role of thromboxane in hypertension and its complications, we studied mice with targeted disruption of the TXA2 receptor gene in an angiotensin-II-dependent model of hypertension. To determine whether genetic background might alter the physiological actions of the TP receptor, we studied two lines of TP knockout (Tp-/-) mice with distinct genetic backgrounds (C57BL/6 and BALB/c). During chronic angiotensin II infusion (1000 ng/kg per minute x 28 days by subcutaneous osmotic pump), TP deficiency prevented mortality in the C57BL/6 background but not in the BALB/c strain. Chronic angiotensin II infusion also caused a rapid and significant increase in blood pressure in wild-type (WT) C57BL/6 and BALB/c animals, which was significantly attenuated in Tp-/- mice on either background. After 28 days of infusion, cardiac hypertrophy only occurred in the C57BL/6 strain: heart/body weight ratio increased by 57%±8% in WT mice compared with 17%±6.5% for the Tp-/- mice (P<0.01). Chronic angiotensin II infusion caused albuminuria only in the C57BL/6 strain, and TP deficiency did not alter its development. Cyclooxygenase-1 knockout mice also had attenuated blood pressure increase during chronic angiotensin II infusion, suggesting that cyclooxygenase-1 metabolites are involved in angiotensin-II-dependent hypertension. Thus, on the C57BL/6 background, TP receptors contribute to cardiac hypertrophy but not proteinuria. However, irrespective of genetic background, the TP receptor makes a robust contribution to the pathogenesis of angiotensin II-dependent hypertension.
Revised on November 5, 2003
Role for Thromboxane Receptors in Angiotensin-II-Induced Hypertension
Helene Francois;
Key words: thromboxane • hypertension • angiotensin II • hypertrophy • proteinuria • cyclooxygenase
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