Published online before print January 12, 2004, doi: 10.1161/01.HYP.0000112225.27560.24
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(Hypertension. 2004;43:364.)
© 2004 American Heart Association, Inc.
Scientific Contribution |
Role for Thromboxane Receptors in Angiotensin-II–Induced Hypertension
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.
Correspondence to Thomas M. Coffman, Building 6/Nephrology (111I), VA Medical Center, 508 Fulton Street, Durham, NC 27705. E-mail tcoffman{at}acpub.duke.edu
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.
Key Words: thromboxane • hypertension • angiotensin II • hypertrophy • proteinuria • cyclooxygenase
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