Role for thromboxane receptors in angiotensin-II-induced hypertension.
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.
Francois
Helene
H
Division of Nephrology, Department of Medicine, Duke University, and Durham VA Medical Centers, Durham, NC 27705, USA.
Athirakul
Krairerk
K
Mao
Lan
L
Rockman
Howard
H
Coffman
Thomas M
TM
D000419:Albuminuria / Q000139:chemically induced; D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000139:chemically induced; D051545:Cyclooxygenase 1; D006321:Heart / Q000503:physiopathology; D006339:Heart Rate; D006973:Hypertension / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000502:physiology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics / Q000502:physiology*; D016019:Survival Analysis
D007527:Isoenzymes; D008565:Membrane Proteins; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D000804:Angiotensin II; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse