A role for the thromboxane receptor in L-NAME hypertension.
Actions of the lipid mediator thromboxane (Tx) A2 acting through the TP receptor contribute to the pathogenesis of cardiovascular disease. To further explore the role of TxA2 in hypertension, we examined the consequences of deficiency of the TP receptor on the course of hypertension associated with endothelial dysfunction and salt sensitivity. To this end, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was administered to TP-deficient (Tp-/-) and wild-type (Tp+/+) control mice in drinking water for 21 wk along with a high-salt (HS; 6% NaCl) diet. Administration of L-NAME increased urinary excretion of TxB2 to a similar extent in both Tp+/+ and Tp-/- animals. L-NAME also caused significant and sustained elevations in blood pressure that reached a maximum between weeks 3 and 6. However, the severity of hypertension was attenuated in the Tp-/- mice throughout the study period (P<0.001). At the end of the study, the wild-type mice developed significant cardiac hypertrophy (23.6+/-2% increase in heart-to-body weight ratio). The severity of cardiac hypertrophy was attenuated in the TP-deficient group (11.1+/-2.6%; P<0.05). In contrast, kidney hypertrophy was exaggerated in the Tp-/- mice compared with controls (37.1+/-5.4 vs. 12.3+/-2.3%; P<0.01). Moreover, the severity of glomerulosclerosis, tubule vacuolization, and interstitial chronic inflammation was also enhanced in the Tp-/- group (P<0.01). Thus, in L-NAME hypertension, TP receptors contribute to elevated blood pressure and cardiac hypertrophy. In this model, TP receptors also provided unexpected protection against kidney injury.
Francois
Helene
H
Department of Medicine, Duke University Medical Center, Rm. 2018 MSRB II, 106 Research Drive, Durham, NC 27710, USA.
Makhanova
Natalia
N
Ruiz
Philip
P
Ellison
Jonathan
J
Mao
Lan
L
Rockman
Howard A
HA
Coffman
Thomas M
TM
D000419:Albuminuria / Q000139:chemically induced / Q000150:complications / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006332:Cardiomegaly / Q000150:complications; D004195:Disease Models, Animal; D004326:Drinking; D004435:Eating; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006977:Hypertension, Renal / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism*; D028421:Isoprostanes / Q000652:urine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D012982:Sodium, Dietary / Q000494:pharmacology; D013929:Thromboxane B2 / Q000652:urine
D004791:Enzyme Inhibitors; D028421:Isoprostanes; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D012982:Sodium, Dietary; D009569:Nitric Oxide; D013929:Thromboxane B2; D019331:NG-Nitroarginine Methyl Ester