Prostacyclin protects against elevated blood pressure and cardiac fibrosis.
Specific inhibitors of COX-2 have been associated with increased risk for cardiovascular complications. These agents reduce prostacyclin (PGI2) without affecting production of thromboxane (Tx) A2. While this abnormal pattern of eicosanoid generation has been implicated in the development of vascular disease associated with COX-2 inhibition, its role in the development of hypertension, the most common cardiovascular complication associated with COX-2 inhibition, is not known. We report here that mice lacking the receptor for PGI2 (IPKOs) develop salt-sensitive hypertension, cardiac hypertrophy, and severe cardiac fibrosis. Coincidental deletion of the TxA2 (TP) receptor does not prevent the development of hypertension, but cardiac hypertrophy is ameliorated and fibrosis is prevented in IPTP double knockouts (DKOs). Thus, deletion of the IP receptor removes a constraint revealing adverse cardiovascular consequences of TxA2. Our data suggest that adjuvant therapy that blocks unrestrained Tx actions might protect against end-organ damage without affecting blood pressure in patients taking COX-2 inhibitors.
Francois
Helene
H
Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina 27705.
Athirakul
Krairerk
K
Howell
David
D
Dash
Rajesh
R
Mao
Lan
L
Kim
Hyung-Suk
HS
Rockman
Howard A
HA
Fitzgerald
Garret A
GA
Koller
Beverly H
BH
Coffman
Thomas M
TM
D000375:Aging; D000450:Aldosterone / Q000652:urine; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D011464:Epoprostenol / Q000494:pharmacology*; D005355:Fibrosis / Q000473:pathology / Q000517:prevention & control; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D009929:Organ Size / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D012083:Renin / Q000378:metabolism; D012982:Sodium, Dietary / Q000008:administration & dosage; D013929:Thromboxane B2 / Q000652:urine
D000959:Antihypertensive Agents; D002316:Cardiotonic Agents; D016861:Cyclooxygenase Inhibitors; D006834:Hydrazines; D012333:RNA, Messenger; D012982:Sodium, Dietary; C029424:hydrazine; D000450:Aldosterone; D013929:Thromboxane B2; D011464:Epoprostenol; D012083:Renin