Inhibition of lipoxygenase pathway reduces blood pressure in renovascular hypertensive rats.
To assess the potential role of the lipoxygenase (LO) pathway in the vasculature in an angiotensin II (ANG II)-dependent model of hypertension, we investigated the effect of LO pathway inhibition on blood pressure in the two-kidney, one-clip (2K,1C) Goldblatt hypertensive rat. The development of renovascular hypertension in 2K,1C rats was attenuated by oral administration of phenidone (Phe, 60 mg.kg-1.day-1), a nonselective LO inhibitor, throughout the 3 wk of observation after renal artery constriction. In contrast, the same treatment protocol had no effect on the evolution of hypertension in the deoxycorticosterone acetate-salt rat, which is considered to be an ANG II-independent form of hypertension. The hypotensive effect of Phe was not associated with changes in plasma renin or aldosterone concentration (PRC and PAC, respectively). In vitro synthesis of 12-hydroxyeicosatetraenoic acid (12-HETE) by aortic segments was increased in 2K,1C hypertensive rats compared with sham-operated rats. In addition, the synthesis of 12-HETE was suppressed by the in vitro addition of Phe (10(-4) M) to aortic-segment incubates obtained from 2K,1C rats and sham-operated rats. Acute administration of Phe (30 or 60 mg/kg) in 2K,1C hypertensive rats produced a rapid and sustained decrease in mean blood pressure (MBP). This decrease in MBP was accompanied by a brisk rise in PRC and PAC. In contrast, bolus administration of indomethacin, a selective cyclooxygenase inhibitor, did not affect MBP, PRC, or PAC.(ABSTRACT TRUNCATED AT 250 WORDS)
Nozawa
K
K
Division of Endocrinology, Sepulveda Veterans Administration Medical Center, California.
Tuck
M L
ML
Golub
M
M
Eggena
P
P
Nadler
J L
JL
Stern
N
N
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006978:Hypertension, Renovascular / Q000378:metabolism / Q000503:physiopathology*; D016859:Lipoxygenase Inhibitors; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C015429:phenidone