The lipoxygenase inhibitor phenidone protects against proteinuria and stroke in stroke-prone spontaneously hypertensive rats.
The present study examined whether the dual cyclooxygenase/lipoxygenase inhibitor phenidone would protect stroke-prone spontaneously hypertensive rats (SHRSP) from stroke and hypertensive renal disease. Vehicle-treated SHRSP (N = 6), fed stroke-prone rodent diet and 1% saline, exhibited severe systolic blood pressure elevation (261 +/- 10 mm Hg, mean +/- SEM), marked proteinuria (90 +/- 12 mg/day), and stroke, with an average age at death of 14 +/- 1 weeks. In a second group of six saline-loaded SHRSP, treatment with phenidone (60 mg/kg/day) was started at 8.4 weeks of age. Despite establishment of severe hypertension in this group (274 +/- 10 mm Hg), proteinuria remained at basal levels (28 +/- 13 mg/day), and signs of stroke were absent (P less than .01 v vehicle) through at least 16 weeks of age. Phenidone treatment also prevented the declines in body weight and food intake observed in vehicle-treated SHRSP, and maintained urine volume and saline intake. Serum 12-hydroxy-eicosatetraenoic acid (12-HETE) generation was significantly inhibited greater than 50% in incubates of whole blood from phenidone-treated SHRSP. We have previously shown that agents which interfere with the renin-angiotensin system afford protection from renal and cerebrovascular injury in saline-loaded SHRSP; cyclooxygenase inhibition alone will hasten the onset of these pathologic changes. Whether phenidone, which has been reported to attenuate angiotensin II-mediated effects, affords vascular protection by interference with a lipoxygenase-mediated action of angiotensin II remains to be elucidated.
Munsiff
A V
AV
Department of Pharmacology, New York Medical College, Valhalla 10595.
Chander
P N
PN
Levine
S
S
Stier
C T
CT
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000517:prevention & control*; D015777:Eicosanoids / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D014677:Pharmaceutical Vehicles; D011507:Proteinuria / Q000517:prevention & control*; D011720:Pyrazoles / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR
D015777:Eicosanoids; D016859:Lipoxygenase Inhibitors; D014677:Pharmaceutical Vehicles; D011720:Pyrazoles; C015429:phenidone