TONIC INHIBITION OF RENIN SECRETION BY THE 12-LIPOXYGENASE PATHWAY - AUGMENTATION BY HIGH-SALT INTAKE

Recent evidence suggests that lipoxygenase (LO) metabolites inhibit re nin production in vitro. However, the physiological significance of th is effect has not been determined. This study examined the role of the LO pathway in the regulation of plasma renin concentration (PRC) in v ivo. The acute administration of two structurally unrelated LO inhibit ors, phenidone (30 and 60 mg/kg) and esculetin (60 mg/kg), resulted in suppression of platelet 12 hydroxyeicosatetraenoic acid (12HETE) prod uction, reduction in systemic arterial pressure and a 2- to 3-fold inc rease in PRC. To determine whether the esculetin-induced increase in P RC was secondary to hypotension, esculetin was also admininstered to r ats preinfused with a presser dose of norepinephrine. In these acutely hypertensive rats, esculetin still induced a 2.5-fold increase in PRC , whereas blood pressure remained over 40 mm Hg above basal levels. Fu rther, esculetin [10(-6) M) increased renin release in renal slices fr om 150 +/- 10 to 310 +/- 20 ng/ml . h (P < 0.05) and this rise was ent irely blocked in the presence of 12HETE (10(-7) M; 130 +/- 40 ng/ml . h). In rats placed on high salt intake, 12HETE concentration in renal slices from the outer cortex was considerably higher than in renal sli ces from salt-restricted rats (116.5 +/- 15.7 us. 65 +/- 12 pg/mg prot ein; P < 0.05). Chronic administration of the LO inhibitor phenidone a lso resulted in an increase of PRC, which was independent of changes i n blood pressure On either high salt (3.15%) or low salt (0.05%) diet phenidone-treated rats had higher PRC levels than the respective contr ol groups [high salt 9.7 +/- 3.5 vs. 1.9 +/- 1.4 ng/ml h; P < 0.05; lo w salt 33.2 +/- 5.3 vs. 19.4 +/- 3.10 ng/ml . h; P < 0.05]. The findin g that LO blockers are potent stimulators of PRC in vivo suggests the existence of a physiological tonic inhibition of renin secretion by LO products that is operative under a wide range of salt intake. High sa lt intake enhances this inhibitory tone by increasing renal cortical 1 2 LO activity and, in fact, normal suppression of PRC during high salt diet does not occur in LO-blocked animals. Thus, the LO pathway exert s a tonic inhibitory effect on renin release, which appears particular ly important for renin suppression during high salt intake.