Evidence for a Direct Stimulatory Effect of Prostacyclin on Renin Release in Man

Abstract

A B ST R A C T The objectives of this investigation were: (a) to characterize the time and dose dependence of the effects of prostacyclin (PGI2) on renin release in healthy men; (b) to define whether PGI2-induced renin release is secondary to hemodynamic changes; (c) to determine the plasma and urine concentrations of 6-keto-PGFIa (the stable breakdown product of PGI2) associated with renin release induced by exogenous or pharmacologically enhanced endogenous PGI2. Intravenous PGI2 or 6-keto-PGFIa infusions at nominal rates of 2.5, 5.0, 10.0, and 20.0 ng/kg per min were performed in each of six normal human subjects; in three of them, PGI2 infusion was repeated after ,B-adrenergic blockade and cyclooxygenase inhibition.PGI2, but not 6-keto-PGFIa, caused a time-and dosedependent increase of plasma renin activity, which reached statistical significance at 5.0 ng/kg per min and was still significantly elevated 30 min after discontinuing the infusion. Although combined propranolol and indomethacin treatment significantly enhanced the hypotensive effects of infused PGI2, it did not modify the dose-related pattern of PGI2-induced renin release.Plasma 6-keto-PGFIa levels rose from undetectable levels (<7.5 pg/ml) in a stepwise fashion during increasingly higher infusion rates of PGI2 or 6-ketoPGFia. The threshold concentration of plasma 6-ketoReceived for publication 27 PGFIa associated with a statistically significant stimulation of renin release was -200 pg/ml. Upon discontinuing PGI2 or 6-keto-PGFIar infusion, the disappearance of 6-keto-PGFIa from blood showed an identical biphasic behavior, the initial phase having an apparent t1/2 of 3.2 min. The intravenous infusion of furosemide, which is known to stimulate renin release via a cyclooxygenase-dependent mechanism, caused a three-to fourfold increase of urinary 6-keto-PGF1, excretion rate, concomitant with the elevation of plasma renin activity levels, in six healthy women. 6-Keto-PGFIa remained undetectable in peripheral venous plasma throughout the study. We conclude that in human subjects: (a) PGI2-induced renin release occurs with a dose and time dependence similar to its reported platelet effects; (b) PGI2-induced renin release is not mediated by adrenergic stimuli or cyclooxygenase-dependent mechanisms secondary to hemodynamic changes; (c) furosemide-induced renin release is associated with increased renal PGI2 formation; and (d) PGI2 appears to act as a local modulator rather than a circulating hormone in controlling juxtaglomerular function.

Contribution of prostaglandins to the systemic and renal vascular response to frusemide in normal man.

“…Changes in renal synthesis of PGI2 and/or PGE could explain the prostaglandin related events that occur in the kidney after frusemide in view of their known ability to increase renal blood flow and renin secretion (McGiff, 1980). Although in this study there was no correlation between the excretion rates of urinary PGE and the changes in these parameters after frusemide the time course of change in excretion of both 6-keto-PGFIa and PGE previously demonstrated by others (Scherer & Weber, 1979;Patrono et al, 1982) and confirmed here with respect to PGE, provides further support for such a relationship. Urinary PGE excretion provides a measure of renal PGE synthesis (Frolich et al, 1975).…”

The influence of indomethacin and sulindac on some pharmacological actions of atenolol in hypertensive patients.

“…(1) (Patrono, 1980) and urinary 6-keto-PGFI, as an index of renal epoprostinol (PGI2) production (Patrono et al, 1982). The finding that indomethacin reduced both, whereas sulindac inhibited only serum TXB2, confirms that sulindac exerts a selective inhibition of prostaglandin synthesis (Ciabattoni et al, 1980).…”

“…However, these conclusions must be drawn with caution for the following reasons: (a) the small number of patients studied; (b) sulindac reduced PRA as did indomethacin, an unexpected finding, considering the known role of PGI2 in the stimulation of renin secretion (Ciabattoni et al, 1980;Patrono et al, 1982); (c) although sulindac significantly reduced (circa 75%) serum TXB2, this effect was significantly (P < 0.01) less than that exerted by indomethacin which reduced it by about 95%.…”

Biochemical and pharmacological consequences of the interaction between methotrexate and ketoprofen in the rabbit

“…Analysis of renal excretion of 6-keto-PGFI, illustrates this situation. This prostaglandin was selected because it is the stable metabolite of PGI2 (Schlondorff & Ardaillou, 1986), mainly synthesised by the kidney (Patrono et al, 1982), and because prostacyclins play a determinant role in renal blood flow regulation (Dunn, 1987). Predictably (Carmichael & Shankel, 1985), pretreatment by KP significantly reduced renal excretion of 6-keto-PGF,C.…”