Short-term increase in prostaglandin I2 synthesis caused by cicletanine in patients with essential hypertension

Abstract

Cicletanine is a new antihypertensive drug that stimulates renal and vascular synthesis of prostaglandin (PG) I2 in experimental animals. However, there is little evidence that cicletanine increases the level of PGI2 in systemic blood of human subjects. To investigate the short-term antihypertensive mechanism of cicletanine, we measured serially the systemic blood pressure, the levels of 6-keto-PGF1 alpha (a stable metabolite of PGI2) and PGE2, and renin activity in plasma after administration of the drug. Nine patients with essential hypertension on a diet without severe sodium restriction took 100 mg of the drug by mouth. Systemic blood pressure was measured hourly for 24 h before and after cicletanine administration. The two PGs of interest were extracted, purified by high pressure liquid chromatography, and measured by radioimmunoassay. Cicletanine decreased blood pressure 3 and 6 h after administration and increased the plasma level of 6-keto-PGF1 alpha. The increase in 6-keto-PGF1 alpha was small but significant (mean +/- SD, from 3.21 +/- 1.26 to 3.88 +/- 1.44 and later 4.15 +/- 1.08 pg/mL by 3 and 6 h after administration; P < .05 and .01, respectively). The level of PGE2 had increased at 3 h after administration but returned to baseline by 6 h. Plasma renin activity was increased only at 24 h after administration. Cicletanine increased systemic PGI2 levels short-term, producing an antihypertensive effect in patients with essential hypertension.

Effects of the antihypertensive agent, cicletanine, on noradrenaline release and vasoconstriction in perfused mesenteric artery of SHR

“…Altered prejunctional control mechanisms may modify NA release in the peripheral vascular beds of SHR and this may contribute to the pathogenesis of hypertension and the antihypertensive mechanism of CIC. It has been shown that plasma levels of PGE 2 and the urinary level of PGE 2 are increased after CIC administration in patients with essential hypertension (Yasu et al , 1995; Guinot & Frolich, 1985). Rump et al (1990) suggested that in rat kidney there is a transjunctional PGE 2 inhibition of NA release, i.e., NA released from nerve endings may induce the local formation and release of PGE 2 which then transjunctionally inhibits further NA release via activation of presynaptic PGE 2 receptors.…”

“…In addition, since the α 1 ‐adrenoceptor blocking action of CIC has been shown to be weak (Auguet et al , 1988), the vasoconstriction to PNS should be reduced by CIC more effectively than that to exogenous vasoconstrictor agents. It has been shown that CIC increases the plasma concentrations of prostaglandin E 2 (PGE 2 ) and prostaglandin I 2 (Yasu et al , 1995), and PGE 2 is known to inhibit NA release via the activation of presynaptic PGE 2 receptors (Tsuda et al , 1987; Rump et al , 1990). For this reason, the possible involvement of prostaglandin‐mediated inhibition of NA release in the action of CIC was also examined.…”

Prostaglandin I 2 /E 2 Ratios in Unilateral Renovascular Hypertension of Different Severities

“…Recently, however, modification of the method used in a laboratory study 4 made possible the accurate measurement of the levels of 6-keto-PGF 1␣ in plasma. 5,6 For the present study, we gathered patients with various degrees of renal arterial stenosis to establish a way to assess the renal synthesis of PGs. We investigated the renal synthesis and pathophysiological roles of PGI 2 , in addition to those of PGE 2 .…”