Cicletanine - New insights into its pharmacological actions

Cicletanine ((+/-)3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3, 4-c] pyridine) 3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c ] pyridine) is a novel antihypertensive agent that has been shown to posses s vasorelaxant, natriuretic, and diuretic properties in preclinical and cli nical studies. The mechanism(s) by which cicletanine induces these biologic al effects has not been definitely established, although it appears to diff er from that of other classes of antihypertensive drugs. The salidiuretic a ctivity appears to be the result of an action of the sulfoconjugated metabo lite of cicletanine, which inhibits the apical Na+-dependent Cl-/HCO3- anio n exchanger in the distal convoluted tubule. The mechanism of the vasodilat ing effect of cicletanine seems to be complex; it may include stimulation o f vascular prostaglandin synthesis, inhibition of the low K-m cyclic GMP ph osphodiesterases, and blockade of Ca2+ channels either directly or indirect ly through a K+-channel opening effect. The drug has also been shown to int eract with alpha-adrenergic, vascular histamine, and muscarinic receptors. We have also reviewed the other vascular effects of the drug, such as stimu lation of nitric oxide synthesis and inhibition of both myosin light chain kinase and protein kinase C. Cicletanine protects cardiovascular and renal systems against the injuries induced by hypertension, in addition to its lo wering of arterial pressure. Similarly to the vasorelaxant action of ciclet anine, the various properties of the drug likely contribute to its protecti ve effect against injury in hypertension. (C) 1999 Elsevier Science Inc. Al l rights reserved.