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 possess
vasorelaxant, natriuretic, and
diuretic properties in preclinical and clinical studies. The mechanism(s) by which
cicletanine induces these
biological effects has not been definitely established, although it appears to differ from that of other classes of
antihypertensive drugs. The salidiuretic activity appears to be the result of an action of the sulfoconjugated metabolite of
cicletanine, which inhibits the apical Na+-dependent Cl-/HCO3-
anion exchanger in the distal convoluted tubule. The mechanism of the vasodilating effect of
cicletanine seems to be complex; it may include stimulation of vascular
prostaglandin synthesis, inhibition of the low Km
cyclic GMP phosphodiesterases, and blockade of Ca2+ channels either directly or indirectly through a K+-channel opening effect. The
drug has also been shown to interact with alpha-
adrenergic, vascular
histamine, and
muscarinic receptors. We have also reviewed the other vascular effects of the
drug, such as stimulation 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 lowering of arterial pressure. Similarly to the
vasorelaxant action of
cicletanine, the various properties of the
drug likely contribute to its protective effect against injury in
hypertension.