Background: Colforsin, a novel water-soluble forskolin derivative, increase
s intracellular cyclic AMP by direct stimulation of adenylate cyclase and h
as strong positive inotropic and vasodilative effects. However, it is not k
nown whether colforsin causes nitric oxide (NO) release and enhances endoth
elium-dependent vascular relaxation.
Methods: We studied NO production and relaxation on exposure to colforsin i
n thoracic aorta from rats aged 4, 12 and 60 weeks.
Results: When a low concentration of colforsin was added to a solution bath
ing ring segments of aorta from 12-week-old rats, relaxation was greater in
the ring segments with intact endothelium than in those from which the end
othelium had been removed. A high concentration of colforsin induced the sa
me degree of relaxation of ring segments with or without endothelium, proba
bly by a direct effect on vascular smooth muscle cells. Production of NO in
response to colforsin by cultured endothelial cells from 12-week-old rat a
orta was demonstrated by the electron paramagnetic resonance spin trapping
method. A low concentration of colforsin relaxed aortic segments with intac
t endothelium from 4-week-old rats more than those from 12-week-old or 60-w
eek-old rats. Reversal of relaxation by N-G-nitro L-arginine, an NO synthes
is inhibitor, was most significant in arteries from 4-week-old rats. Produc
tion of NO after exposure to colforsin was greater in aortic segments from
4-week-old rats than older rats, as detected by an NO-selective electrode.
Conclusions: Colforsin induces vasodilation in part by releasing NO from th
e endothelium in rat thoracic aorta. In addition to a direct vasodilative e
ffect on the vascular smooth muscle cells, an endothelium-dependent vasodil
ative effect is also important in younger arteries.