Serotonin (5-HT) and endothelin (ET-1) are both involved in the pathophysiology of idiopathic pulmonary arterial hypertension. In addition to the release of calcium (Ca
++
) from the internal stores in the smooth muscle cells (SMCs), these agents stimulate entry of Ca
++
through the L-type Ca
++
channel. In isolated rat pulmonary resistance artery (PA) rings, 5-HT (10 μM) caused a contraction of 110 ± 14 % of the contraction elicited by 60 mM KCl. After inhibition of K
V
and K
Ca
channels by 4-AP and TEA, 5-HT caused a stronger contraction of 176 ± 4% (p<0.01). Consequently, we studied the relationship of 5-HT- stimulated contraction to membrane potential (E
m
) and L-type calcium current in rat resistance PASMCs. Contrary to expectation, 5-HT (1, 10, 100 μM) had no effect on I
K
or E
m
(n=5 for each). However, 5-HT (10 μM) increased L-type calcium current between E
m
-20 and +30 mV (n=7). This effect was inhibited by a PKC blocker (BIS-1, 3 μM), which also caused a marked reduction of 5-HT-stimulated contraction of PA rings (>70% decrease at 10 μM 5-HT). In contrast to 5-HT, ET-1 (10 nM) reduced I
K
and caused membrane depolarization (from −41 ± 5 to −31 ± 3 mV, n=4). In addition to this effect, ET-1, like 5-HT, increased L-type calcium current over the same range of E
m
(n=7). This increase was inhibited by nifedipine (3 μM). These experiments indicate that both 5-HT and ET-1 increase calcium influx through the L-type calcium channel in a manner independent of E
m
. ET-1 has an additional effect of causing membrane depolarization, which also increases calcium entry through L-type channels by altering voltage gating of the channel.
Regulation of calcium current by intracellular calcium in smooth muscle cells of rabbit portal vein.
