M. Fukao et al., THAPSIGARGIN AND CYCLOPIAZONIC ACID-INDUCED ENDOTHELIUM-DEPENDENT HYPERPOLARIZATION IN RAT MESENTERIC-ARTERY, British Journal of Pharmacology, 115(6), 1995, pp. 987-992
1 The present study was designed to determine whether putative, select
ive inhibitors of the Ca2+-pump ATPase of endoplasmic reticulum, thaps
igargin (TSG) and cyclopiazonic acid (CPA), induce endothelium-depende
nt hyperpolarization in the rat isolated mesenteric artery. The membra
ne potentials of smooth muscle cells of main superior mesenteric arter
ies were measured by the microelectrode technique. 2 In tissues with e
ndothelium, TSG (10(-8)-10(-5) M) caused sustained hyperpolarization i
n a concentration-dependent manner. In tissues without endothelium, TS
G did not cause any change in membrane potential. CPA (10(-5) M) also
hyperpolarized the smooth muscle membrane, an effect that was endothel
ium-dependent and long-lasting. 3 The hyperpolarizing responses to the
se agents were not affected by indomethacin or N-G-nitro-L-arginine (L
-NOARG). 4 In Ca2+-free medium, neither TSG nor CPA elicited hyperpola
rization, in contrast to acetylcholine which generated a transient hyp
erpolarizing response. 5 In rings of mesenteric artery precontracted w
ith phenylephrine, TSG and CPA produced endothelium-dependent relaxati
ons. L-NOARG significantly inhibited the relaxations to these agents,
but about 40-60% of the total relaxation was resistant to L-NOARG. The
L-NOARG-resistant relaxations were abolished by potassium depolarizat
ion. 6 These results indicate that TSG and CPA. can cause endothelium-
dependent hyperpolarization in rat mesenteric artery possibly by relea
sing endothelium-derived hyperpolarizing factor and that membrane hype
rpolarization can contribute to the endothelium-dependent relaxations
to these agents. The mechanism of hyperpolarization may be related to
increased Ca2+ influx into endothelial cells triggered by depletion of
intracellular Ca2+ stores due to inhibition of endoplasmic reticulum
Ca2+-pump ATPase activity.