Thapsigargin‐ and cyclopiazonic acid‐induced endothelium‐dependent hyperpolarization in rat mesenteric artery

Abstract

1 The present study was designed to determine whether putative, selective inhibitors of the Ca2+-pump ATPase of endoplasmic reticulum, thapsigargin (TSG) and cyclopiazonic acid (CPA), induce endothelium-dependent hyperpolarization in the rat isolated mesenteric artery. The membrane potentials of smooth muscle cells of main superior mesenteric arteries were measured by the microelectrode technique. 2 In tissues with endothelium, TSG (10--10-S M) caused sustained hyperpolarization in a concentration-dependent manner. In tissues without endothelium, TSG did not cause any change in membrane potential. CPA (10-5 M) also hyperpolarized the smooth muscle membrane, an effect that was endothelium-dependent and long-lasting. 3 The hyperpolarizing responses to these agents were not affected by indomethacin or NG-nitro-Larginine (L-NOARG). 4 In Ca2+-free medium, neither TSG nor CPA elicited hyperpolarization, in contrast to acetylcholine which generated a transient hyperpolarizing response. 5 In rings of mesenteric artery precontracted with phenylephrine, TSG and CPA produced endothelium-dependent relaxations. 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 depolarization. 6 These results indicate that TSG and CPA can cause endothelium-dependent hyperpolarization in rat mesenteric artery possibly by releasing endothelium-derived hyperpolarizing factor and that membrane hyperpolarization 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 Ca21 stores due to inhibition of endoplasmic reticulum Ca2"-pump ATPase activity.

Mechanism of Ca2+release and entry during contraction elicited by norepinephrine in rat resistance arteries

“…This interpretation is consistent with the recent finding that a thapsigargin-insensitive Ca 2ϩ pool is present in a subcompartment of the endoplasmic reticulum in different mammalian cells (29). In addition, the presence of SERCA2a and SERCA2b in the endothelium layer of small mesenteric arteries found in the present study is consistent with previously reported endothelium-dependent relaxation elicited by SERCA inhibitors in these vessels (11).…”

Activity of Endothelium-Derived Hyperpolarizing Factor Is Augmented in Monocrotaline-Induced Pulmonary Hypertension of Rat Lungs

“…After blockade of both NO and PGI 2 synthesis, we tested the effects of charybdotoxin plus apamin on basal perfusion pressure and acute hypoxic vasoconstriction. Thapsigargin (TG) caused NO- and PGI 2 -independent vasodilation, consistent with previous reports [11, 38, 39]. We examined the effect of charybdotoxin plus apamin on the vasodilation induced by TG.…”

Increased Ca2+ Buffering Function of Sarcoplasmic Reticulum in Small Mesenteric Arteries from Spontaneously Hypertensive Rats

“…Thus, the Ca 2 influx during rest was completely buffered by the SR. Although the membrane depolarizing effects of CPA, thapsigargin or ryanodine were reported in the rat pressurized posterior cerebral artery (25) and rat carotid artery (18), such effects were not observed in rat large and small mesenteric arteries (26,27). Based on these observations, we believe that CPA, thapsigargin and ryanodine induced a large contraction in the SHR resistance artery by compromising the Ca channel activity was also reported in small mesenteric arteries from Dahl salt-sensitive rats (32).…”