1. Cyclopiazonic acid decreases spontaneous transient depolarizations in guinea pig mesenteric lymphatic vessels in endothelium-dependent and -independent manners
- Author
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Ferrusi, Ilia, Zhao, Jun, van Helden, Dirk, and von der Weid, Pierre-Yves
- Subjects
Heart -- Research ,Biological sciences - Abstract
Cyclopiazonic acid decreases spontaneous transient depolarizations in guinea pig mesenteric lymphatic vessels in endotheliumdependent and -independent manners. Am J Physiol Heart Circ Physiol 286: H2287-H2295, 2004. First published February 19, 2004; 10.1152/ajpheart.00739.2003.--Guinea pig mesenteric lymphatic vessels exhibit vasomotion through a pacemaker mechanism that involves intracellular [Ca.sub.2+] release and resultant spontaneous transient depolarizations (STDs) of the smooth muscle membrane potential. This study presents a detailed characterization of the effects of cyclopiazonic acid (CPA) on this pacemaker activity. Microelectrode recordings from smooth muscle in vessel segments revealed that application of CPA (1-10 [micro]M) caused a hyperpolarization accompanied by a decrease in the frequency and amplitude of STDs. The CPA-induced hyperpolarization was abolished after destruction of the endothelium and in the presence of [N.sup.G]-nitro-L-arginine (100 [micro]M) or 1H-[1,2,4]oxadiazolol-[4,3-a]quinoxaline- 1-one (10 [micro]M), which suggests a contribution of endothelium-derived nitric oxide (EDNO) in this response. In the absence of EDNO-induced effects, CPA decreased the frequency and amplitude of STDs recorded before and in the presence of the thromboxane [A.sub.2] mimetic U-46619, norepinephrine, or thimerosal. CPA abolished U-46619-induced vasomotion as determined by measurement of constriction-associated intracellular [Ca.sup.2+] concentration using the ratiometric [Ca.sup.2+] indicator fura-2. The endothelial actions of CPA were compared with those of ACh, which is known to cause EDNO release in this preparation. Although CPA and ACh both increased endothelial intracellular [Ca.sup.2+] concentration and depolarized the membrane potential, the kinetics of action for both parameters were markedly slower for CPA than ACh. These results suggest that CPA first hyperpolarizes the lymphatic smooth muscle and decreases STD frequency and amplitude through endothelial release of EDNO, and second, consistent with the action of CPA to inhibit sarcoplasmic reticulum [Ca.sup.2+]-ATPase and deplete [Ca.sup.2+] stores, it further reduces STD activity. Inhibition of the lymphatic smooth muscle pacemaker mechanism is thought to abolish agonist-induced vasomotion. pumping; nitric oxide; smooth muscle; lymphatic vasomotion
- Published
- 2004