Ferrusi I, Zhao J, van Helden D, von der Weid PY.
Cyclopiazonic acid decreases spontaneous transient
depolarizations in guinea pig mesenteric lymphatic vessels in
endothelium-dependent and -independent manners.
Am J Physiol Heart Circ Physiol. 2004 Jun;286(6):H2287-95
Mucosal Inflammation and Smooth Muscle Research Groups, Dept.
of Physiology and Biophysics, Faculty of Medicine, University of
Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N
4N1.
Guinea pig mesenteric lymphatic vessels exhibit vasomotion
through a pacemaker mechanism that involves intracellular Ca(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 microM) 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(G)-nitro-L-arginine (100 microM) or
1H-[1,2,4]oxadiazolol-[4,3-a]quinoxaline-1-one (10 microM),
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(2)
mimetic U-46619, norepinephrine, or thimerosal. CPA abolished
U-46619-induced vasomotion as determined by measurement of
constriction-associated intracellular Ca2+ concentration using
the ratiometric Ca2+ 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 Ca2+ 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 Ca2+-ATPase and
deplete Ca2+ stores, it further reduces STD activity. Inhibition
of the lymphatic smooth muscle pacemaker mechanism is thought to
abolish agonist-induced vasomotion.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 14975927 |
