Circulation, Vol 90, 2425-2431, Copyright © 1994 by American Heart Association
A Ito, H Shimokawa, R Nakaike, T Fukai, M Sakata, T Takayanagi, K Egashira and A Takeshita
BACKGROUND--The intracellular mechanism of coronary artery spasm is still
unknown. The pathway mediated by protein kinase C (PKC) is an important
intracellular process of various cellular responses, including vascular
smooth muscle contraction. Thus, we examined the role of the PKC-mediated
pathway in the pathogenesis of coronary artery spasm in our in vivo swine
model. METHODS AND RESULTS--Seven Gottingen miniature pigs underwent
coronary balloon injury and x-ray irradiation to induce atherosclerotic
lesion. After 6 to 18 months, intracoronary serotonin (3 micrograms/kg) or
histamine (3 micrograms/kg) repeatedly induced coronary artery spasm at the
atherosclerotic site. At the spastic site, intracoronary administration of
phorbol-12,13-dibutyrate (PDBu) (10(-9) mol/kg), a PKC-activating phorbol
ester, also induced coronary artery spasm, which was completely blocked by
pretreatment with intracoronary staurosporine (10 micrograms/kg), a PKC
inhibitor. Intracoronary administration of an inactive phorbol ester,
phorbol- 12,13-didecanoate (10(-9) mol/kg), did not induce coronary
vasoconstriction. Coronary artery spasm induced by the autacoids was
significantly augmented by pretreatment with intracoronary PDBu and
partially inhibited by staurosporine. Intracoronary administration of Bay K
8644 (10 micrograms/kg), a dihydropyridine-sensitive L-type calcium channel
agonist, also induced coronary artery spasm at the spastic site, which was
significantly inhibited by pretreatment with intracoronary staurosporine or
nifedipine (0.1 mg/kg). CONCLUSIONS-- These results suggest (1) the
PKC-mediated pathway is importantly involved in the pathogenesis of
coronary artery spasm, (2) activation of the PKC-mediated pathway partially
accounts for serotonin- and histamine-induced coronary artery spasm, and
(3) at the spastic site, calcium influx through dihydropyridine-sensitive
L-type calcium channel and/or calcium sensitivity of the contractile
proteins may be augmented by the PKC-mediated pathway.
ARTICLES
Role of protein kinase C-mediated pathway in the pathogenesis of coronary artery spasm in a swine model
Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, Fukuoka, Japan.
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