1991 Fiscal Year Final Research Report Summary
Pathophysiological Role of Arachidonic Acid Metabolites in the Regulation of Cardiac and Vascular Smooth Muscle Cell Function.
| Project/Area Number |
02454253
|
|---|
| Research Category |
Grant-in-Aid for General Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Research Field |
Circulatory organs internal medicine
|
|---|
| Research Institution | Faculty of Medicine, University of Tokyo |
|---|
Principal Investigator |
SUGIMOTO Tsuneaki Faculty of Medicine, Univ. of Tokyo, Professor, 医学部(病), 教授 (60019883)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
NAKAJIMA Toshiaki Faculty of Medicine, Univ. of Tokyo, Associate, 医学部(病), 助手 (50227790)
UEHARA Yoshio Faculty of Medicine, Univ. of Tokyo, Associate, 医学部(病), 助手 (40184965)
TOYOOKA Teruhiko Health Center, Univ. of Tokyo, Professor, 保健センター, 教授 (00146151)
|
|---|
| Project Period (FY) |
1990 – 1991
|
| Keywords | arachidonic acid / muscarinic K+ channel / single cardiac cells / GTP-binding protein / vascular smooth muscle cells / cell growth / hypertension / cytoskeleton protein |
|---|
| Research Abstract |
1) Acetylcholine activates a specific population of cardiac channels (IK. Ach) via the pertussis-toxin sensitive G proteins (GK). The major aim of the present study was to clarify. the modulation of IK. Ach channel by arachidonic metabolites and also the regulatory mechanisms of G-proteins on the IK. Ach.
The intracellular anions, Cl- ion, were found to play an important role on the activation of IK. Ach. The effects of Cl- ion were thought to be due to the inhibitory action on the GTPase activity of GK. Besides the direct gating of the IK. Ach channel by G protein, we found that the G-protein-gated channel system can be modulated in a stimulatory manner by arachidonic acid and its metabolites. The IK. Ach channel activity could be also stimulated by alpha-adrenergic agonis and platelet activating factor via the arachidonic metabolic pathway.
Thus, it was suggested that archidonic acid metabolites are possibly new common intracellular messengers to the IK. Ach channel in a variety of phy
… More
siological and pathophysiological regulations of cardiac excitation.
2) We designed experiments to reveal the role of endogenous eicosanoid system in the regulation of vascular smooth muscle cell(VSMC)growth and assess the implication in the vascular and organ injuries in hypertensive state. Prostacyclin regulated the GO/GI transit in cell cycle via a short loop circuit. This mechanism-was mediated by de novo phospholipase A2 synthesis. Thromboxane stimulated the formation of cytoskeleton xprotein, leading to rapid cell growth with a short G2/M transit.
Impaired prostacyclin generation is responsible for the rapid cell growth seen in VSMC from spontaneously hypertensive rats. An increase in endogenous prostacyclin in vivo is found to attenuate the vascular and renal injuries in salt-induced hypertension in Dahl salt-sensitive rats, whereas blood pressure reduction by thiazide diuretic results in a decrease in endogenous eicosanoid synthesis and failure of regression of the vascular and renal injuries.
3)The study elucidated the role of arachidonic metabolites in the intracellular regulatory mechanisms of cellular electrical acitivity and also cellular proliferation. This understanding would contribute to the further study of signal transduction modification mediating the interaction in the receptor and effector systems. Less
|
