Inositol phosphates formed in rat aorta after alpha 1-adrenoceptor stimulation are inhibited by forskolin.
Rat aortic smooth muscle rings without endothelial cells were subjected to alpha 1-adrenoceptor stimulation. We measured the contractile state of the smooth muscle cells and the formation of inositol phosphates (InsPs) on receptor stimulation. Using different extracellular calcium-containing solutions (2.5 mM, 0.1 mM and Ca(2+)-free) enabled us to discriminate three contractile phases after noradrenaline (10(-5) M) stimulation: an initial fast contraction (15 s) and a fast and slow component of the sustained contraction, which was established 10 min after stimulation. Under normal calcium conditions in the presence of 10 mM LiCl the formation of Ins(1,4,5)P3 was increased predominantly after stimulation, while the formation of Ins(1,3,4)P3, Ins(1,3,4,6)P4, Ins(1,3,4,5)P4, Ins(3,4,5,6)P4 and InsP5/InsP6 was also stimulated. The cAMP-inducing agent forskolin (0.5 microM) induced a relaxation of the basal tone and increased the level of the InsP4 isomers. The noradrenaline-induced contractile responses as well as the formation of InsP fractions mentioned were inhibited by forskolin. Further an increase in the formation of phosphatidylinositol bisphosphate was observed. It is concluded that in rat aorta InsPs and in particular Ins(1,4,5)P3 is involved in the different contractile phases caused by alpha 1-adrenoceptor stimulation. The relaxation induced by forskolin under these circumstances could be explained by an interaction of forskolin, most likely via the formation of cAMP, with InsPs formation at the level of phospholipase C activation.
Department of Pharmacology, School of Medicine, University of Patras, Greece.
V G
VG
Manolopoulos
E
E
Pipili-Synetos
A
A
Den Hertog
A
A
Nelemans
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007537:Isometric Contraction; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000316:Adrenergic alpha-Agonists; D007295:Inositol Phosphates; D005576:Colforsin; D000242:Cyclic AMP; D009638:Norepinephrine