Effects of some novel D-myo-inositol-phosphate derivatives on binding and sympathetic transmission.
The vascular effects of myo-inositol and a series of D-myo-inositol phosphate derivatives: D-myo inositol-1-monophosphate (Ins[1]P1), D-myo-inositol-2-monophosphate (Ins[2]P1), D-myo-inositol-1, 2-biphosphate (Ins[1,2,6]P2), D-myo-inositol-1,2,6-trisphosphate (Ins[1,2,6]P3, alpha-trinositol; PP56), D-myo-inositol-1,2,5,6-tetraphosphate (Ins[1,2,5,6]P4), and D-myo-inositol-1,2,3,4,5,6-hexa-phosphate (InsP6, phytic acid) were studied in binding assays in rat heart membranes, in vitro in isolated guinea pig basilar artery, and in vivo in pithed rats. In binding assays in rat heart membranes, Ins[1,2,6]P3, Ins[1,2,5,6]P4, and InsP6 displaced the binding of [3H] alpha-trinositol [3H]Ins[1,2,6]P3). In the isolated guinea pig basilar artery, Ins[1,2]P2 and Ins[1,2,6]P3 inhibited the contractile effects of exogenous neuropeptide Y (NPY) in the concentration range of 10(-8)-10(-6) M. In pithed Sprague-Dawley rats, Ins[1,2,6]P3 inhibited the NPY-induced pressor response in the dose range [2 mg/kg (3.8 mumol/kg) combined with an infusion of 20 mg/kg/h (38 mumol/kg/h) for 30 min] in which no inhibitory effects on the pressor responses were elicited by preganglionic nerve stimulation (PNS) or a bolus injection of phenylephrine (Phe). Ins[1,2]P2 had only slight NPY inhibitory effects in vivo. We conclude that selected inositol derivatives may inhibit the vasopressor effects to NPY in vitro and in vivo. In particular, Ins[1,2,6]P3, which most readily inhibited the NPY-induced pressor response in vivo, may represent a new class of synthetic nonpeptide drugs, which may inhibit the vascular effects of NPY without binding to the NPY receptor itself.
Sun
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Department of Pharmacology, University of Göteborg, Sweden.
Edvinsson
L
L
Yoo
H
H
Wahlestedt
C
C
Hedner
T
T
D000704:Analysis of Variance; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000378:metabolism; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D003655:Decerebrate State; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D009478:Neuropeptide Y / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D007295:Inositol Phosphates; D009478:Neuropeptide Y