alpha(1D)-adrenoceptors cause endothelium-dependent vasodilatation in the rat mesenteric vascular bed.
The vasodilator activity of alpha(1)-adrenoceptor agonists was tested in the rat mesenteric vascular bed (MVB), and the mechanism involved was investigated in cultured endothelial cells isolated from the bovine coronary vascular bed. In preparations preconstricted by U46619, noradrenaline and phenylephrine induced a slight relaxant effect at nanomolar concentrations. This effect was abolished in endothelium-denuded preparations and in preparations pretreated with 100 microM N(omega)-nitro-L-arginine methyl ester plus 3 microM indomethacin. Both the phospholipase C inhibitor U73122 and the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin inhibited the vasorelaxant effect of phenylephrine. The cellular level of inositol monophosphate (IP(1)) in bovine endothelial cells doubled after a 15-min exposure to 0.03 to 0.1 nM phenylephrine. The activity of cNOS was significantly increased following exposure to the same concentrations of phenylephrine. Both chloroethylclonidine and the selective alpha(1D)-adrenoceptor antagonist BMY 7378 reduced, in a concentration-dependent manner, the relaxant effect induced by phenylephrine, whereas the selective alpha(1A)-adrenoceptor antagonist (+)-niguldipine was ineffective. BMY 7378 also blocked the cNOS activation induced by phenylephrine. Conversely, the increase in perfusion pressure induced by micromolar concentrations of phenylephrine was blocked by 1 nM (+)-niguldipine, but was unaffected by BMY 7378. These findings demonstrate that nanomolar concentrations of phenylephrine, which are devoid of any contractile effect, induced a slight endothelium-dependent vasorelaxation in the rat MVB through the stimulation of alpha(1D)-adrenoceptors, located on endothelial cells, which act through phospholipase C stimulation, followed by IP(1) generation, and nitric-oxide synthase activation. Conversely, the increase in perfusion pressure induced by micromolar concentrations of phenylephrine is attributable to the stimulation of alpha(1A)-adrenoceptors.
Filippi
S
S
Laboratory of Microvascular and Cardiovascular Pharmacology, Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
Parenti
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A
Donnini
S
S
Granger
H J
HJ
Fazzini
A
A
Ledda
F
F
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D020033:Protein Isoforms / Q000502:physiology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D015398:Signal Transduction; D013152:Splanchnic Circulation; D019284:Thapsigargin / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
C547721:Adra1d protein, rat; D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D004791:Enzyme Inhibitors; D004963:Estrenes; D007295:Inositol Phosphates; D010975:Platelet Aggregation Inhibitors; D020033:Protein Isoforms; D011760:Pyrrolidinones; D018340:Receptors, Adrenergic, alpha-1; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D010656:Phenylephrine; D019284:Thapsigargin; D019001:Nitric Oxide Synthase; D009638:Norepinephrine