alpha(1D)-Adrenoceptors cause endothelium-dependent vasodilatation in the rat mesenteric vascular bed

The vasodilator activity of alpha (1)-adrenoceptor agonists was tested in t he rat mesenteric vascular bed (MVB), and the mechanism involved was invest igated in cultured endothelial cells isolated from the bovine coronary vasc ular bed. In preparations preconstricted by U46619, noradrenaline and pheny lephrine induced a slight relaxant effect at nanomolar concentrations. This effect was abolished in endothelium-denuded preparations and in preparatio ns pretreated with 100 muM N-omega-nitro-L-arginine methyl ester plus 3 muM indomethacin. Both the phospholipase C inhibitor U73122 and the endoplasmi c reticulum Ca2+-ATPase inhibitor thapsigargin inhibited the vasorelaxant e ffect of phenylephrine. The cellular level of inositol monophosphate (IP1) 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 followin g exposure to the same concentrations of phenylephrine. Both chloroethylclo nidine and the selective alpha (1D)-adrenoceptor antagonist BMY 7378 reduce d, in a concentration-dependent manner, the relaxant effect induced by phen ylephrine, whereas the selective alpha (1A)-adrenoceptor antagonist (+)-nig uldipine was ineffective. BMY 7378 also blocked the cNOS activation induced by phenylephrine. Conversely, the increase in perfusion pressure induced b y micromolar concentrations of phenylephrine was blocked by 1 nM (+)-niguld ipine, but was unaffected by BMY 7378. These findings demonstrate that nano molar concentrations of phenylephrine, which are devoid of any contractile effect, induced a slight endothelium-dependent vasorelaxation in the rat MV B through the stimulation of alpha (1D)-adrenoceptors, located on endotheli al cells, which act through phospholipase C stimulation, followed by IP1 ge neration, and nitric-oxide synthase activation. Conversely, the increase in perfusion pressure induced by micromolar concentrations of phenylephrine i s attributable to the stimulation of alpha (1A)-adrenoceptors.