title: Endothelin-1 released by vascular smooth muscle cells enhances vascular responsiveness of rat mesenteric arterial bed exposed to high perfusion flow.
abstract: Vasodilation of resistance vessels ensues in response to increased perfusion flow to maintain tissue perfusion. The flow-induced vasodilation is mainly dependent on nitric oxide (NO), which also regulates vascular responsiveness to vasoconstrictors. Besides NO, however; high flow increases endothelin-1 (ET-1) production from endothelial cells. It is likely, therefore, that the interaction between NO and ET-1 may play a critical role in the control of arterial vascular tone under high perfusion flow. In this study, the vascular responsiveness (VR) to high flow rate and the role of ET-1 released by vascular smooth muscle cells (VSMC) were evaluated in isolated and in vitro-perfused mesenteric arteries (MA). MA were perfused at constant (3.5 mL/min; CPF) and increased flow rate (4.5, 5.5, 6.5 mL/min; IPF). VR was evaluated by infusing norepinephrine (NE; 5 micromol/L) and potassium chloride (KCl; 80 mmol/L). Mesenteric vascular resistance (MVR), ET-1, and cGMP release were measured under different flow rates. The role of endothelium-derived ET-1 was evaluated by perfusing MA with phosphoramidon (endothelin converting enzyme inhibitor), whereas the role of other endothelium-derived vasoactive substances was excluded by measuring VR in MA without endothelium. Finally, ETA and ETB receptor antagonists were perfused in disendothelized MA. In the IPF group of intact MA, MVR dropped (P<.05) and both ET-1 and cGMP increased in the perfusate (P<.05). VR was enhanced by high flow after NE (101+/-9 v. 56+/-12 mm Hg in CPF, P<.005) and KCl (119+/-12 v. 51+/-10 mm Hg in CPF, P<.005) and it was unaffected by either phosphoramidon or endothelium removal. On the contrary, BQ-610 abolished the flow-dependent increase in VR. No further additive effect was achieved with BQ-788. In conclusion, in MA, high flow reduces MVR and concurrently enhances VR, likely through VSMC-derived ET-1.
authors.affiliation: Department of Nephrology, School of Medicine, University Federico II, Naples, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Russo
authors.forename: R
authors.initials: R
authors.lastname: Minutolo
authors.forename: C
authors.initials: C
authors.lastname: Clienti
authors.forename: L
authors.initials: L
authors.lastname: De Nicola
authors.forename: C
authors.initials: C
authors.lastname: Iodice
authors.forename: F A
authors.initials: FA
authors.lastname: Savino
authors.forename: V E
authors.initials: VE
authors.lastname: Andreucci
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D001783:Blood Flow Velocity; D006152:Cyclic GMP / Q000096:biosynthesis; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis*; D000072396:Endothelin-Converting Enzymes; D006020:Glycopeptides / Q000494:pharmacology; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D010477:Perfusion / Q000379:methods*; D011189:Potassium Chloride / Q000494:pharmacology; D011312:Pressure; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D006020:Glycopeptides; D011480:Protease Inhibitors; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014662:Vasoconstrictor Agents; D011189:Potassium Chloride; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D006152:Cyclic GMP; C008890:phosphoramidon; D009638:Norepinephrine