Endothelin-1 released by vascular smooth muscle cells enhances vascular responsiveness of rat mesenteric arterial bed exposed to high perfusion flow

Vasodilation of resistance vessels ensues in response to increased perfusio n now to maintain tissue perfusion. The now-induced vasadilation is mainly dependent on nitric oxide (NO), which also regulates vascular responsivenes s to vasoconstrictors. Besides NO, however, high Mow increases endothelin-l (ET-1) production from endothelial cells. Ii: is likely, therefore, that t he 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 r ole of ET-1 released by vascular smooth muscle cells (VSMC) were evaluated in isolated and in vitro-perfused mesenteric arteries (MA). MA were perfuse d at constant (3.5 mL/min; CPF) and increased flow rate (4.5, 5.5, 6.5 mL/m in; IPF). VR was evaluated by infusing norepinephrine (NE; 5 mu mol/L) and potassium chloride (KCI; 80 mmol/L). Mesenteric vascular resistance (MVR), ET-1, and cGMP release were measured under different now rates. The role of endothelium-derived ET-1 was evaluated by perfusing MA with phosphoramidon (endothelin converting enzyme inhibitor), whereas the role of other endoth elium-derived vasoactive substances was excluded by measuring Vp in MA with out endothelium. Finally, ETA and ETB receptor antagonists were perfused in disendothelized MA. In the IPF group of intact MA, MVR dropped (P < .05) a nd 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 K CI (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 abol ished the now-dependent increase in VR. No further additive effect was achi eved with BQ-788. In conclusion, in MA, high flow reduces MVR and concurren tly enhances Vp, likely through VSMC-derived ET-1. (C) 1999 American Journa l of Hypertension, Ltd.