Nitric oxide limits coronary vasoconstriction by a shear stress-dependent mechanism

Increases in shear stress promote coronary vasodilation by stimulating the production of nitric oxide (NO). Whether shear stress-induced NO production also limits vasoconstriction in the coronary microcirculation in vivo is u nknown. Accordingly, we measured microvascular diameter and flow velocity i n the beating heart along with estimated blood viscosity to calculate shear stress during vasoconstriction with endothelin or vasopressin. Measurement s were repeated in the presence of N-G-monomethyl-L-arginine (L-NMMA) to in hibit NO production and BQ-788 to block NO-linked endothelin type B recepto rs. BQ-788 did not augment steady-state constriction to endothelin, suggest ing that NO production via activation of this receptor is inconsequential. L-NMMA potentiated constriction to both agonists, particularly in small art eries (inner diameter >120 mum). Shear stresses in small arteries were elev ated during constriction and further elevated during constriction after L-N MMA. These observations suggest that NO production limits vasoconstriction in the coronary microcirculation and that the principal stimulus for this g overnance is elevated shear stress. The degree of shear stress moderation o f constriction is heterogeneously distributed, with small arteries displayi ng a higher degree of shear stress regulation than arterioles. These result s provide the strongest evidence to date that shear stress-mediated product ion of NO exerts a "braking" influence on constriction in the coronary micr ocirculation.