Endothelium-Dependent Modulation of Adrenergic Tone:

Signals and Mechanisms

 

In the intestine, we have found that inhibition of nitric oxide (NO) production with NG monomethyl-L-arginine (L-NMMA) increases both the magnitude and rate of arteriolar constriction in response to sympathetic nerve stimulation. This effect of L-NMMA is completely reversed by excess L-arginine, indicating that endogenous NO normally limits arteriolar responsiveness to increased sympathetic nerve activity in the intestine. After passage of a CO2 embolus through the arteriolar lumen (and verification that this microembolization disrupts endothelial function without any effect on vascular smooth muscle), arteriolar responses to sympathetic nerve stimulation are significantly increased and no longer sensitive to L-NMMA. These findings indicate that the arteriolar endothelium is the source of the NO that modulates sympathetic neurogenic constriction in intestinal arterioles.

Our more recent findings suggest that a local reduction in oxygen levels serves as the trigger for arteriolar endothelial NO release when sympathetic nerve activity is increased. We found that arteriolar constriction and the resulting fall in blood flow during sympathetic nerve stimulation is accompanied by a marked fall in arteriolar wall and tissue PO2 (as measured with oxygen microelectrodes). As mentioned above, this constriction is significantly increased in the presence of L-NMMA. However, in a high-oxygen environment that prevents the fall in local oxygen levels with sympathetic constriction, the magnitude of constriction is increased and no longer sensitive to L-NMMA. These findings are illustrated in the figure below.

We are currently exploring the possibility that an increased formation of the metabolic dilator adenosine serves as the link between the reduction in oxygen and endothelial NO release under these conditions.