The limited relationship between Gilenya vasoconstrictor infusions and hyperemic responses in our studies suggest that exogenous catecholamines do not play a large role (compared to endogenous factors) in dampening hyperemic responses. Because Ang II was equally elevated in patients who did or did not receive exogenous vasoconstrictors, we are urged to investigate relationships between circulating RAS mediators and microvascular function in sepsis.We considered that RAS activation might simply reflect glomerular hypoperfusion due to hypovolemia, hypotension, or insufficient resuscitation. The clinical use of vasopressors, mechanical ventilation, and fluid resuscitation in our subjects was consistent with aggressive resuscitative efforts during the first day of sepsis, although we did not standardize resuscitation to measures of cardiac output, pulmonary artery occlusion (wedge) pressure, or pulse pressure variation in accord with uncertainties regarding what these goals should be [30-32].

Similarly, preexisting hypertension, diabetes, and coronary disease are associated with increased RAS activity, and no doubt are co-morbid conditions in clinical sepsis. We note that the levels of PRA and Ang II measured in our septic subjects are elevated nearly two-fold compared to outpatients with risk factors for vascular disease [33,34], arguing that the acute septic state contributes to RAS activation.

Although we did identify a relationship between arterial hypotension and circulating Ang II after the first day of severe sepsis, the modest statistical significance and lack of a similar relationship between hypotension and PRA (a biologic precursor to Ang II) temper our enthusiasm to declare arterial pressure a dominant factor leading to persistent RAS activation during sepsis.Our most novel finding is the association of circulating mediators of RAS with impaired hyperemic responses to ischemia during sepsis. This association raises the possibility that sepsis stimulates RAS, which contributes to microvascular perfusion heterogeneity (manifested as impaired response to local ischemia), and that perfusion heterogeneity contributes to organ failure. We cautiously note that our studies do not define a causal role of RAS in the pathogenesis of septic microvascular dysfunction, and RAS activation may be unrelated or even compensatory for microvascular dysfunction.

However, findings of Cilengitide increased small vessel density and decreased heterogeneity following vasodilator administration to septic subjects [35,36] suggest that an enhanced vasoconstrictor tone contributes to perturbations of the microvasculature. Thus our findings suggest that RAS contributes to the enhanced microvascular tone in human sepsis.Ang II inhibits endothelium-dependent relaxation of resistance arteries [37] and thus modulates the response to ischemia.