CAPILLARY AND ARTERIOLAR RESPONSES TO LOCAL VASODILATORS ARE IMPAIREDIN A RAT MODEL OF SEPSIS

Although sepsis is known to affect vascular function, little is known about changes at the capillary level. We hypothesized that sepsis atte nuates the ''upstream'' arteriolar response to vasoactive agents appli ed locally to capillaries. Sepsis in rats was induced by cecal ligatio n and perforation. After 24 h, extensor digitorum longus muscle was pr epared for intravital microscopy. Phenylephrine (PE, 10 mM) and acetyl choline (ACh, 10 mM) were applied iontophoretically on terminal arteri oles and on their downstream daughter capillaries (300 mu m from arter iole). There was no significant difference between control and septic rats in baseline arteriolar diameters [8.0 +/- 0.6 vs. 9.8 +/- 0.8 (SE ) mu m] or baseline red blood cell velocity (V-RBC) in perfused daught er capillaries (255 +/- 10 vs. 264 +/- 13 mu m/s). Application of PE o nto arterioles resulted in comparable constrictions (i.e., -22% diamet er change) and V-RBC reductions (-100%) in control and septic rats. In contrast, arteriolar diameter and V-RBC increases after application o f ACh were attenuated in sepsis (diameter: from 41 to 14%; V-RBC: from 67 to 24%). Application of PE onto the capillary reduced VRBC to the same level(-100%) in both groups, whereas application of ACh increased V-RBC less in septic than in control rats (20 vs. 73%). On the basis of arteriolar-capillary pair stimulations, sepsis affected V-RBC respo nses to ACh more in the capillary than in the arteriole. When the aden osine analog 5'-N-ethylcarboxamidoadenosine (0.1 mM) was used instead of ACh, similar effects of sepsis were seen. To test for a possible in volvement of inducible NO synthase (iNOS) in sepsis-induced attenuated ACh responses, arterioles and capillaries in septic animals were loca lly pretreated with the iNOS blocker aminoguanidine (10 mM). In both m icrovessels, aminoguanidine restored the ACh response to the control l evel. We conclude that impaired capillary V-RBC and arteriolar diamete r responses to vasodilators applied to capillaries in septic rat skele tal muscle were due to dysfunction at arteriolar and capillary levels. The study underscores the significant role iNOS/NO may play in sepsis -induced alteration of vascular reactivity in vivo.