Capillary and arteriolar responses to local vasodilators are impaired in a rat model of sepsis

Abstract

Although sepsis is known to affect vascular function, little is known about changes at the capillary level. We hypothesized that sepsis attenuates the "upstream" arteriolar response to vasoactive agents applied locally to capillaries. Sepsis in rats was induced by cecal ligation and perforation. After 24 h, extensor digitorum longus muscle was prepared for intravital microscopy. Phenylephrine (PE, 10 mM) and acetylcholine (ACh, 10 mM) were applied iontophoretically on terminal arterioles and on their downstream daughter capillaries (300 micron from arteriole). There was no significant difference between control and septic rats in baseline arteriolar diameters [8.0 +/- 0.6 vs. 9.8 +/- 0.8 (SE) micron- or baseline red blood cell velocity (VRBC) in perfused daughter capillaries (255 +/- 10 vs. 264 +/- 13 micron/s). Application of PE onto arterioles resulted in comparable constrictions (i.e., -22% diameter change) and VRBC reductions (-100%) in control and septic rats. In contrast, arteriolar diameter and VRBC increases after application of ACh were attenuated in sepsis (diameter: from 41 to 14%; VRBC: 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 VRBC less in septic than in control rats (20 vs. 73%). On the basis of arteriolar-capillary pair stimulations, sepsis affected VRBC responses to ACh more in the capillary than in the arteriole. When the adenosine analog 5'-N-ethylcarboxamidoadenosine (0.1 mM) was used instead of ACh, similar effects of sepsis were seen. To test for a possible involvement of inducible NO synthase (iNOS) in sepsis-induced attenuated ACh responses, arterioles and capillaries in septic animals were locally pretreated with the iNOS blocker aminoguanidine (10 mM). In both microvessels, aminoguanidine restored the ACh response to the control level. We conclude that impaired capillary VRBC and arteriolar diameter responses to vasodilators applied to capillaries in septic rat skeletal 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.