The effect of critical limb ischaemia on human small arteries.

Critical limb ischaemia (CLI) affects a significant proportion of the population, often resulting in disability or death. This study was designed to investigate the effects of CLI on the structure and function of small arteries in the leg. Measurement using light microscopy showed evidence of structural remodelling in the ischaemic vessel wall. The media to lumen ratio of subcutaneous and skeletal muscle small arteries in the affected limb was significantly reduced. New techniques using laser scanning confocal microscopy were developed to examine these structural differences. Functional changes were also observed in the subcutaneous ischaemic vessels. A significantly impaired contractile response to noradrenaline was observed which was attenuated by free radical scavengers but was unaffected by inhibition of endothelial nitric oxide (EDNO). Furthermore, the relaxation response to the cGMP-mediated agonists acetylcholine and sodium nitroprusside were also reduced. The reduced acetylcholine response was not due to the release of a vasoconstrictor prostanoid or free radical action. In contrast, skeletal muscle small arteries displayed a marked hyperreactivity to noradrenaline despite a thinner wall and a significant effect of EDNO. A consistent observation in ischaemic vessels from all CLI patients was a reduced contractile response to angiotensin II which may reflect a specific effect of ischaemia on the local RAS system. Ischaemic arteries from diabetics did not show any substantial differences from their paired non-ischaemic vessels however ischaemic vessels from hypertensive patients showed a highly significant increase in relaxation response to all vasodilator agonists compared to nonischaemic vessels. This is a surprising observation since hypertension has been shown to be associated with impaired endothelium-dependent relaxation of human subcutaneous small arteries. This study has shown important effects of ischaemia on small vessels in particular a marked difference in the response of subcutaneous and skeletal muscle small arteries.