A model of coronary artery endothelial dysfunction in the sleeping lamb

Background and purposeMuch remains unknown about the regulation of coronary artery blood flow (CBF), particularly during sleep and sleep-related disease states such as obstructive sleep apnoea (OSA). Mediators produced by the endothelium are known to be crucial in the regulation of CBF, particularly vasodilator substances such as nitric oxide. Endothelial dysfunction with altered vascular reactivity has been identified in disease states such as atherosclerosis, OSA and sepsis, but as yet its potential effects on CBF during sleep or OSA is unknown. We aimed to produce a novel animal model of coronary artery endothelial dysfunction, subsequently to be used to study the role of the endothelium in regulating CBF during OSA.MethodsLambs (n=6) were instrumented under general anaesthesia (2% Halothane, 50% O2, balance N2O) for recording CBF (Transonic™ flow probe around circumflex coronary artery), central arterial blood pressure (Pca), central venous pressure (Pjv) and sleep monitoring (bio-electrodes). Coronary vascular resistance (CVR) was calculated as (Pca–Pjv)/CBF. Following ≥72 h of recovery, endothelial damage was induced by infusing lipopolysaccharide (LPS, 2 μg/kg over 30 min) on 3 successive days. The day before and the day after the period of LPS infusion, sleep studies were performed and coronary artery endothelial function was assessed by comparing CBF and CVR responses to left atrial injection of endothelial-dependent (Acetylcholine [Ach]) and independent (sodium nitroprusside [SNP]) vasodilators.ResultsPrior to LPS, arterial blood pressure was lower in tonic active sleep (AS) and higher in phasic AS than wakefulness. CBF and arterial blood pressure were slightly higher in phasic AS compared to tonic AS, and were the same in quiet sleep compared to quiet wakefulness. CVR did not differ across sleep states. After LPS, systolic blood pressure was reduced compared to before LPS in all sleep states, while other parameters were unchanged. Prior to LPS treatment, increasing doses of Ach (0.0001–1.0 μg/kg) and SNP (0.45–4.5 μg/kg) led to progressive reductions in CVR and increases in CBF. After LPS treatment, the fall in CVR and increase in CBF in response to Ach was attenuated (two-way repeated measures analysis of variance (ANOVA), P<0.05), whereas it was unchanged in response to SNP.ConclusionLPS leads to impaired coronary artery vasodilation in response to endothelial-dependent, but not endothelial-independent vasodilators. This novel model of coronary artery endothelial dysfunction in the sleeping lamb will provide the opportunity to study the regulation of CBF during OSA.