Agonist induced modulation of the endothelial glycocalyx The endothelial glycocalyx profoundly reduces functionally perfused capillary volume by being inaccessible for flowing blood. Because the accessibility of the glycocalyx for flowing plasma was suggested to be increased by adenosine and metabolic stimuli, the aim of our project was to investigate whether agonist-induced glycocalyx modulation is occurring in the systemic and coronary circulation and whether this might be an additional mechanism by which vasoactive substances can contribute to flow and volume regulation, as well as the exchange capacity in the heart. Systemic blood volume was measured using labeled red blood cells. Total blood volume was defined as the sum of red blood cell and red blood cell derived plasma volume using large vessel hematocrit. Systemic glycocalyx volume was determined from the difference in distribution volume of circulating plasma and the distribution volume of dextrans with a molecular weight of 40 kDa. Volume measurements were done at baseline and during intravenous administration of adenosine (157 ± 11.6 μg/kg/min). In the systemic circulation of goats it was observed that during intravenous administration of adenosine the difference between a glycocalyx permeable and impermeable tracer was reduced from 23.9 ± 5.3 (SEM) ml/kg bodyweight (BW) to 3.3 ± 3.2 ml/kg BW (P<0.05), illustrating that adenosine indeed has the potency to greatly increase glycocalyx accessibility for flowing blood. The reduction in glycocalyx volume was not accompanied with an increase in plasma or blood volume, but appeared to be due to a reduction in anatomic vascular volume. Coronary blood volume was determined using the indicator dilution technique. Total coronary blood volume was defined as the sum of red blood cell volume and the distribution volume of an assumed plasma tracer (dextrans with a molecular weight of 2000 kDa). After comparing the suitability of four models, the local density random walk model was chosen to analyze the measured data. Volume measurements were done at baseline and during intracoronary adenosine administration (0.2–0.6 mg/kg/h) in the presence of an intact glycocalyx and after enzymatic degradation using the enzyme hyaluronidase (170.000 Units). Coronary blood flow was measured continuously by having a flowprobe around the left main coronary artery. Coronary adenosine infusion resulted in a profound recruitment of coronary blood volume; it increased significantly from 18.9 ± 1.1 ml/100gr heart tissue under baseline conditions to 33.2 ± 5.3 ml/100gr during adenosine. After hyaluronidase, the blood volume increased to 26.3 ± 2.7 ml/100gr, without an effect on coronary blood flow. Infusion of adenosine after hyaluronidase increased the blood volume to 33.9 ± 6.8 ml/100gr, illustrating impairment of adenosine-induced recruitment of coronary blood volume in case of glycocalyx loss. The increase in volume during hyaluronidase without a change in coronary blood flow and the increase in coronary blood flow during adenosine after hyaluronidase with a limited increase in coronary blood volume suggest that flow reserve and volume recruitment are, to some extent, two independent processes. Measurement of coronary flow reserve with adenosine, as done in the clinic, is therefore not sensitive to glycocalyx damage. Coronary oxygen exchange capacity was determined from simultaneously taken arterial and coronary venous blood samples and coronary blood flow. Arterial and coronary venous blood samples were taken at heart rates of 80, 110, 140 and 170 beats per minute in the presence and absence (by hyaluronidase) of endothelial glycocalyx. When studying the exchange capacity in the heart a loss of blood excluding glycocalyx volume was associated with an increased oxygen exchange. The myocardial arteriovenous oxygen difference increased significantly from 7.0 ± 0.2 to 8.3 ± 0.3 ml/100ml, while no change in myocardial arteriovenous oxygen difference was observed in the control group. These data suggest that the presence of endothelial glycocalyx limits the myocardial oxygen exchange capacity under baseline conditions. Thus, (1) adenosine administration results in a decrease in blood inaccessible glycocalyx volume; (2) loss of glycocalyx reduced volume recruitment capacity without having an effect on flow reserve, and (3) recruitment of glycocalyx volume increases oxygen extraction.
|Qualification||Doctor of Philosophy|
|Award date||29 Oct 2010|
|Place of Publication||Maastricht|
|Publication status||Published - 2010|