Small artery tone under control of the endothelium:on the importance of EDHF and myogenic tone in organ (dys)function

摘要

Small artery tone is a major determinant of organ tissue blood flow and of total peripheral resistance. Pathophysiological alterations in small artery function towards a more constrictive state (“small artery dysfunction”) restricts the organ’s blood supply, and increases peripheral vascular resistance, and hence blood pressure. The endothelium plays an important role in the control of small artery tone by releasing dilative mediators, i.e. nitric oxide (NO), prostaglandins (PGs), and endothelium-derived hyperpolarizing factor (EDHF), which act in balance to mediate endothelium-dependent dilation. An impaired dilative function of the endothelium (“endothelial dysfunction”) has been demonstrated to underlie the highly constrictive state of small arteries in many forms of cardiovascular and renal disease, which could play a role in disease progression and/or disease induction. However, cause-effect relations between small artery dysfunction and disease progression are not well explored. For a long time the impairment of the NO system has been the focus of attention regarding endothelial dysfunction in cardiovascular and renal disease. Recently, an important role of endothelium-derived hyperpolarizing factor (EDHF), and the importance of differences between endothelium-derived mediators in arteries of different vascular beds, and in arteries with different vessel size has been proposed. Therefore, the first important aim of this thesis was to investigate disease-related endothelial alterations in more detail, with emphasis on EDHF and the underlying mechanisms of its impairment, and with respect to differences in arteries derived from different vascular beds. The results presented in this thesis to treat this aim indicate an important role of an impairment of the arterial EDHF response in different animal models of renal and cardiovascular disease. More specifically, the data show that renal organ dysfunction (in the MWF rat strain) gives rise to localized rather than generalized EDHF impairment preferentially in small coronary arteries, as to (partly) explain the relatively high incidence of cardiovascular complications in renal disease.