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.