Reduced venous responsiveness to endothelin-1 but not noradrenaline in hypertensive chronic renal failure

Background. Endothelin-1 (ET-1), acting mainly through the ETA receptor, is a potent endothelium-derived vasoconstrictor peptide. Circulating concentr ations of ET-1 are increased in chronic renal failure (CRF) and may influen ce vascular tone. Methods. We investigated dorsal hand vein responsiveness to local infusion of ET-1 and nonadrenaline in 12 hypertensive and 12 normotensive CRF patien ts and in 12 age and sex matched control subjects. We also investigated dor sal hand vein responses to the ETA receptor antagonist, BQ-123, and the end othelium-independent vasodilator glyceryl trinitrate (GTN), in six patients with CRF. Results. The dose of noradrenaline causing a 50% of maximal vasoconstrictio n was similar in the hypertensive (32 +/- 11 pmol/min) and normotensive (26 +/- 7 pmol/min) CRI; patients and control subjects (21 +/- 6 pmol/min). Va soconstriction to ET-1 (5 pmol/min) was similar in CRF patients as a whole (AUC 35 +/- 5%) and controls (32 +/- 4%; P = 0.70). However, venoconstricti on was significantly less in hypertensive (23 +/- 6%) than in normotensive CRF patients (48 +/- 8%; P = 0.01). Overall, venoconstriction to ET-1 corre lated inversely with mean arterial blood pressure in the CRF patients (R = -0.43, P = 0.04). In addition, basal vein size was smaller, and plasma endo thelin concentrations greater, in the hypertensive CRF group. However, infu sion of BQ-123 or GTN did not cause venodilatation in these subjects. Conclusions. These studies are consistent with the hypothesis that elevated plasma ET-1 contributes to vascular tone, and elevated blood pressure, in hypertensive CRF patients, and is associated with vascular receptor downreg ulation consequent on the increased exposure to ET-1. The reduced vein size in CRF patients appears to be structural rather than functional in nature. Further long-term studies with endothelin antagonists are required to dete rmine the pathophysiological role of ET-1 in the altered structure and func tion of blood vessels in patients with CRF.