br In some but not all
In some, but not all, human vessels, a small population of ETB (usually <15%) can be measured by ligand binding. Although in some human beings isolated renal vessel responses to high concentrations of ET-3 were detected, comparison of equipotent concentrations of ET-3 and ET-1 in healthy volunteers found that ET-3 had no effect on blood pressure or renal hemodynamics, which might have been expected if ETB contributed significantly to a contractile response. Whether the proportion of vascular ETB changes with disease remains controversial and has not been studied in detail in pathophysiological renal tissue. However, detailed studies in vitro in human coronary Calpeptin with atherosclerotic lesions did not show any increase. In agreement, in experimental medicine studies in both heart failure patients and volunteer controls, selective ETA antagonism (BQ123) caused the expected potent vasodilatation in the peripheral circulation. However, BQ788 caused vasoconstriction in both groups, consistent with blocking endothelial cell ETB-mediated vasodilatation, with no evidence of contractile ETB.36, 37
ETA have been shown to be present on human and rat podocytes (glomerular epithelial cells) that wrap around the capillaries of the glomerulus within Bowman׳s capsule.38, 39 Ortmann et al also detected messenger RNA encoding ETB as well as ETA on human podocytes. However, ETA contribute to podocyte injury through cytoskeleton disruption and apoptosis and only ETA antagonists are effective in preventing podocyte injury. In renal disease, proliferation in mesangial cells, extracellular matrix production, and inflammation41, 42 are mediated mainly by ETA.
In peripheral tissues such as the heart (Fig. 1), ETA are more abundant (>60%) than ETB (Fig. 2). In marked contrast, in the kidney, lungs, and liver this ratio is reversed. Although measurements of receptors within smooth muscle throughout the renal vasculature show a predominance of ETA, 70% of the ET receptors in both cortex and medulla in human kidney are ETB. ETB predominate, reflecting, at least in part, that these are endothelial cell–rich tissues similar to liver and lungs.24, 25, 26 Endothelial cells line every vessel wall and have a mass comparable with other endocrine organs. Although ETB also are expressed by other cell types, selective deletion of the endothelial cell ETB, leaving ETB on other cells intact, shows that in many organs, including the kidney, liver, and lungs, endothelial cells represent the majority of the receptors. A consensus has emerged that ETB mediates vasodilatation by the release of endothelium-derived relaxing factors (nitric oxide, prostacyclin, and/or endothelium-derived hyperpolarizing factor), acting as a feedback mechanism to limit the vasoconstrictor action of ET-1. Infusions of ET-1 into the brachial artery of volunteers produces a biphasic response: low doses of ET-1 cause ETB-mediated vasodilatation, however, as the concentration increases to higher pathophysiological concentrations, vasodilatation is overwhelmed by ETA-mediated constrictor responses. When endothelial dysregulation occurs in renal disease there is a loss of opposing vasodilators, leading to increased vasoconstriction and vasospasm. Endothelial cell ETB function as scavenging or clearing receptors to remove ET-1 from the circulation,23, 43, 44 particularly by the ETB-rich tissues: kidney, lungs, and liver (Fig. 1). Selectively blocking ETA, but not ETB, with a low dose of the peptide antagonist TAK-044 infused into volunteers caused no change in measured plasma ET-1 levels. However, a higher dose that blocked both subtypes increased ET-1 levels by more than three-fold as a result of reducing clearing by ETB. In renal circulation, in agreement with other vascular beds in human beings, systemic infusion of ET-1, which activates both receptors, into volunteers increased blood pressure (6 mm Hg), and decreased renal plasma flow, glomerular filtration rate, and sodium excretion rate. Although BQ123 infused alone did not affect basal arterial blood pressure or renal or splanchnic vascular resistance, the antagonist inhibited the increase in vascular resistance induced by co-infusion of ET-1. In contrast, BQ788 alone caused the opposite effect: increased renal or splanchnic vascular resistance, consistent with blocking endothelial cell–receptor vasodilatation. Second, BQ788 potentiated the ET-1–induced increase in vascular resistance mediated by ETA, suggesting that blocking the scavenging receptors modulated plasma ET-1 levels. Inhibition of tonic nitric oxide production by inhibition of nitric oxide synthase elicits vasoconstriction with an increase in mean arterial pressure and vascular resistance in many organs, including the kidney. Renal and systemic vasoconstriction in volunteers caused by the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester were attenuated by BQ123, supporting the concept that the balance between endogenous nitric oxide production and ET-1/ETA activity contributes to renal and systemic tone in human beings.46, 47