ET_A receptor‐mediated responses to endothelin‐1 and big endothelin‐1 in the rat kidney

Abstract

1 Renal clearance experiments were conducted in anaesthetized Sprague-Dawley rats to determine the effect of the ETA receptor antagonist, BQ-123, on the renal haemodynamic response to endothelin-1 (ET-1) and its precursor, big endothelin-1 (big ET-1) at doses that produce an equivalent degree of renal vasoconstriction.2 Infusion of either big ET-1 at 100 pmol kg-min' or ET-1 at 12pmolkg-'min'1 for 60min produced almost identical decreases in renal blood flow (RBF) and glomerular filtration rate (GFR). Big ET-1 produced an increase in mean arterial pressure (MAP) that was significantly larger than the increase produced by ET-1. 3 Co-infusion with BQ-123 (0.1 mg kg-' min-') prevented the rise in MAP produced by big ET-1 and completely blocked the renal response. Similarly, BQ-123 inhibited both the increase in MAP and the decrease in RPF and GFR produced by ET-1. 4 Big ET-1 but not ET-1, produced a significant increase in water and sodium excretion. BQ-123 had no effect on the diuretic and natriuretic response to big ET-1 consistent with possible ETB-mediated inhibition of tubular reabsorption. 5 We have previously shown that at higher doses of ET-1, BQ-123 was unable to inhibit the renal vasoconstrictor response despite blockade of the pressor response. Taken together, these results indicate that ET-1 activates primarily ETA receptors at moderately low doses to produce renal vasoconstriction while higher doses also involve non-ETA receptors. 6 Since ET-l has a similar binding affinity for both ETA and ETB receptors, we suggest that there may be a third type of ET-1 receptor in the rat kidney with lower affinity for ET-1 that is coupled to a vasoconstrictor mechanism.

Interactions Between Vasoconstrictors and Vasodilators in Regulating Hemodynamics of Distinct Vascular Beds

“…Thus, ET did not seem to have the same predilection for the renal vasculature as Ang II. This lack of effect of the ET antagonists on basal renal tone is consistent with previous studies in rat kidneys 17,18 that also suggest that the balance between Ang II and NO/PGs is more important in the maintenance of basal renal vascular tone than ET. However, although ET blockade did not alter RBF significantly when Ang II was present, its effect was striking when Ang II was blocked (group 3); RBF increased dramatically (by 46%).…”

Dual constrictor and dilator actions of ETB receptors in the rat renal microcirculation: interactions with ETA receptors

“…Although indications for slight differences in the susceptibility of the two ET B receptor locations to different ET B antagonists have been reported (26, 28), the similarity of the responses to ET B agonists S6C and IRL-1620 in the present study speaks against a major difference in sensitivity of endothelial and smooth muscle ET B receptors, at least at the employed doses of ET B agonists. Finally, it has been suggested that the relative influence of the dilator effect of endothelial ETB receptors is smaller or absent at lower doses of ET-1 (35,36), possibly due to a higher affinity of endothelial than smooth muscle ET B receptors for ET-1. However, binding curves for ET-1 are typically monophasic, including renal microvascular tissue (15,17), thus giving no indication for different affinities of endothelial and smooth muscle receptors.…”

“…Specific vascular beds, vessel size, species (22,33), hydration status (34), or strength of stimulation (34) may play a role. Anesthesia does not seem to be a major factor for either the finding of predominant ET Amediated constriction (7,8,23,36) or predominant ET Bmediated renal vasoconstriction (25,36). However, an important contributing factor seems to be the experimental strategy employed.…”

“…However, reports on the relative influence of receptor subtypes are highly variable. This ranges from exclusive mediation by ET A receptors (8,23,36) to only that of ET B receptors (12,25,30), including other studies suggesting a more balanced contribution (4,11,18,28,31,41). Furthermore, there is also controversy about the actions of endothelial ET B receptors, ranging from no dilation (10,12,18,27,40) to strong dilator effects of ET B receptors (1,2,5,28,31).…”

Vasoconstrictor endothelin receptors characterized in human renal artery and vein in vitro

“…Even if some of the constrictor effects of endothelin intrarenally are mediated via ETB receptors, ETA-selective compounds have already proved effective not only in antagonizing the haemodynamic responses in rats to infused ET-1 and big ET-1 (Pollock & Opgenorth, 1994) but also in limiting tissue necrosis and biochemical changes in at least two rat models; a cyclosporine-induced model of nephrotoxicity (Fogo et al, 1992) and a model of chronic renal failure associated with reduced renal mass (Benigni et al, 1993). This is despite reports that, in rats at least, some part of renal vasoconstriction is ETB-mediated.…”