Studies were designed to examine the effect of a selective endothelinA (ETA) receptor antagonist, BQ123, on severe postischemic acute renal failure (ARF) in Sprague-Dawley rats. Severe ARF was induced in uninephectomized, chronically instrumented rats by 45-min renal artery occlusion. BQ123 (0.1 mg/kg. min) or vehicle was infused intravenously for 3 h on the day after ischemia. Measurements before infusion (24 h control) showed a 98% decrease in glomerular filtration rate (GFR), increase in fractional excretion of sodium from 0.6 to 39%, and in plasma K+ from 4.3 to 6.5 mEq/liter. All vehicletreated rats died in 4 d because of continuous deterioration of renal function, resulting in an increase of plasma K+ to fatal levels (> 8 mEq/liter). Infusion of BQ123 significantly improved survival rate (75%) by markedly improving tubular reabsorption of Na' and moderately increasing GFR and K+ excretion. Plasma K+ returned to basal levels by the 5th d after ischemia. Improved tubular function was followed by gradual recovery in GFR and urinary concentrating mechanism.Additional data from renal clearance studies in rats with moderate ARF (30-min ischemia) and in normal rats with intact kidneys showed that ETA receptor blockade increases Nan reabsorption and has no effect on renal hemodynamics. These results indicate that in the rat, the ETA receptor subtype mediates tubular epithelial function, and it plays a significant role in the pathogenesis of ischemia-induced ARF. Treatment with the selective ETA receptor antagonist reverses deteriorating tubular function in established ARF, an effect of possible therapeutic significance. (J. Clin. Invest. 1994. 93:900-906.) Key words: ischemia * moderate and severe acute renal failure * endothelinA receptor * BQ123
Experiments were designed to compare the distribution and physiological roles of endothelin (ET) receptor subtypes, ETA and ETB, in the kidneys of normotensive Sprague-Dawley (SD) and spontaneously hypertensive (SH) rats. Using [125I] ET-1 and subtype-selective ligands sarafotoxin 6c (S6c, ETB-selective agonist) and BQ123 (ETA-selective antagonist), the distribution of ETA and ETB receptors in SD rat kidney cortex, outer medulla and papilla was calculated to be 50:50, 30:70 and 10:90, respectively. The ET receptor subtypes in outer medulla and papilla of age-matched SH rats were similar to those of SD. However, in the cortex of SH rats, the ratio of ETA to ETB was 25:75 compared to 50:50 in SD rats. In addition, the affinity of the ET receptors was also higher in SH rats (117 pM vs. 235 pM). In the conscious SD rats, bolus i.v. injections of ET-1 and S6c elicited similar dose-dependent decrease in renal blood flow (RBF), which were unaffected by the infusion of the selective ETA receptor antagonist, BQ123. The SH rats were more sensitive to the renal vasoconstrictor effect of S6c and ET-1. Also, the dose-response curve to S6c was shifted to the left when compared to ET-1; however, BQ123 infusion abolished this difference. In renal clearance studies, BQ123 infusions decreased RBF and glomerular filtration rate (GFR) only in SH rats, and the fractional excretion of sodium only in SD rats. The combined data indicate that the distribution and functional roles of ETA and ETB receptor subtypes are altered in the kidneys of SH rats.
The effects of the novel antihypertensive agent, carvedilol, on renal hemodynamics and excretory function have been investigated and compared with the effects of labetalol in conscious, spontaneously hypertensive rats. Sustained intravenous infusion of carvedilol or labetalol at a rate of 10 μg/kg/min resulted in a significant decrease in blood pressure which was equivalent in magnitude for both drugs. Carvedilol had no effect on renal hemodynamic parameters; glomerular filtration rate, renal blood flow, and filtration fraction were unchanged. In contrast, labetalol decreased the glomerular filtration rate by 13 % (p < 0.01) and the filtration fraction was reduced from 28 to 24%. Inasmuch as renal blood flow was unchanged and perfusion pressure was reduced, both compounds decreased renal vascular resistance. Urine flow decreased and osmolality increased with both carvedilol and labetalol. However, excretion of electrolytes was affected differently with the two compounds. While sodium and potassium excretion were significantly decreased with labetalol, sodium and potassium excretion remained stable during carvedilol infusion, which represents an important beneficial effect for a potent systemic vasodilator. We conclude, therefore, that carvedilol does not compromise the renal autoregulatory integrity in hypertensive rats, and that the antihypertensive activity of the compound is associated with an apparent ‘renal sparing’ effect, in that the decrease in blood pressure does not compromise the urinary excretion of sodium.
Atrial natriuretic factors, polypeptides released by atrial myocytes, may play a role in the control of blood pressure and the regulation of renal salt and water excretion. Our studies were designed to assess the role of a synthetic peptide, atriopeptin II, on blood pressure and heart rate, renal hemodynamics, and salt and water excretion in conscious, spontaneously hypertensive rats and in normotensive Wistar-Kyoto rats. Changes in mean arterial pressure and heart rate were recorded following intravenous bolus injections (0.1, 1.0, 10, 100 micrograms/kg) of atriopeptin II in 5 spontaneously hypertensive and 5 Wistar-Kyoto rats. In a second group of rats the peptide was infused for 90 minutes in two different doses: low dose, 1 microgram/kg + 2 micrograms/kg/hr; and high dose, 10 micrograms/kg + 20 micrograms/kg/hr. Bolus injections of atriopeptin II resulted in dose-dependent decreases in mean arterial pressure in the hypertensive, but not in the normotensive, rats; heart rates remained unchanged. Blood pressure decreased gradually during the sustained infusion of both doses of atriopeptin II, with the spontaneously hypertensive strain showing increased sensitivity compared to the Wistar-Kyoto strain. Heart rate decreased in both strains during infusion of the high dose; the decrease was significant only in the hypertensive rats. The low dose of atriopeptin II increased the clearance of free water in both strains of rats; sodium excretion was increased only in the hypertensive rats. The high-dose atriopeptin II was associated with transient natriuresis, unaltered glomerular filtration rate, and decreased effective renal blood flow in both strains.(ABSTRACT TRUNCATED AT 250 WORDS)
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