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

In the present study, we demonstrate that the intravenous infusion of endothelin-1 (3 and 10 ng/kg/min) causes a decrease in the mean micturition volume of rats in addition to an increase in mean arterial pressure. These effects are blocked by both the ET_A/ET_B-non-selective and the ET_A-selective endothelin antagonists SB 217242 and SB 247083 respectively (both 30 mg/kg). However, it was also observed that the ET_B-selective agonist sarafotoxin 6c (3 and 10 ng/kg/min) had similar effects on both mean arterial pressure and micturition volume. Initial experiments indicated that spontaneously hypertensive rats have a much lower mean micturition volume than normal rats. Binding studies comparing the total number and ratio of ET_A/ET_B receptors in spontaneously hypertensive, Wister-Kyoto and Sprague-Dawley rats revealed no significant differences in receptor expression. However, the magnitude of the response to endothelin-1 was greater in spontaneously hypertensive versus normal rats.

To gain further insights into the molecular mechanisms involved in acute renal failure, we have isolated a new gene from rat and human, named KSP32 (kidney-specific protein with a molecular mass of 32 kDa). KSP32 encodes a novel gene that shows little homology to other mammalian proteins. It, however, shares extensive homology with several proteins found in the nematode Caenorhabditis elegans and plants. The expression of KSP32 mRNA is highly restricted to kidney. In situ hybidization analysis revealed that the expression of KSP32 mRNA was prominent in the boundary of kidney cortex and outer medulla, exhibiting a raylike formation extending from the medulla into the cortex. Finally, KSP32 mRNA was dramatically downregulated in rat following induction of acute ischemic renal failure. Rapid loss of KSP32 mRNA expression was observed beginning at approximately 5 h following renal injury and mRNA levels remained depressed for at least 96 h. Both KSP32 mRNA levels as well as renal function recovered 14 days after injury. Administration of an endothelin receptor antagonist (SB-209670), known to restore renal function, significantly increased KSP32 expression.

Cystometry of the conscious rat is an effective method to study bladder function without compromising micturition reflexes with anesthetics. This model can be influenced by inflammation, hormones and potentially strain of animal. Therefore, we examined whether gender has any impact on the micturition pattern of Sprague-Dawley (SD), Wistar Kyoto (WKY) and Spontaneously Hypertensive rat (SHR). In this study, recovery after surgery had a major impact on cystometry during the early days of post-surgery. Void intervals were shorter with very low void volume on the first day after surgery. However, there was a gradual increase in void interval and void volume from the second day onwards and were stable on the fifth through seventh days post-surgery. Regarding strains, it was found that void volume and void interval were similar between SD and WKY rat. SHR, had a lower void volume with a shorter void interval than the WKY. Interestingly, the void interval in male rats, regardless of strain, was shorter compared to the females of the respective strain. It is concluded that a stable cystometric pattern is observed in the conscious SD rat after the fifth day of post-surgery which suggests that at least 1 week should be allowed after bladder surgery to observe a stable cystometric data. There was a clear sex difference in the micturition pattern among the strains in that the frequency of micturition of the male was higher than female SD, WKY and SHR. Studying the sex differences in the micturition pattern might improve understanding the different pathophysiology of bladder control in men and women.

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