Chronic vascular constrictions and measurements of renal function in conscious rats

Although a tremendous amount of physiologic information has been gained from experiments on anesthetized animals, there is often the question to what extent anesthesia itself, as well as the losses and replacement of fluid that accompany surgical preparations, might have influenced the function being studied. This possible pitfall may apply especially to studies on the kidney because the renal circulation is so exquisitely sensitive to anesthetic agents and changes in fluid balance. Chronic preparations in dogs have been [1] and continue to be used [2] successfully. But the far lesser expense of rats, as well as their common use in physiologic experiments, points up the desirability of a successful chronic preparation in this species. Renal clearances have been performed previously on unanesthetized rats [3, 4], but the methods have not been generally adopted.We here describe a method that can measure renal clearances and extraction of PAH accurately and repeatedly in the same conscious rat over a period of weeks. For our own purposes [5] we also needed a method for constricting blood vessels. The design and construction of a suitable cuff for this purpose, likewise usable in unanesthetized rats, also form part of this report

Nambi P. Reversal of postischemic acute renal failure with a selective endothelin A receptor antagonist in the rat

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 therapeuti

Nonpeptide Endothelin Receptor Antagonists. XI. Pharmacological Characterization of SB 234551, a High-Affinity and Selective Nonpeptide ET A Receptor Antagonist

ABSTRACT The present study describes the pharmacological profile of ((E)-alpha- [[1-butyl-5-[2-[(2-carboxyphenyl)methoxy]-4-methoxy-phenyl]-1H-pyrazol-4-yl]methlene]-6-methoxy-1,3-benzodioxole-5-propanoic acid) (SB 234551), a high-affinity, nonpeptide endothelin type A (ET A )-selective receptor antagonist. In human cloned ET A and endothelin type B (ET B ) receptors, SB 234551 produced a concentration-dependent displacement of [ 125 I]-endothelin-1 with K i values of 0.13 and 500 nM, respectively. SB 234551 elicited concentration-dependent, rightward competitive shifts in the endothelin-1 concentration-response curves in isolated rat aorta and isolated human pulmonary artery (ET A receptor-mediated vascular contraction) with K b values of 1.9 and 1.0 nM, respectively. SB 234551 antagonized ET B receptor-mediated vasoconstriction in the isolated rabbit pulmonary artery, as demonstrated by concentration-dependent, rightward shifts in the sarafotoxin S6c concentrationresponse curves (K b ϭ 555 nM). SB 234551 produced weak functional inhibition of sarafotoxin S6c-mediated endotheliumdependent relaxation (IC 50 ϭ 7 M). SB 234551 (10 M) had no significant effect against contraction produced by several other vasoactive agents and did not significantly influence radioligand binding to a number of diverse receptors. SB 234551 (0.1-1.0 mg/kg i.v.) dose-dependently inhibited the pressor response to exogenous endothelin-1 in conscious rats. In vivo pharmacokinetic analysis in the rat demonstrated that SB 234551 was rapidly absorbed from the GI tract with a bioavailability of 30%. SB 234551 had a plasma half-life of 125 min and a systemic clearance of 25.0 ml/min/kg. The present study demonstrates that SB 234551 is an antagonist with high affinity for the ET A receptor, while sparing the ET B receptor. SB 234551 is a new pharmacological tool that should assist in the elucidation of the role of endothelin in pathophysiology. A critical need in the search for endothelin-based therapeutics is clarification of the physiological and pathophysiological functions of the endothelin receptor subtypes. Effects associated with ET A receptor activation include vasoconstriction, mitogenic activity, electrolyte excretion, microvascular permeability and release of biological mediator