Calcium entry and 5‐HT₂ receptor blockade in oliguric ischaemic acute renal failure: effects of levemopamil in conscious rats

Abstract

1 Unilateral left renal artery occlusion for 1 h in a group of 8 untreated female Sprague-Dawley rats resulted in oliguric acute renal failure (ARF) persisting for more than 6 h after reflow, i.e. after reperfusion of the kidney by removal of the arterial clamp. In a second group of 8 rats with left unilateral ARF the effects of levemopamil (L), a calcium entry blocker with 5-hydroxytryptamine2 (5-HT2) receptor antagonistic properties, were studied. Rats received L as a continuous infusion (6 mg kg-' h-') from 1 h before ischaemia until 6 h after reflow. 2 Endogenous creatinine clearance, an estimate of glomerular filtration rate (GFR), of left ischaemic kidneys of untreated rats was almost completely abolished and urine flow was 0.05 + 0.02 and 0.03 + 0.01 ml h'-100 g' body weight (body wt.) at 2 and at 6 h of reflow, respectively. In contrast, left ischaemic kidneys of L-treated rats revealed significantly higher GFR (0.10 + 0.02 and 0.03+0.01 mlmin-' g kidney weight (k.wt.); P<0.01) and urine flow (0.51+0.05 and 0.15 +0.04 ml h-' 100 g' body wt.; P<0.05) at 2 and 6 h of reflow, respectively. 3 At 6 h of reflow, mitochondria from the cortex of left ischaemic kidneys of untreated rats showed significantly reduced ATP synthesis when compared to right intact kidneys (0.06 + 0.02 vs 0.26+0.02 ymol ATP mg-' protein min-' (P<0.01)). In contrast, in L-treated rats, ATP synthesis of left ischaemic kidneys was largely preserved (0.17+0.01 ymol ATP mg-' protein min-').4 Ischaemia of left kidneys resulted in a significant decrease in medullary Na-K-ATPase activity to 9.6+2.4 as compared to 20.4+3.7 ,umol Pi h-' mg-' protein in the intact right kidneys which was not prevented by L (9.4+2.4 ymol Pi h-' mg-' protein).5 In untreated rats the calcium content in cortical mitochondria from left ischaemic kidneys had risen 2 fold to 23.0+1.8 at 6 h of reflow as compared to 12.2 + 0.3 nmol mg-' protein in right intact kidneys (P<0.01). This rise in mitochondrial calcium was not significantly attenuated by treatment with L (19.9 + 1.7 nmol mg'-protein). 6 The results show that L transiently converted oliguria into non-oliguria during the early phase after reflow in ischaemic ARF, i.e. after reperfusion following 1 h of complete interruption of renal perfusion. The present data suggest indirectly that the 5-HT2-antagonistic properties of L rather than its calcium channel blocking action maintains GFR at low level and protects mitochondrial function early after reflow in this model of ischaemic ARF.

Impaired Renal Function in Obstructive Jaundice: Roles of the Thromboxane and Endothelin Systems

“…which was accompanied by a rise in urinary T X excretion, suggests that enhanced glomeru lar synthesis of T X A 2 with its renal vasoconstrictor action [71,72] contributes to the reduction in G F R after BDL. In analogy, we and others found in previous studies an increased glomerular T X synthesis in experimental ure teral obstruction [73] and an initial increase in urinary T X excretion after relief of ureteral obstruction in clinical obstructive uropathy [74], Others also observed enhanced glomerular T X synthesis in experimental glycerol-in duced A R F [75] and we found increased urinary T X excretion in ischemia-induced A R F [76], Thus, T X of renal glomerular origin may be responsible for reduced G F R and RPF in these disease states as well.…”

“…Some increase in G F R was observed in SO rats as well, suggest ing that T X A 2 and/or PGHb contributes also to the basal renal vascular tone. We also observed recently a tempora ry beneficial effect of the T X A 2/PGH2 receptor antagonist sulotroban in the very early phase of reflow in experimen tal ischemic A R F [76] suggesting that it prevented the ini tial vasoconstriction accompanying this type of ARF.…”

Lack of prostanoid receptor involvement in ischemic acute renal failure in mice

“…19 TP antagonists also protected conscious rats against ischemic ARF. 21 It has also been reported that the production of TXA 2 in ischemic-reperfusion injury might be associated with leukotriene (LT)B 4 and free radicals. 26,27 In the present study, 24 and 48 h after bilateral renal pedicle clamping for 20 min, serum creatinine levels increased in wild-type mice as well as in TP knockout mice and there were no significant differences between them.…”

“…3 Renal prostanoids have important local functions, including the regulation of renal circulatory and excretory functions. 4,5 Previous studies have shown increased renal TXB 2 release during the development of acute renal failure (ARF), 6,7,19 and some studies have reported that selective TXA-synthase inhibition, 7,8 TXA 2 receptor (TP) antagonists, 9,21 or the infusion of PGE 1 , PGE 2 , and/or PGI 2 [10][11][12][13] partially protected experimental animals from the development of this syndrome. Thus, it appears that the excessive production of TXA 2 , or an imbalance in the PGI 2 /TXA 2 ratio, serves to aggravate this condition.…”

The role of eicosanoids in renal diseases – potential therapeutic possibilities

“…It also increases the inflammatory state and provokes renal dysfunction. (Kramer et al, 1993) Rats Sulotroban can stop TXA2 dependent vasoconstriction in the early phase of AKI. (Li et al, 2009) Mice Selective EP4 receptor agonists may reduce all major manifestations of XNDI, including changes in renal morphology, and may become a new treatment strategy for hereditary nephrogenic diabetes insipidus.…”