CALCIUM-ENTRY AND 5-HT2 RECEPTOR BLOCKADE IN OLIGURIC ISCHEMIC ACUTE-RENAL-FAILURE - EFFECTS OF LEVEMOPAMIL IN CONSCIOUS RATS

1 Unilateral left renal artery occlusion for 1 h in a group of 8 untre ated female Sprague-Dawley rats resulted in oliguric acute renal failu re (ARF) persisting for more than 6 h after reflow, i.e. after reperfu sion 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-hydroxytryptamine(2) (5-HT2) receptor ant agonistic properties, were studied. Rats received L as a continuous in fusion (6 mg kg(-1) h(-1)) from 1 h before ischaemia until 6 h after r eflow. 2 Endogenous creatinine clearance, an estimate of glomerular fi ltration rate (GFR), of left ischaemic kidneys of untreated rats was a lmost completely abolished and urine flow was 0.05 +/- 0.02 and 0.03 /- 0.01 ml h(-1) 100 g(-1) body weight (body wt.) at 2 and at 6 h of r eflow, respectively. In contrast, left ischaemic kidneys of L-treated rats revealed significantly higher GFR (0.10 +/- 0.02 and 0.03 +/- 0.0 1 ml min(-1) g(-1) kidney weight (k.wt.); P<0.01) and urine flow (0.51 +/- 0.05 and 0.15 +/- 0.04 mi h(-1) 100 g(-1) 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 signifi cantly reduced ATP synthesis when compared to right intact kidneys (0. 06 +/- 0.02 vs 0.26 +/- 0.02 mu mol ATP mg(-1) protein min(-1) (P<0.01 )). In contrast, in L-treated rats, ATP synthesis of left ischaemic ki dneys was largely preserved (0.17 +/- 0.01 mu mol ATP mg(-1) protein m in(-1)). 4 Ischaemia of left kidneys resulted in a significant decreas e in medullary Na-K-ATPase activity to 9.6 +/- 2.4 as compared to 20.4 +/- 3.7 mu mol P-i h(-1) mg(-1) protein in the intact right kidneys w hich was not prevented by L (9.4 +/- 2.4 mu mol P-i h(-1) mg(-1) prote in). 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(-1) protein in right intac t kidneys (P<0.01). This rise in mitochondrial calcium was not signifi cantly attenuated by treatment with L (19.9 +/- 1.7 nmol mg(-1) protei n). 6 The results show that L transiently converted oliguria into non- oliguria during the early phase after reflow in ischaemic ARF, i.e. af ter reperfusion following 1 h of complete interruption of renal perfus ion. The present data suggest indirectly that the 5-HT2-antagonistic p roperties of L rather than its calcium channel blocking action maintai ns GFR at low level and protects mitochondrial function early after re flow in this model of ischaemic ARF.