Calcium entry and 5‐HT 2 receptor blockade in oliguric ischaemic acute renal failure: effects of levemopamil in conscious rats

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‐hydroxytryptamine 2 (5‐HT 2 ) receptor antagonistic properties, were studied. Rats received L as a continuous infusion (6 mg kg −1 h −1 ) 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 −1 100 g −1 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 ml min −1 g −1 kidney weight (k.wt.); P <0.01) and urine flow (0.51±0.05 and 0.15±0.04 ml 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 significantly reduced ATP synthesis when compared to right intact kidneys (0.06±0.02 vs 0.26±0.02 μmol ATP mg −1 protein min −1 ( P <0.01)). In contrast, in L‐treated rats, ATP synthesis of left ischaemic kidneys was largely preserved (0.17±0.01 μmol ATP mg −1 protein min −1 ). 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 μmol P i h −1 mg −1 protein in the intact right kidneys which was not prevented by L (9.4±2.4 μmol P i h −1 mg −1 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 −1 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 −1 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‐HT 2 ‐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.