Renal hemodynamics and blood flow autoregulation during acute cyclooxygenase inhibition in male rats

Abstract

After the acute inhibition of prostanoid synthesis, adjustments of renal hemodynamics may not be characterized immediately. Therefore, time-related effects of indomethacin on hemodynamics and renal blood flow (RBF) autoregulation were studied in anesthetized euvolemic male rats injected intravenously with vehicle, indomethacin (3, 4, or 5 mg/kg body wt), or meclofenamate (4 or 5 mg/kg body wt). Hemodynamics and RBF autoregulation were not influenced by vehicle injection, nor by time (n = 6). In contrast, mean arterial pressure (MAP) decreased significantly from 117 +/- 4 to 103 +/- 3 mmHg, and RBF progressively and significantly increased from 8.00 +/- 0.34 to 9.17 +/- 0.50 ml/min in the 3 mg/kg body wt indomethacin group (n = 8). Treatment with the higher doses of indomethacin (n = 9) or meclofenamate (n = 6) did not change RBF, while MAP decreased by 15 mmHg. A time-dependent significant enhancement of RBF autoregulatory efficiency was found in the drug-treated rats. Changes in renal function and reductions of prostanoid excretion in urine, of plasma renin activity, or serum aldosterone were similar in the nonsteroidal antiinflammatory drug groups. In conclusion, our findings demonstrate important time-related adjustments of renal hemodynamics in male rats treated with indomethacin, especially with the lower dose (3 mg/kg body wt iv). The factor(s) responsible for the hemodynamic changes remains unknown.

Renal Autoregulation in Health and Disease

“…Thus the poor autoregulation of papillary blood flow in the rat kidney was improved by COX inhibition (1127), while whole kidney RBF autoregulation was slowly enhanced following COX inhibition (833). Efficient autoregulation of GFR in superficial nephrons depended on COX metabolites contributing to MD-TGF (1313).…”

“…An AI of zero indicates perfect autoregulation, whereas an AI close to 1.0 or above signifies very ineffective RBF autoregulation. Low AI values (Ͻ0.2), reflecting effective steady-state RBF autoregulation, have been reported in the kidneys of anesthetized dogs (90,269,745,763,799,953,954,1295,1344,1531), mice (583,751,756,1360), rabbits (80,385,902,1141,1270,1623), and rats (41,45,46,269,422,709,790,833,1105,1131,1188,1270) as well as in conscious rats (270,423,668,1195,1376) and dogs (69, 97, 421, 510, 511, 753-755, 760, 799, 1172, 1172-1174, 1263, 1618) in both short and prolonged settings (42,1241). Autoregulation in the kidneys of conscious dogs and anesthetized rats is considerably more complete than in the mesenteric or hindlimb vascular beds (602,750).…”

Changes in renal haemodynamics induced by indomethacin in the rat involve cytochrome P450 arachidonic acid‐dependent epoxygenases‡

“…In contrast, renal vasoconstriction occurred rapidly after the injection of indomethacin in our anaesthetized rats in the absence of euvolaemic conditions 5 . Interestingly, the differential effect of indomethacin on renal haemodynamics was not due to differences in the extent of COX inhibition because urinary excretion of prostanoids was similarly reduced by the doses of indomethacin used in our study (3 and 5 mg/kg) 5 . Moreover, these dose‐dependent haemodynamic effects could be reproduced with sulindac, another non‐steroidal anti‐inflammatory drug (NSAID) of the same chemical class as indomethacin 7 …”

Cyclooxygenase-2 Modulates Afferent Arteriolar Responses to Increases in Pressure

“…10 In rat kidneys, nonselective COX inhibition with meclofenamate and indomethacin blunted arterial pressure-mediated increases in papillary blood flow when RPP was elevated. 11 Nevertheless, in dog 12 and rat 13 kidney preparations, nonselective COX inhibition has consistently failed to alter the autoregulatory responses to changes in perfusion pressure. Thus, the contribution of COX-derived metabolites to overall autoregulatory responsiveness remains controversial.…”