COMPARATIVE EFFECTS OF HYDRALAZINE ON PERFUSION OF KHT TUMOR, KIDNEY AND LIVER AND ON RENAL-FUNCTION IN MICE

Hydralazine has been widely used to reduce tumor blood flow in mice. It has an application in the deliberate creation of reducing environments within tumors and has been used in conjunction with both bioreductive and cytotoxic drugs. We have compared the dose-response to hydralazine of relative tissue perfusion of KHT tumor, kidney and liver, assayed by Rb-86 extraction, over the dose range 0.2 to 5.0 mgkg-1 and shown that doses of 1.0 mgkg-1 and higher cause significant reductions in perfusion of all three tissues but 0.2 mgkg-1 has no effect. Tumor perfusion (+/- 2 se) was reduced to 80 +/- 8% of control by 1.0 mgkg-1, to 38 +/- 13% by 2.5 mgkg-1 and to 35 +/- 7% by 5.0 mgkg-1. Relative kidney perfusion was reduced to 83 +/- 11% of control by 1.0 mgkg-1 and to 73 +/- 9% by 5.0 mgkg-1; relative liver perfusion was reduced to 71 +/- 10% of control by 1.0 mgkg-1 and to 64 +/- 10% by 5.0 mgkg-1. This reduction in kidney and liver perfusion may indicate that there would be impairment of elimination and/or metabolism of co-administered drugs. We have therefore also measured the dose-response of the effect of hydralazine on glomerular filtration rate and effective renal plasma flow, assayed by clearance of (EDTA)Cr-51 and I-125-iodohippurate, respectively. 5.0 mgkg-1 hydralazine blocks clearance of EDTA for 40 min, slows subsequent clearance by a factor (+/- 2 se) of 2.4 +/- 1.2, and slows I-125-iodohippurate clearance by a factor of 5.5 +/- 0.8; 1.0 mgkg-1 hydralazine slows EDTA clearance by a factor of 1.5 +/- 0.3. The time-course of the effect of 5.0 mgkg-1 hydralazine on isotope clearance was measured and this dose was shown to affect isotope clearance at times up to 4 h after administration. These data confirm that hydralazine at doses effective at reducing tumor blood flow also impairs renal function, and is therefore likely to affect the pharmacokinetics of any co-administered drug that is cleared by the kidney.