Renal Hemodynamic and Excretory Responses to Infusion of Tyrosine Kinase Inhibitor, Imatinib in Anesthetized Mice

Systemic administration of a tyrosine kinase inhibitor, imatinib has been shown to have potent vasodilator activity in pulmonary and systemic vascular beds in rats. Chronic treatment with imatinib was also shown to cause marked attenuation of the renal injury in AngII induced hypertensive rats. However, the involvement of tyrosine kinases in the regulation of renal hemodynamics and excretory function is not yet clearly defined. To examine the role of constitutively active tyrosine kinases in the kidney, we have examined the renal effects of intravenous infusion of imatinib mesylate (Novartis Pharma, AG, Basel, Switzerland) at incremental doses (0.02, 0.2 and 2 mg/min/kg bw) as well as its interaction with nitric oxide (NO) activity in anesthetized mice. Systemic blood pressure (SBP) was recorded from a cannula placed in the left carotid artery. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by renal clearances of PAH and inulin respectively. From a control SBP value of 91 ± 3 mmHg in one group of mice (n=5), imatinib caused minimal changes in SBP at lower doses (87 ± 4 and 86 ± 5mmHg; n=5) but caused significant reduction (75 ± 4 mmHg; P<0.01) at the highest dose. During infusion of imatinib doses, there were no significant changes in RBF (from control value of 9.2 ± 0.9 to 9.2 ± 1.1, 9.9 ± 1.8 and 8.7 ± 2.2 mL/min/g kw respectively), but interestingly, there were dose-depended reductions in GFR (from a control value of 1.8 ± 0.2 to 1.7 ± 0.3, 1.5 ± 0.3, and 1.1 ± 0.3 mmHg). However, only at the highest dose, there were significant reductions in urine flow (from 6.5 ± 0.9 to 4.6 ± 0.5 μL/min/g) and sodium excretion (from 0.42 ± 0.09 to 0.17 ± 0.03 μmol/min/g) but not in fractional excretion of sodium (0.16 ± 0.04 to 0.13 ± 0.04 % ) indicating that the excretory changes were mostly dependent on hemodynamic changes. It is also observed that the usual responses (reductions in RBF, GFR etc) to the infusion of NO synthase inhibitor, nitro-L-arginine (L-NAME; 200mg/min/kg) remain intact in mice (separate group; n=5) pretreated with imatinib (0.2 mg/min/kg). These data suggest that a constitutively active tyrosine kinase pathway plays a regulatory role in maintaining glomerular filtration rate and excretory function in the kidney which seems independent of NO activity.