Angiogenesis inhibition with the VEGF inhibitor sunitinib is an established anti-cancer therapy inducing hypertension and nephrotoxicity. Here we compared the effects of the endothelin antagonist (ET-R) macitentan (30 mg/kg/day, p.o; n=8), the calcium channel blocker (CCB) amlodipine (3 mg/kg/day, p.o; n=9), or the ACE-inhibitor captopril (3 or 12 mg/kg/day, s.c.; n=9) vs. no treatment (n=14) in sunitinib (26.7 mg/kg/day, p.o)-exposed hypertensive WKY rats. Treatment lasted 8 days; mean arterial pressure (MAP) was monitored telemetrically. At the end of the treatment period, 24-hour urine samples for protein and endothelin-1 (ET-1) measurements, and blood samples and kidneys for histological evaluation were collected.
With sunitinib, MAP increased from 94.7±0.9 mmHg to 125.8±1.5 mmHg (Δ31.1±0.9 mmHg, p<0.001). Co-administration of macitentan (Δ12.3±1.5 mmHg, p<0.001) or amlodipine (Δ11.4±1.7 mmHg, p<0.001) attenuated the sunitinib-induced MAP rise, whereas low and high captopril doses did not (Δ28.1±2.0 and Δ27.2±1.1 mmHg). With sunitinib, serum creatinine increased from 8.0±2.7 to 29.9±4.6 μmol/l (p<0.01) and proteinuria from 7.5±1.3 to 33.3±4.8 mg/day, p<0.05. Although no agent could prevent the sunitinib-induced rise in creatinine, the induced proteinuria was attenuated by 62% (p<0.01) with macitentan and by 88% with low and 114% (p<0.001) with high dose of captopril, while proteinuria increased by 56% (p=NS) with amlodipine. With sunitinib, urinary ET-1 increased from 3.3±0.5 to 4.8±1.0 pg/day (p<0.05). Macitentan and captopril abolished this increase. Renal histology revealed extensive glomerular ischemia and endothelial cell swelling. Concomitant with the decrease in proteinuria, glomerular intra-epithelial protein deposition decreased with macitentan and captopril.
In conclusion, ET-R antagonism and CCB effectively reduced the sunitinib-induced hypertension, whereas ACE-inhibition did not. Both ET-R antagonism and ACE inhibition diminished the sunitinib-induced proteinuria. Since ET-R antagonists are not yet available as anti-hypertensive agents, CCBs are preferred in angiogenesis inhibition-induced hypertension, while adding an ACE-inhibitor might be considered when proteinuria is also present.