Abstract P246: Salt-sensitivity of Angiogenesis Inhibition-induced Blood Pressure (BP) Rise: Role of Interstitial Sodium Accumulation?
Objective: Angiogenesis inhibition with the VEGF-inhibitor sunitinib, an established anti-cancer therapy, induces hypertension and proteinuria. Exposed to osmotic stress, the mononuclear-phagocyte-system (MPS) cells produces VEGF-C and exert homeostatic regulatory activity by promoting lymphatic Na+ drainage; interference with this process resulted in salt-sensitive hypertension. Therefore, we hypothesized that sunitinib, via blockade of the VEGF pathway, leads to Na+ accumulation in the skin and salt-sensitive hypertension.
Design and Methods: In male WKY rats, mean arterial pressure (MAP) was monitored telemetrically during oral treatment with sunitinib (7 mg/kg.day, n=7-8) or vehicle (n=7-8) after a normal salt diet (NSD: 0.5-1.0% NaCl and tap water) or a high salt diet (HSD: 8% NaCl and saline water) for 2 weeks. After 8 days of sunitinib or vehicle administration, 24-h urine was collected. After sacrificing, blood was collected for biochemical measurements, skin for Na+ concentration ([Na+]) using dry-ashing, and ears for staining of MPS cells (CD68).
Results: MAP during NSD was 101±0.9 mmHg. HSD increased MAP by 27±3 mmHg (P<0.05 vs. NSD). Sunitinib increased MAP by 15±1 mmHg during NSD (P<0.05 vs. NSD alone) and by 23±4 mmHg during HSD (P<0.05 vs. HSD alone). Although body weight, plasma [Na+] and plasma [cystatin-C] did not change in response to HSD and/or sunitinib, skin [Na+] increased from 90±1 (NSD) to 100±4 (HSD), and 108±4 mmol/L (HSD+sunitinib), respectively (P<0.01 for linear trend). Skin [Na+] correlated with MAP (r=0.57, P<0.01). Compared to NSD, proteinuria increased during HSD, rising further (P<0.05) with sunitinib. CD68 positive area increased during HSD from 0.29% to 0.43% (P<0.05), and increased even further with sunitinib (0.63%, P<0.05).
Conclusions: Angiogenesis inhibition-induced hypertension is salt-sensitive. The parallel increases in BP and skin [Na+], in the face of unaltered plasma [Na+] and bodyweight, support the existence of a Na+-buffering compartment in the skin that may contribute to the salt-dependent volume and BP homeostasis during VEGF inhibition.
Author Disclosures: S. Lankhorst: None. D. Severs: None. L. Marko: None. N. Rakova: None. V.A. Giménez-Rivera: None. J. Titze: None. D.N. Müller: None. A.H.J. Danser: None. A. van den Meiracker: None.
- © 2015 by American Heart Association, Inc.