Salt Sensitivity of Angiogenesis Inhibition-Induced Blood Pressure Rise: Role of Interstitial Sodium Accumulation?
In response to salt loading, Na+and Cl-accumulate in the skin in excess of water, stimulating skin lymphangiogenesis via activation of the mononuclear phagocyte system cell-derived vascular endothelial growth factor-C-vascular endothelial growth factor type 3 receptor signaling pathway. Inhibition of this pathway results in salt-sensitive hypertension. Sunitinib is an antiangiogenic, anticancer agent that blocks all 3 vascular endothelial growth factor receptors and increases blood pressure. We explored the salt dependency of sunitinib-induced hypertension and whether impairment of skin lymphangiogenesis is an underlying mechanism. Normotensive Wistar-Kyoto rats were exposed to a normal or high salt with or without sunitinib administration. Sunitinib induced a 15 mm Hg rise in telemetrically measured blood pressure, which was aggravated by a high-salt diet (HSD), resulting in a decline of the slope of the pressure-natriuresis curve. Without affecting body weight, plasma Na+concentration or renal function, Na+and Cl-skin content increased by 31% and 32% with the high salt and by 49% and 50% with the HSD plus sunitinib, whereas skin water increased by 17% and 24%, respectively. Skin mononuclear phagocyte system cell density increased both during sunitinib and a HSD, but no further increment was seen when HSD and sunitinib were combined. HSD increased skin lymphangiogenesis, while sunitinib tended to decrease lymphangiogenesis, both during a normal-salt diet and HSD. We conclude that sunitinib induces hypertension that is aggravated by high salt intake and not accompanied by impaired skin lymphangiogenesis.
From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (S.L., A.H.J.D., A.H.v.d.M.), Department of Nephrology & Transplantation (D.S.), Erasmus Medical Center, Rotterdam, The Netherlands; Experimental and Clinical Research Center, a Joint Cooperation of Max-Delbrück Center for Molecular Medicine and Charité University Medicine Berlin, Germany (L.M., N.R., D.N.M.); Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (J.T.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (D.N.M.); and Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen-Nürnberg, Germany (N.R.).
Stephanie
S
Lankhorst
From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (S.L., A.H.J.D., A.H.v.d.M.), Department of Nephrology & Transplantation (D.S.), Erasmus Medical Center, Rotterdam, The Netherlands; Experimental and Clinical Research Center, a Joint Cooperation of Max-Delbrück Center for Molecular Medicine and Charité University Medicine Berlin, Germany (L.M., N.R., D.N.M.); Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (J.T.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (D.N.M.); and Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen-Nürnberg, Germany (N.R.).
David
D
Severs
From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (S.L., A.H.J.D., A.H.v.d.M.), Department of Nephrology & Transplantation (D.S.), Erasmus Medical Center, Rotterdam, The Netherlands; Experimental and Clinical Research Center, a Joint Cooperation of Max-Delbrück Center for Molecular Medicine and Charité University Medicine Berlin, Germany (L.M., N.R., D.N.M.); Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (J.T.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (D.N.M.); and Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen-Nürnberg, Germany (N.R.).
Lajos
L
Markó
From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (S.L., A.H.J.D., A.H.v.d.M.), Department of Nephrology & Transplantation (D.S.), Erasmus Medical Center, Rotterdam, The Netherlands; Experimental and Clinical Research Center, a Joint Cooperation of Max-Delbrück Center for Molecular Medicine and Charité University Medicine Berlin, Germany (L.M., N.R., D.N.M.); Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (J.T.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (D.N.M.); and Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen-Nürnberg, Germany (N.R.).
Natalia
N
Rakova
From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (S.L., A.H.J.D., A.H.v.d.M.), Department of Nephrology & Transplantation (D.S.), Erasmus Medical Center, Rotterdam, The Netherlands; Experimental and Clinical Research Center, a Joint Cooperation of Max-Delbrück Center for Molecular Medicine and Charité University Medicine Berlin, Germany (L.M., N.R., D.N.M.); Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (J.T.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (D.N.M.); and Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen-Nürnberg, Germany (N.R.).
Jens
J
Titze
From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (S.L., A.H.J.D., A.H.v.d.M.), Department of Nephrology & Transplantation (D.S.), Erasmus Medical Center, Rotterdam, The Netherlands; Experimental and Clinical Research Center, a Joint Cooperation of Max-Delbrück Center for Molecular Medicine and Charité University Medicine Berlin, Germany (L.M., N.R., D.N.M.); Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (J.T.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (D.N.M.); and Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen-Nürnberg, Germany (N.R.).
Dominik N
DN
Müller
From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (S.L., A.H.J.D., A.H.v.d.M.), Department of Nephrology & Transplantation (D.S.), Erasmus Medical Center, Rotterdam, The Netherlands; Experimental and Clinical Research Center, a Joint Cooperation of Max-Delbrück Center for Molecular Medicine and Charité University Medicine Berlin, Germany (L.M., N.R., D.N.M.); Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (J.T.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (D.N.M.); and Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen-Nürnberg, Germany (N.R.).
A H Jan
AH
Danser
From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (S.L., A.H.J.D., A.H.v.d.M.), Department of Nephrology & Transplantation (D.S.), Erasmus Medical Center, Rotterdam, The Netherlands; Experimental and Clinical Research Center, a Joint Cooperation of Max-Delbrück Center for Molecular Medicine and Charité University Medicine Berlin, Germany (L.M., N.R., D.N.M.); Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (J.T.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (D.N.M.); and Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen-Nürnberg, Germany (N.R.). a.vandenmeiracker@erasmusmc.nl.
Anton H
AH
van den Meiracker
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007211:Indoles; D042583:Lymphangiogenesis / Q000187:drug effects; D008297:Male; D011758:Pyrroles; D051381:Rats; D011921:Rats, Inbred WKY; D012867:Skin / Q000187:drug effects* / Q000503:physiopathology; D012982:Sodium, Dietary / Q000008:administration & dosage*; D000077210:Sunitinib
D007211:Indoles; D011758:Pyrroles; D012982:Sodium, Dietary; D000077210:Sunitinib
Na+ storage; angiogenesis inhibition; hypertension; lymphangiogenesis; salt sensitivity; sunitinib; vascular endothelial growth factor