title: Rho kinase inhibition mitigates sunitinib-induced rise in arterial pressure and renal vascular resistance but not increased renal sodium reabsorption.
abstract: OBJECTIVE
  The therapeutic use of the vascular endothelial growth factor (VEGF) antagonist sunitinib is limited by sunitinib-induced hypertension. The hypotheses were tested that sunitinib increases renal vascular resistance (RVR) and renal Na+ reabsorption, and that Rho kinase (ROCK) inhibition blunts sunitinib-induced hypertension.
  
  
  METHODS
  Sunitinib actions on human and rat resistance arteries were investigated by myography. The effects of sunitinib alone or in combination with a ROCK inhibitor on arterial pressure and renal function were investigated in rats by radiotelemetry, renal function and metabolism studies accompanied by biochemical, molecular and histological analyses.
  
  
  RESULTS
  Sunitinib blunted agonist-induced vasoconstriction and facilitated endothelium-dependent vasodilation. Within 4 days, sunitinib treatment caused arterial pressure and RVR to rise by 30 mmHg and 5 mmHg × ml × min × g kidney weight, respectively, accompanied by reduced glomerular filtration rate and fractional Na+ excretion with unaffected fractional Li+ excretion. ROCK inhibition blunted sunitinib-induced hypertension and prevented the early rise in RVR, but not the decrease in fractional Na+ excretion, which may explain its modest effect on sunitinib-induced hypertension.
  
  
  CONCLUSIONS
  Our data indicate that early sunitinib-induced hypertension is associated with modest alterations in renal vascular function, but markedly increased renal sodium reabsorption, probably due to direct actions of the VEGF antagonist on the collecting duct, suggesting that VEGF receptors regulate renal Na+ absorption.
authors.affiliation: aInstitute of Physiology bInstitute of Pharmacy cInstitute of Pathology dClinic of Urology, University of Greifswald, Greifswald eHeart and Diabetes Center Mecklenburg-Vorpommern, Karlsburg fSanofi Aventis GmbH, Frankfurt am Main, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Grisk
authors.forename: Anna
authors.initials: A
authors.lastname: Koenen
authors.forename: Thomas
authors.initials: T
authors.lastname: Meissner
authors.forename: Alexander
authors.initials: A
authors.lastname: Donner
authors.forename: Diana
authors.initials: D
authors.lastname: Braun
authors.forename: Antje
authors.initials: A
authors.lastname: Steinbach
authors.forename: Gunnar
authors.initials: G
authors.lastname: Glöckl
authors.forename: Uwe
authors.initials: U
authors.lastname: Zimmermann
authors.forename: Katja
authors.initials: K
authors.lastname: Evert
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.forename: Elpiniki
authors.initials: E
authors.lastname: Katsari
authors.forename: Matthias
authors.initials: M
authors.lastname: Löhn
authors.forename: Oliver
authors.initials: O
authors.lastname: Plettenburg
authors.forename: Rainer
authors.initials: R
authors.lastname: Rettig
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D062186:Arterial Pressure / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000201:enzymology; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects*; D007684:Kidney Tubules / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D012964:Sodium / Q000378:metabolism; D012982:Sodium, Dietary / Q000378:metabolism; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D012982:Sodium, Dietary; D042461:Vascular Endothelial Growth Factor A; D012964:Sodium; D040262:Receptors, Vascular Endothelial Growth Factor; D054460:rho-Associated Kinases; D000077210:Sunitinib