Details
| Originalsprache | Englisch |
|---|---|
| Seiten (von - bis) | 2199-2210 |
| Seitenumfang | 12 |
| Fachzeitschrift | Journal of hypertension |
| Jahrgang | 32 |
| Ausgabenummer | 11 |
| Publikationsstatus | Veröffentlicht - Nov. 2014 |
| Extern publiziert | Ja |
Abstract
Objectives: 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 30mmHg and 5mmHg×ml-1×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. Conclusion: Our data indicate that early sunitinibinduced 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.
ASJC Scopus Sachgebiete
- Medizin (insg.)
- Innere Medizin
- Biochemie, Genetik und Molekularbiologie (insg.)
- Physiologie
- Medizin (insg.)
- Kardiologie und kardiovaskuläre Medizin
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in: Journal of hypertension, Jahrgang 32, Nr. 11, 11.2014, S. 2199-2210.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - Rho kinase inhibition mitigates sunitinib-induced rise in arterial pressure and renal vascular resistance but not increased renal sodium reabsorption
AU - Grisk, Olaf
AU - Koenen, Anna
AU - Meissner, Thomas
AU - Donner, Alexander
AU - Braun, Diana
AU - Steinbach, Antje
AU - Glöckl, Gunnar
AU - Zimmermann, Uwe
AU - Evert, Katja
AU - Evert, Matthias
AU - Katsari, Elpiniki
AU - Löhn, Matthias
AU - Plettenburg, Oliver
AU - Rettig, Rainer
PY - 2014/11
Y1 - 2014/11
N2 - Objectives: 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 30mmHg and 5mmHg×ml-1×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. Conclusion: Our data indicate that early sunitinibinduced 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.
AB - Objectives: 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 30mmHg and 5mmHg×ml-1×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. Conclusion: Our data indicate that early sunitinibinduced 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.
KW - Blood vessels
KW - Humans
KW - Kidney
KW - Rats
KW - Rho kinase
KW - Tyrosine kinase
KW - Vascular endothelial growth factor
UR - http://www.scopus.com/inward/record.url?scp=84927616080&partnerID=8YFLogxK
U2 - 10.1097/HJH.0000000000000326
DO - 10.1097/HJH.0000000000000326
M3 - Article
C2 - 25275248
AN - SCOPUS:84927616080
VL - 32
SP - 2199
EP - 2210
JO - Journal of hypertension
JF - Journal of hypertension
SN - 0263-6352
IS - 11
ER -