Rho kinase inhibition mitigates sunitinib-induced rise in arterial pressure and renal vascular resistance but not increased renal sodium reabsorption.
J Hypertens
; 32(11): 2199-210; discussion 2110, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-25275248
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 30âmmHg and 5âmmHgâ×âmlâ×âminâ×âg 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 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirróis
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Receptores de Fatores de Crescimento do Endotélio Vascular
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Fator A de Crescimento do Endotélio Vascular
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Quinases Associadas a rho
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Pressão Arterial
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Hipertensão
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Indóis
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Túbulos Renais
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Antineoplásicos
Limite:
Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Hypertens
Ano de publicação:
2014
Tipo de documento:
Article